Report

Transgenic Animals
Status-quo in relation to
risk assessment and the
state of research

Forschungsberichte der
Sektion IV

Band 2/2008
 Report

Transgenic Animals
Status-quo in relation to
risk assessment and the
state of research

Forschungsberichte der
Sektion IV

Band 2/2008
Impressum:

Herausgeber, Medieninhaber und Hersteller:

Bundesministerium für Gesundheit, Familie und Jugend, Sektion IV
Radetzkystraße 2, 1031 Wien

Für den Inhalt verantwortlich:

BL Mag. Ulrich Herzog

Erscheinungstermin: April 2008

Autoren:
Konzeption, Durchführung: Mag. Alice Schmatzberger
Wissenschaftliche Mitarbeit: Mag. Heike Schultz

Die vorliegende Studie stellt die Übersetzung des Forschungsprojekts “Transgene

Tiere – Status-quo bezüglich Risikoabschätzung und Stand der Forschung”
(erschienen im Dezember 2007 als Band 6-07, ISBN 978-3-902611-10-9) in die
englische Sprache dar.

Druck: Kopierstelle des BMGFJ, Radetzkystraße 2, 1031 Wien

Bestellmöglichkeiten:
Telefon: +43-1/711 00-4700 DW
Fax: +43-1/715 58 30
E-Mail: broschuerenservice.bmgfj@bmgfj.gv.at
Internet: http://www.bmgfj.gv.at

ISBN 978-3-902611-16-1

Diese Studie/Broschüre ist kostenlos beim Bundesministerium für Gesundheit,

Familie und Jugend, Radetzkystraße 2, 1031 Wien, erhältlich.
 Transgenic animals

Transgenic Animals

Status-quo in relation to risk assessment

and the state of research

Concept and realisation: Mag. Alice Schmatzberger

Scientific support: Mag. Heike Schultz

November 2007
commissioned by
the Austrian Federal Ministry for Health, Family and Youth

Page 1 of 131
 Transgenic animals

Mag. Alice Schmatzberger

alice.schmatzberger@science-art.at
www.science-art.at

Mag. Heike Schultz

heschu@gmx.at

Translation:
Fiona Salter-Townshend, LL.B., LL.M.
fstranslate@chello.at

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 Foreword

Foreword
The genetic modification of animals has long been a fixed component of the most various
research areas. As, however, commercialisation in the area of food and pharmaceuticals
from transgenic animals is a long time in the coming, the international discussion of this
topic is mostly only temporary, i.e. arises out of particular occasion and in small circles.
Declarations of intent and progress reports are regularly found in scientific literature,
these hardly ever enable a concrete assessment of the respective current status-quo of
the research work. Risk assessment in relation to possible effects on human health
and/or the environment – as is shown even still by the experiences surrounding the
discussions on genetically modified plants – quickly form the focus of public interest,
nevertheless differentiated discourses or research findings are hard to find.

However, the topic transgenic animals– while more slowly than was propagated some
years ago – really is becoming more and more pressing. In January 2006 in Brussels, an
international workshop organised by the Netherlands Ministry of the Environment took
place, which with the title “Application of the Directive 2001/18/EC on genetically
modified animals” was for the first time devoted exclusively to the topic of genetically
modified animals. In parallel with this at an international level, since September 2005, is
the work of the FAO/WHO Codex Ad Hoc Intergovernmental Task Force on Foods derived
from Biotechnology. A working group1 on transgenic animals set up by this task force has
drawn up a proposal for specific risk assessment, the “Proposed draft guideline for the
conduct of food safety assessment of foods derived from rDNA animals”. This proposal
was conclusively discussed at the end of September 2007 within the framework of the
7th session of the task force and is now with the International Codex Alimentarius
Commission for final adoption.2 The author of the present study took part both in the
workshop in Brussels and in the above-mentioned international working group, on behalf
of the Federal Ministry for Health, Family and Youth. The current developments of the last
two years show, furthermore, that transgenic animals can also quite inadvertently
become topical, as shown by the cases of the genetically modified ornamental fish which
have turned up illegally in the European Union or the transgenic pigs in Canada (see
chapter 3.3.1 and 3.1.2).

The overview of this ever more current of topics, developed within the framework of this
study, should prospectively enable the Federal Ministry for Health, Family and Youth, as
the competent authority, to quantitatively and qualitatively evaluate those developments
which make applications for the approval of a transgenic animal or a food /-product from
such animal probable in coming years. Moreover, the scientific questions arising in
connection therewith and potentially problematic aspects in relation to risk assessment
shall be pointed out and the existing instruments in this context (relevant legal
provisions, guidelines, etc.) shall be described and analysed for possible deficits.

1
Codex Working Group on the Safety Assessment of Foods derived from rDNA animals
2
This is due to happen at the 31st session from 30.6.-5.7.2008

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Seite 4 von 131
List of contents

Foreword ............................................................................................................. 3
List of contents .................................................................................................... 5
Summary ............................................................................................................ 7
1 Introduction ................................................................................................. 12
1.1 Problem, focus questions and objectives .................................................. 12
1.2 Methodological approach ........................................................................ 14
1.3 The structure of the report ..................................................................... 14
2 Risk assessment. Legal provisions and Guidelines ............................................. 15
2.1 Risk assessment theory.......................................................................... 15
2.2 European Union .................................................................................... 16
2.2.1 Directive 2001/18/EC ........................................................................ 16
2.2.2 Regulation (EC) No 1829/2003 ........................................................... 18
2.3 FAO/WHO............................................................................................. 20
2.3.1 FAO/WHO Expert consultation on the safety assessment of foods derived
from genetically modified animals, including fish .............................................. 20
2.3.2 Proposed draft guideline for the conduct of food safety assessment of foods
derived from recombinant DNA animals ........................................................... 21
2.3.3 Analysis........................................................................................... 22
2.4 Countries ............................................................................................. 27
2.4.1 USA ................................................................................................ 27
2.4.2 Canada............................................................................................ 28
2.4.3 Argentina......................................................................................... 30
2.4.4 Other countries................................................................................. 31
Excursus: ethical aspects..................................................................................... 35
3 Transgenic animals. Examples ........................................................................ 42
3.1 Agricultural animals, fish........................................................................ 43
3.1.1 Cattle .............................................................................................. 43
3.1.2 Pigs................................................................................................. 44
3.1.3 Chickens.......................................................................................... 45
3.1.4 Sheep.............................................................................................. 45
3.1.5 Fish................................................................................................. 46
3.2 Gene-pharming..................................................................................... 48
3.2.1 Goats .............................................................................................. 49
3.2.2 Chickens ....................................................................................... 49
3.2.3 Cattle .............................................................................................. 50
3.2.4 Other animals................................................................................... 50
3.3 House pets ........................................................................................... 51
3.3.1 Ornamental fish ................................................................................ 51
3.3.2 Cats ................................................................................................ 54
3.3.3 Other kinds of animal ........................................................................ 55
4 Conclusions.................................................................................................. 56
List of references ................................................................................................ 65
Annexes ............................................................................................................ 72
Annex I, FAO/WHO Draft Guideline for the conduct of food safety assessment of foods
derived from recombinant DNA animals .............................................................. 73
Annex II, Canada: Notification Guidelines for the Environmental Assessment of
Biotechnology - Derived Livestock Animals.......................................................... 88
Annex III, Canada: Novel Food Regulation (Health Canada) ................................ 104
Annex IV, Canada: Animal Health Risk Analysis Framework for Biotechnology-Derived
Animals ........................................................................................................ 106
Annex V, Argentina: Application for Permit for Experiments with and/or Release into the
Environment of Genetically Modified Animals..................................................... 121

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Seite 6 von 131
 Summary

Summary
Problem and objectives

Risk assessment with regard to genetically modified plants has long been discussed
intensively; there are numerous models and approaches and just as much criticism and
suggestions for improvement. With respect to risk assessment regarding genetically
modified animals on the other hand, this report is one of the first breakdowns of the
problem with a synoptic representation of relevant aspects and statutory instruments as
well as identified need for action.

The overview developed within the framework of this study should prospectively enable
the Federal Ministry for Health, Family and Youth to quantitatively and qualitatively
evaluate those developments which make applications for the approval of transgenic
animals or by-products from such animals probable in coming years. The focus lies on
questions of risk assessment regarding genetically modified agricultural animals including
fish intended for use as food as well as on animals that have been genetically modified in
the course of so-called gene pharming3, furthermore, examples of genetically modified
pet animals have been compiled. The relevant protection objectives are human health,
food safety and protection of the environment. Thus, topics such as animals genetically
modified for scientific or medical research purposes (model animals, xeno-
transplantation), genetically modified forage crops, genetically produced medications and
cloning aspects are not covered in this study.

The genetic modification of animals has long been a fixed component of the most various
research areas since the first transgenic animal was developed in the early 1980s.
Several publications and reviews have since then regularly predicted that in the next 5-
10 years respectively, correspondingly genetically modified animals and/or applications
for their approval on the market should be expected. However, differentiated discourse or
research findings on the aspects of risk assessment in this context are hard to find. As
commercialisation in the area of food and pharmaceuticals from transgenic animals is a
long time in the coming and the current status-quo of research can hardly be concretely
assessed, the international discussion of this topic is mostly only temporary, i.e. arises
out of particular occasion and in small circles.

Nevertheless, the topic transgenic animals is becoming – although more slowly than was
thought some years ago – more and more pressing. In September 2005 a special working
group4 on transgenic animals was set up by the FAO/WHO Codex Ad Hoc
Intergovernmental Task Force on Foods derived from Biotechnology, which drew up a first
proposal for specific risk assessment, the “Proposed draft guideline for the conduct of
food safety assessment of foods derived from rDNA animals”. This proposal has been
finally discussed during the seventh session of the above mentioned Task Force
(September 2007) and is now on hand to be adopted by the International Codex
Alimentarius Commission.5 The current developments of the last two years show,
furthermore, that transgenic animals could also quite inadvertently become topical, as
shown by the cases of the genetically modified ornamental fish which turned up illegally
in the European Union or the transgenic pigs in Canada.

3
Gene pharming aims at the production of pharmaceutically/therapeutically relevant proteins in
the animal system, which can be harvested from the serum, urine or milk of the respective animal.
The terms “gene farming” and “gene pharming” are used synonymously in the relevant literature.
4
Codex Working Group on the Safety Assessment of Foods derived from rDNA animals,
participation by the author of this study commissioned by the Federal Ministry for Health, Women
and Youth.
5
This should take place during their 31st session from 30.6.-5.7.2008

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 Summary

Risk assessment

Within the framework of this study, legal regulations, recommendations and other similar
instruments which are applied in connection with the risk assessment of genetically
modified animals were researched. The following regulations were subjected to detailed
analysis:

Directive 2001/18/EC of the European Parliament and of the Council of 12 March 2001
on the deliberate release into the environment of genetically modified organisms and
repealing Council Directive 90/220/EEC

Regulation (EC) No 1829/2003 of the European Parliament and of the Council of 22
September 2003 on genetically modified food and feed

FAO/WHO Expert consultation on the safety assessment of foods derived from
genetically modified animals, including fish (2003)

FAO/WHO Codex Alimentarius Commission, Draft Guideline for the conduct of food
safety assessment of foods derived from recombinant DNA animals (2007). This
report contains one of the first extensive commentaries on this proposal.

The Canadian legal position with regard to the risk assessment of genetically modified
animals

The Australian legal position with regard to the risk assessment of genetically
modified animals

With reference to the protection objective Environment, Directive 2001/18/EC offers an

extensive catalogue of criteria which could also be implemented usefully in connection
with genetically modified animals, although some specification seems to be required.

With regard to human health or food safety, the EU regulations basically formulate the
corresponding protection objective at a general level; however, there are hardly any
concretely defined criteria for how this protection objective should be fulfilled in the
course of a risk assessment. Especially Regulation (EC) No 1829/2003 on genetically
modified food requires to be supplemented and concretised. In this context, the above-
mentioned proposal for a corresponding FAO/WHO Draft Guideline for the conduct of food
safety assessment formulates further-reaching and more precise requirements. Overall,
Canada has the furthest-reaching regulations; this will be all the more true once the
development of a specific guideline for the assessment of food safety has been
concluded. Moreover, in Canada a separate risk assessment under the aspect of animal
welfare must be conducted. Australia, too, has comprehensive regulation together with
specifying guidelines concerning the environmental risk assessment as well as food
safety.

There is fragmentary information for Argentina, Japan and the USA, which is also
described. For some Member States of the European Union specific aspects, e.g.
questions concerning animal welfare or animal ethics, are presented.

Finally, the report presents generally to be considered aspects of risk assessment

regarding genetically modified animals and their by-products, these are derived from a
synopsis of the assessments of diverse public authorities, respondent enterprises or
scientists, comparative analyses of the existing regulatory instruments and their
shortcomings, scientific literature and similar analyses of risk assessment regarding
genetically modified plants.

Transgenic animals, research and commercialisation

It became apparent that in purely quantitative terms significantly more research trials on
the genetic modification of animals are in progress than was assumed when the study
was begun. In fact, there is such an abundance of publications available that a complete
overview of the status-quo and/or the respective relevance is hardly possible any more.
So, genetic modifications of animals have been topical for many years, research on and

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 Summary

use of genetic methods in the context of agricultural animals or pets is performed on

every major animal species.

Significantly more is being done in the field of pharmaceuticals than for food purposes,
where the initial euphoria seems to have diminished as the coding genes for the
characteristics of interest are obviously difficult to make available. Thus, transgenic
agricultural animals are used at present in particular as model animals for the purposes
of research or methods development. Work on genetically modified pets has already
crossed the commercialisation threshold in the context of fish and is popular above all in
Asia.

The estimates in scientific publications on when we can expect the commercialisation of

transgenic animals and/or their by-products differ from those of the public authorities
respondents in this study.
Whereas, it is usually assumed among scientists that commercial use is soon to be
expected, representatives of public authorities expect the first applications in five years
at the earliest, on average in 7-10 years. In this connection, it is often emphasised that
tenable estimates are extremely difficult to make because of the manifold and dynamic
developments. Usually it is expected that the first approvals will be in the USA and South
America.

In general, it can be assumed that commercialisation in the field of gene pharming will
ensue significantly earlier than in the field of food. In particular among scientists,
estimates are optimistic in this context and speak of a few years until significant
commercialisation. In this connection, the first approval for a pharmaceutical substance
from a transgenic animal (a goat) by the European Medicines Agency (EMEA) is pointed
out – which could act as a milestone regarding potential further developments.

In the field of food, significantly longer time-frames are estimated, which inter alia is
based on the potential lack of acceptance by consumers. The necessary scientific-
technical principles and methods come up against – constantly changing – limits.
Success is most likely to be ascribed to those animals which are genetically modified in
such a way as to have positive effects on the environment; for example those pigs which
have significantly lower amounts of phosphate in their excretions. Genetic modifications
of this type are significantly easier to carry out on the scientific-technical level, are
almost ready for the market and could encounter less resistance from the public because
of their potential benefits for the environment.

The approval of genetically modified fish is expected relatively soon. The US American
company AquaBounty’s transgenic salmon has already been many years in the approval
process in the USA. According to current information from AquaBounty further (possibly
conclusive) information and data is being compiled for the competent authorities, the US
FDA, an approval could be attained in the second half of 2008.

Ethics

Scientific and technological developments and changes generally bring with them besides
their intended effects also unintended effects and consequences, which for example can
be of social, ecological, economic or ethical nature. The question as to the potential risks
of a technology or method is in itself not an ethical question, but rather more so is the
question of its justification. Ethical concerns and/or arguments are always based on an
individual or a societal value system. In relation to the field of genetically modified
animals, questions like the following may be asked: what suffering, what injury can
justifiably be inflicted on animals from an ethical perspective? What research approaches
are justified? What benefit outweighs what risk?

In general, it may be observed that the higher the animal is developed, that is the nearer
it is ranked taxonomically with the human being, the more critically scientific-technical

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 Summary

work on the animal is viewed. Accordingly, society grants the right to a greater degree of
animal welfare measures more quickly, for example, to vertebrates, to whom a capacity
to suffer and sensitive faculty are ascribed. In this connection, the concept of an animal’s
“telos” is also relevant; this is used in particular in English language literature and means
the nature, the specific needs, wants and interests of an animal on the basis of its
belonging to a particular species – i.e. “the pigness of a pig, the dogness of a dog”. This
term concerns much more than the absence of pain, it also concerns social aspects of
animal husbandry and the animal’s psychological capacity to suffer. This argumentation
approach is of particular significance in the context of the potentialities of genetic
modifications, where questions regarding the possible changing of the telos must be
discussed.
The ethical arguments and/or questions advanced in connection with the genetic
modification of animals are not always specific to genetics. In other words, the perception
and evaluation of such work and developments often do not differentiate between
problems of conventional animal breeding, ethical questions relating to animal
experiments in general, cloning on the one hand and specific aspects of genetic
engineering on the other. With respect to genetic methods, the focus is sometimes on the
process in itself (i.e. modifications of animals by means of conventional methods would
be acceptable; intrinsic approach) or also the respective result aimed at and/or the
associated speed on the way thereto. Concrete discussion must also distinguish between
specific qualities of genetic interventions and the practices and methods usually
employed thereby. There would seem to be especial potential for conflict whenever
decisions must be taken between animal ethics and human health aspects.

The societal need for discussion of ethical aspects and concerns should also be taken into
account in this context. Various food scandals, the occurrences around the
commercialisation of genetically modified plants and similar happenings have sensitised
the public in recent years and helped create a principle of scepticism with regard to the
scientific-political decision-making processes.

Conclusion

With respect to risk assessment regarding genetically modified animals on the other
hand, this report is one of the first breakdowns of the problem with a synoptic
representation of all relevant aspects and statutory instruments as well as identified need
for action.

In the course of research, it could be established that both in international organisations

(OECD, APEC, ILSI, OIE) and at the most various public authorities in the European Union
States, the risk assessment of genetically modified animals is not yet endowed with any
great significance, independent of the progress which has meanwhile been made in
science and application. The FAO/WHO Codex Alimentarius Ad Hoc Intergovernmental
Task Force on Foods derived from Biotechnology initiative is, therefore, in spite of its
deficits of special significance. All in all, in comparison with the extent of the ongoing
research, there is a spectacular lack of publications or studies on the risks connected with
genetically modified animals.

Accordingly, it has to be remarked in this context, that the Austrian Ministry for Health,
Family and Youth has shown great foresight in commissioning this study.

Ultimately, it can be assumed that the prospective approval of the transgenic salmon and
the EMEA’s first approval of a pharmaceutical (anti-thrombin) from a transgenic goat will
have considerable significance for future developments, as through this the further
possible economic potential of genetically modified animals and their by-products can
hence really be exploited. Furthermore, the numerous ongoing scientific projects
worldwide mean corresponding advances, e.g. with respect to the greater efficiency of
the technologies, can be anticipated. And finally, cases like that of the transgenic
ornamental fish which is already officially available in Asian countries and in the USA and

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 Summary

was also found (illegally) in several European pet stores, show that transgenic animals
are slowly becoming established outside of the field of research.

In view of these developments we may assume that genetically modified animals and/or
their by-products – at least in the area of gene pharming, fish and possibly pigs in the
food field as well as pets – will be a topic for regulatory and approval authorities in any
case within the next five years.

In conclusion, open questions and topics requiring further discussion are presented.

The risk assessment of genetically modified animals, above all their by-products in
the field of food, definitely requires specification at European Union level. Guidelines
for example would be conceivable, i.e. the creation of a Guidance Document, as has
already been developed for genetically modified plants and micro-organisms.

Many provisions need further definition as well as establishing precise parameters to
be determined within the risk assessment of transgenic animals and their products
respectively.

These proposals and claims respectively should be positioned on the European level in
order to set off relevant action to be taken.

The topic of cloned animals, whose by-products are expected on the market within a
few years, also requires treatment. These animals and by-products are at present not
subject to any legal regulation and neither would they be subjected to any risk
assessment. Products from cloned animals are expected within the next few years.

This seems all the more imperative as the European Commission has already directed
a request for an opinion on the safety of such food to the European Food Safety
Authority.

With regard to questions concerning ethical aspects of genetically modified animals,
possibilities for public dialogue, for broad discussion, should be considered.

And finally, a risk assessment of animals or by-products from animals that were
administered recombinant nucleic-acid products in somatic cells and/or tissue (so-
called non-heritable constructs, DNA vaccine and the like) is imperative. The problem
is constituted in particular in the fact that these applications are currently not subject
to any regulatory system and so the risks associated with them are not assessed.

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 Introduction

1 Introduction

1.1 Problem, focus questions and objectives

The area of genetic engineering and animals encompasses the most diverse aspects, each
being associated, from the perspective of a regulatory authority, with specific questions
on risk assessment and risk evaluation, of the management of the identified risks and on
external communication. The present study focuses on questions of risk assessment in
relation to genetically modified animals.

Scientists first succeeded in genetically modifying the genetic makeup of an animal (a

mouse) in 1980; since then genetic engineering methods have also been used on
agricultural animals. Many publications and reviews have since then regularly predicted
that in the next 5-10 years respectively, correspondingly genetically modified animals
and/or applications for their approval on the market should be expected. The report for
the Royal Society of Canada, “Elements of precaution: Recommendations for the
Regulation of Food Biotechnology in Canada”6, also assumed in 2001 that the following 5-
10 years would see the technical and methodological requirements necessary for the
commercial use of transgenic animals largely in existence; especially in the event that it
be possible to obtain more detailed information about animal genomes. At that time the
Royal Society strongly expected an application for the approval of a genetically modified
fish within the subsequent 10 years. In 1991, a brochure by the German Consumer
Initiative even extrapolated on the basis of the developments of the time that by the year
2000 10% of all pigs would already be genetically modified, and that by the year 2005
24% of all animals used for meat production would be transgenic. On the other hand, in
2003 the International Life Sciences Institute noted in general: “Much of this technology
is still in its early stages and it is likely to be a decade before large animals with modified
or deleted genes of commercial value have been evaluated and approved by the various
regulatory bodies.”7

In turn, the majority of participants in the international workshop “Application of the

Directive 2001/18/EC on genetically modified animals”8 in January 2006 expected the
first applications for approval of transgenic animals also within the next 5 years. The
representative of AquaBounty9 said during this conference that in the USA about a dozen
applications can be expected in the next 5 years, mainly for pharmaceutical purposes. In
the course of diverse discussions, however, it was possible to establish that in general
precisely those commercialisations are expected about whose research stages one had
personally already heard or read about. According to this, new applications are scarcely
to be anticipated without detailed knowledge of the current publications and/or research
plans and developments.

The report by the European authority for food safety (EFSA), “Food producing animals.
Principles of risk assessment of food producing animals: current and future
approaches”10, which appeared in October 2006, deals especially with risk assessment of
animals and/or their by-products in connection with contagious diseases and with the
field of animal protection. Comprehensive theoretical representations of the possible
components of risk evaluation as well as conclusions and recommendations are equally
part of the EFSA report. The latter are rather general.11 Specific aspects of safety

6
The Royal Society of Canada 2001
7
International Life Sciences Institute (ILSI) 2003
8
Initiative of the Netherlands Ministry of the Environment, the author participated on behalf of the
Austrian Federal Ministry for Health, Family and Youth
9
AquaBounty is the US enterprise that has developed a transgenic salmon which is ready for the
market and has been waiting for a number of years for official approval by the US authorities
10
Report on an EFSA Scientific Colloquium in December 2005
11
For example: “Risk profiles need to be created at the start of the project.” or “Data gaps should
be identified and addressed.”

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 Introduction

evaluation, which could result from genetic modifications to animals are, however, not
treated in this report.

In September 2005, the FAO/WHO Codex Ad Hoc Intergovernmental Task Force on Foods
derived from Biotechnology set up its own working group12 on transgenic animals, which
drew up a proposal for specific risk assessment, the “Proposed draft guideline for the
conduct of food safety assessment of foods derived from rDNA animals”. This represents
one of the first comprehensive initiatives on the specification of risk assessment of food /-
by-products from transgenic animals. The above-mentioned guideline, in the version
valid in November 2007, will be more closely described and analysed in chapter 2.3.2.
This proposal was conclusively discussed at the end of September 2007 during the 7th
session of the task force and is now with the International Codex Alimentarius
Commission for final adoption.13

Objectives

Within the framework of this project, the manifold claims and suppositions about
genetically modified animals have been concretised, the newest developments researched
and an assessment of the possible market readiness of individual approaches developed.
The overview elaborated here should prospectively enable the Federal Ministry for Health,
Family and Youth, as the competent authority, to quantitatively and qualitatively
evaluate those developments which make applications for the approval of a transgenic
animal or a product from such animal probable in coming years.

In order to make this field workable within the framework of a single study, specific focus
questions were defined. The focus lies on transgenic agricultural animals and fish which
are intended for use as food as well as on animals that have been genetically modified in
the course of so-called gene pharming14. Examples of genetically modified pet animals
have been compiled insofar as such would require approval under Directive 2001/18/EC.
Furthermore, the questions associated therewith and/or potentially problematic aspects
in relation to risk assessment have been elaborated. The legal provisions and
international guidelines, etc. relevant in connection with transgenic animals have been
summarised here for the first time and analysed in relation to relevant criteria for risk
assessment as well as possible deficits. The focus thereby is on risk identification with
respect to the protection objectives of food safety, human health and environmental
protection.

Thus, the following topics were per definitionem not the object of this study:

Genetically modified animals that have been developed for scientific research
purposes, e.g. as model animals or for research in developmental biology

Genetically modified animals that were developed for xeno-transplantations

Animals that are fed with genetically modified plants or treated with genetically
engineered medication, hormones, vaccines, etc.

Aspects of risk assessment of the pharmaceutical products resulting from gene-
pharming

Examples of applications like genetically modified insects that can be used for
malaria-control, etc.

Cloning aspects

Risk management or risk communication questions

Social, economic or other consequences which may result from the use of
genetically modified animals

12
Codex Working Group on the Safety Assessment of Foods derived from rDNA animals, the author
of this study participated on behalf of the Austrian Federal Ministry for Health, Family and Youth
13
This is due to happen at the 31st session from 30.6.-5.7.2008
14
Gene pharming aims at the production of pharmaceutically/therapeutically relevant proteins in
the animal system, which can be harvested from the serum, urine or milk of the respective animal.
The terms “gene farming” and “gene pharming” are used synonymously in the relevant literature

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 Introduction

Comparison of pro and contra arguments in connection with the application of

genetic engineering methods to agricultural- / animals

1.2 Methodological approach

Different methods were used to treat the focus questions described in chapter 1.1.
A comprehensive literature research and the evaluation of scientific publications formed
the substantial basis for the overview of possible and current work in research and
development and associated questions concerning transgenic animals. In conjunction, the
relevant legal provisions, recommendations and international instruments in connection
with the risk assessment of genetically modified animals were researched and analysed,
for instance pertinent provisions of EU law or the Guideline of the FAO/WHO Codex
Alimentarius Commission. The secondary literature found in the course of internet
research at relevant institutions and organisations in the form of comments, statements
or discussion papers was incorporated into the analyses and evaluations.

Additionally, there was a poll (by e-mail) of experts from European and other authorities.
This served above all the identification of the questions and developments perceived to
be topical in the field of genetically modified animals from the specific perspective of
these experts. Scientific experts and/or institutions were contacted for specific scientific
questions and/or concrete details which it was possible to identify in the process of the
analyses. Finally, it was also possible to integrate the author’s personal experiences and
the results of her discussions, stemming from the above-mentioned international
workshop in January 2006 and her participation in the Codex-working group on rDNA
animals.

1.3 The structure of the report

Chapter 2 begins with a description of the general theoretical aspects of risk assessment
and then describes existing regulations for the risk assessment of transgenic animals in
particular, including a comment on each one. This part also contains a detailed
commentary on the current version of the “Proposed draft guideline for the conduct of
food safety assessment of foods derived from rDNA animals” of the FAO/WHO Codex Ad
Hoc Intergovernmental Task Force on Foods derived from Biotechnology. Chapter 3 sums
up which animals are currently being genetically engineered in order to derive food
and/or pharmaceuticals. Work on pets is also dealt with there. The concluding chapter 4
covers criteria relevant for comprehensive risk assessment in connection with genetically
modified animals as well as a first comparison of the various instruments researched.
Further, the current developments in relation to release-attempts and commercialisation
of transgenic animals are explained and in conclusion open questions and/or necessary
research avenues are outlined.

An excursus has been included in this report as a thematic supplement. It points out
possible ethical questions and ideas for discussion in connection with transgenic animals.

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2 Risk assessment. Legal provisions and

Guidelines
After a short introduction on general criteria of risk assessment, this chapter discusses
various relevant legal regulations and guidelines. This discussion by no means constitutes
any kind of expert legal opinion. Rather, the provisions relevant in connection with the
risk assessment of genetically modified animals should first be identified and introduced
in a kind of overview.

2.1 Risk assessment theory

The principle of risk assessment was originally applied in a natural sciences context for
the evaluation of individual, defined substances, e.g. chemicals or pesticides. The
approach has up till now been anthropocentric, i.e. taken the human as the object
subject to the risk, related to the single individual and her/his life span, sometimes also
at the level of a population. The numerous, more or less similar international represent-
ations on the methodology and general principles of risk assessment shall not be
described in detail here, instead only the basic foundations are sketched.

In the case of transgenic animals and in relation to organisms in general, the risk
problematic is significantly more complex in all its facets, for instance the possibly
endangered object is more diverse, e.g. the transgenic animal itself, its offspring,
humans, the environment and/or specific ecosystems, other populations, etc. The focus
of a risk assessment can for example lie on food safety, human health, protection of the
environment or on questions of ethics and animal welfare. Also when it comes to
products more complex than single substances, e.g. food, conventional linear risk
assessment reaches its limits. Numerous studies, in particular pertinent documents from
the FAO/WHO Codex Alimentarius Commission, point out regularly in this context that
the classical principles of risk assessment were not developed for complex products and
are thus transferable only to a limited extent.

Risk assessment is a methodological process, which is based substantially on scientific

data and findings in order to assess potential adverse effects of a substance or an
activity, etc. as well as the extent and probability of such effects – this may be associated
with qualitative, quantitative or semi-quantitative statements. Potential risks15 can be
distinguished thereby. At the beginning of each risk assessment there must be a concrete
goal, i.e. what is the central protection objective? This is a prerequisite and is not a part
of the actual risk assessment and science cannot provide the answer. Effects which may
be evaluated as negative must arise or at least it must be possible to hypothetically
anticipate such.

As above-mentioned, the goal of a risk assessment is first to establish potentially adverse

effects, regardless of the probability of their occurrence.

The individual steps can be summarised as follows:

Identification and description of the possible risks as well as their adverse effects in
connection with a concrete occurrence (a substance, a pathogen, an occurrence, etc.),
i.e. potential dangers are identified in this step independently of their probability. The
focus is mostly on human health (food safety) or the environment

Assessment of possible exposure routes, in connection with food possibly the
corresponding nutritional profiles, probabilities and/or incidences of the occurrence of
an identified risk

15
On the distinction between risk and danger see also Müller 2001, according thereto risk derives
from human decisions and actions whereas danger constitutes a risk which cannot be influenced by
humans, e.g. natural disasters

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Finally, the risk evaluation appraises the results of the previous steps: the possible
extent of damage, further criteria which perhaps may have to be integrated (ethical,
economical, social, etc.), consequences resulting from “uncertainty” (see on this
below)

Hence, a possible risk derives from the combination of effect and/or extent of damage of
one occurring potential adverse effect and the probability or incidence of its occurrence
(= likelihood of exposure). This results in a probability, i.e. a quantitative statement,
which however is usually applied qualitatively. This procedure eliminates thinkable but
improbable dangers.

An important supplement to these theoretical steps lies in the consideration of the

“uncertainty” in relation the scientific data, the uncertainty of what is known about
biological processes or structures and/or uncertainty regarding any actual occurrence of
damage.16 This means that decisive scientific data and information are often unavailable,
there is as yet little understanding of relevant biological processes and sequences or
similar deficits. In the course of a risk assessment, existing uncertainties must be
identified in the individual steps, for example: where is the data unclear or not
representative? Where is information and/or data fundamentally missing? These must be
distinguished from such uncertainty as stems from indeterminableness and/or lack of
knowledge. Equally, the consequences resulting such uncertainties should be described in
the risk assessment, e.g. in the sense of where conclusive, purely scientific evaluation is
not possible for such reasons. In which areas can potential effects (qualitatively or
quantitatively) not be estimated?
The final decision in the context of a risk assessment substantially based on scientific
data and findings can never be value-free. Appraisals and definitions must be arrived at,
e.g. what is the protection objective? How much data and/or which data are sufficient?
How much uncertainty or residual risk is acceptable? Even the assessment of what is
evaluated as an adverse effect is dependent on the current time and socioculturally
conditioned, and thus variable, contexts.

2.2 European Union

2.2.1 Directive 2001/18/EC
Directive 2001/18/EC17 on the deliberate release into the environment of genetically
modified organisms (GMOs) currently sets the European standard in relation to the
necessary criteria for risk assessment in the environmental field. It is applicable for the
following uses:

Deliberate releases, i.e. in the case of intentional introduction of a GMO or a
combination of GMOs into the environment

Placing on the market of GMOs as products or in products

Thus, the deliberate release and the placing on the market of transgenic animals, e.g. of
ornamental fish, requires approval under this Directive.18 The risk assessment of these
animals would have to be conducted in accordance with the criteria formulated in
Annexes II (principles for the environmental risk assessment) und III A (information
required in notifications concerning releases of genetically modified organisms other than
higher plants).

16
On “uncertainty” in connection with the risk assessment of GMOs see in particular Müller 2001
17
Directive 2001/18/EC of the European Parliament and of the Council of 12 March 2001 on the
deliberate release into the environment of genetically modified organisms and repealing Council
Directive 90/220[0]/EEC, OJ L601, 17.4.2001
18
Approval for the placing on the market of a transgenic animal and/or products therefrom can
ensue either pursuant to Directive 2001/18/EC or Regulation (EC) No 1829/2003, depending on
the intended use. See also on this chap. 2.2.2

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The Directive is aimed in general at the protection of human health and the environment
in the case of deliberate release and/or placing on the market of GMOs; questions of food
safety are not taken into consideration. There is moreover an explicit reference to the
precautionary principle in the formulation of objectives. In Annex II C.2. the following is
established as a further general principle: “It is important not to discount any potential
adverse effect on the basis that it is unlikely to occur”.

The risk evaluation – referred to in the Directive as “environmental risk assessment” - is

carried out on a case-by-case basis and includes the “evaluation of risks to human health
and the environment, whether direct or indirect, immediate or delayed, which the
deliberate release or the placing on the market of GMOs may pose[…].” Annex II19 sets
out the basic principles for the environmental risk assessment, for instance:

Definition of direct (resulting from the GMO itself), indirect (occurring through a
causal chain of events), immediate and delayed effects

Call for an analysis of the cumulative long-term effects on human health and the
environment relevant to release and placing on the market, covering inter alia flora
and fauna, animal health and the feed/food chain.

Explanations of possible adverse effects of a GMO on humans (including allergenic or
toxic effects), on animals, on the dynamics of populations, etc.

Description of the general steps of risk assessment

Necessity to supply large quantities of ecological data in relation to the GMO
becoming persistent or invasive, selective advantage or disadvantage conferred to the
GMO, potentials for gene transfer, possible interactions of the GMO with non-target
organisms, possible effects on animal health

Annex III A applies to GMOs other than higher plants, it must therefore apply to
genetically modified animals. It specifies the criteria named in Annex II and defines the
information required in relation to:

General characteristics of the donor and the recipient organisms, where appropriate
the parental organism, taxonomic data, description of the geographic distribution,
sexual reproductive cycle, etc.

Nature of the vector

Information relating to the genetic modification, e.g. methods used, description of the
insert and any unknown sequences, selection methods

Information on the GMO, for instance description of phenotypic characteristics, any
(new) characteristics which may be expressed or no longer expressed, remaining
vector or donor nucleic acid, stability

Considerations regarding human health and animal health, e.g. toxic or allergenic
effects of the GMOs and/or their metabolic products, any changed pathogenicity of
the GMO, other product hazards

Information relating to the conditions of release and the receiving environment, e.g.
timepoint, duration, quantities of the GMO, information on location and site,
description of the flora and fauna, of target and non-target ecosystems

Information relating to the interactions between the GMO and the environment, e.g.
characteristics affecting multiplication and survival, genetic transfer capability,
anticipated mechanisms and results of interactions between the released GMO(s) and
the target organisms, known or predicted effects on non-target organisms, possible
competitive advantages of the GMO, description of the ecosystems to which the GMOs
could be disseminated, etc.

19
This Annex is supplemented by guidance notes providing further description; Commission
Decision of 24 July 2002, OJ L200, 30.7.2002

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Comment

The formulations, which are kept general, reveal in parts that mainly genetically modified
plants were thought of in terms of the application of the Directive and its Annexes.
Article 31, exchange of information and reporting, formulates inter alia the obligation of
the Member States to establish registers, which should document the locations of the
releases of GMOs and their placing on the market. The latter aspect would, however,
certainly not apply to genetically modified animals, the formulation in line 3b reads:
“Member States shall also establish registers for recording the location of GMOs grown
under part C […]”. The general term “GMO” is clearly reduced to plants by the word
“grown”. The general requirements formulated in the Annexes are often supplemented by
explanatory examples, these relate nearly exclusively to plants, sometimes to micro-
organisms; e.g. in the case of “pathways of dispersal of viable material” seeds and spores
are mentioned; or in relation to the possibility of GMOs spreading or establishing
themselves in habitats, only in the case of plants and micro-organisms is there a
reference to the necessity of taking into consideration the reproduction and survival
structures. A further example: data must be submitted in respect of previous field testing
over several growing seasons.

All in all, this Directive contains extremely comprehensive requirements for the risk
assessment of genetically modified animals in relation to possible interactions with the
and/or adverse effects on the environment, particularly in Annex III A. The areas to be
considered thereby include a detailed characterisation of the transgenic animal on the
basis of description of the donor and recipient organisms, the characteristics of the vector
utilised, the characteristics of the modified animal itself and detailed information to be
delivered on the release conditions, the environment affected in each case and a
description of the possible interactions with the environment (see in this respect the
description of Annex III A above.)

Aspects concerning human health are dealt with only rudimentarily, food safety is not
discussed due to the fundamental scope of the Directive. Parameters of health and other
similar aspects of the transgenic animal are scarcely included. On the whole, no
particular reference to transgenic animals can be discerned in the Annexes; specification
would be required on this point, however, there are sufficient starting points for risk
assessment in relation to possible environmental effects.

2.2.2 Regulation (EC) No 1829/2003

An application for the placing on the market of a food product (food, food ingredients)
produced from a transgenic animal for human consumption must be submitted in
accordance with Regulation (EC) 1829/200320 on genetically modified food and feed.21
The objects thereof are “to provide a high level of protection of human life and health,
animal health and welfare, environment and consumer interests in relation to genetically
modified food and feed”.

The scope of this regulation is defined as follows in Art.3 (1):

“This section shall apply to
a) GMOs for food use;
b) food containing or consisting of GMOs;
c) food produced from or containing ingredients produced from GMOs.”

20
Regulation (EC) No. 1829/2003 of the European Parliament and of the Council of 22 September
2003 on genetically modified food and feed, OJ L268, 18.10.2003
21
Depending on the intended use, an application for the approval for placing on the market of a
transgenic animal or of derived products must be made under either Directive 2001/18/EC or
Regulation 1829/2003. The release of transgenic animals is subject to the Directive on deliberate
release into the environment

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Art. 5 (4) states: “In the case of an application relating to a GMO for food use, references
to ‘food’ in paragraph 3 shall be interpreted as referring to food containing, consisting of
or produced from the GMO in respect of which an application is made.” This means that
both transgenic animals and the products obtained from such, e.g. meat, sausage, milk
or cheese fall within the scope of the Regulation and must therefore undergo a risk
assessment. Under art. 4 (1), food must not have adverse effects on human health,
animal health or the environment. The fulfilment of these criteria must be “adequately
and sufficiently demonstrated” at the time of application by the submission of studies
carried out, analyses, etc. – and this both for the GMO intended for use as or in food (i.e.
the transgenic animal) and for the food referred to in the scope. Equally, demonstration
of substantial equivalence is required, by “an analysis, supported by appropriate
information and data, showing that the characteristics of the food are not different from
those of its conventional counterpart, having regard to the accepted limits of natural
variations for such characteristics […].”

The text of the Regulation contains no precise references as to which information must be
submitted in the context of the application to demonstrate the above criteria. The
application must in case be accompanied by the “designation of the food, and its
specification, including the transformation event(s) used” as well as “where applicable, a
detailed description of the method of production and manufacturing”.

In certain cases, an environmental risk assessment pursuant to Directive 2001/18/EC

must be carried out: “In the case of GMOs or food containing or consisting of
GMOs, the application shall also be accompanied by: a) the complete technical dossier
supplying the information required by Annexes III and IV to Directive 2001/18/EC
and information and conclusions about the risk assessment carried out in accordance with
the principles set out in Annex II to Directive 2001/18/EC, […]”.

Worthy of mention as an interesting detail is the provision which requires the submission
of “either a reasoned statement that the feed does not give rise to ethical or religious
concerns, or a proposal for labelling it”.

Comment

Among the general objects, the relevant aspects like the health of the animal, food
safety, human health and the environment are listed. While it must be demonstrated that
there are no adverse effects on human health, the Regulation does not contain any
concrete criteria for the conducting of a risk assessment in this regard. Criteria for the
demonstration of food safety are lacking. With respect to the approval of GMOs (e.g.
genetically modified animal) or foods containing or consisting of GMOs (e.g. meat and
sausage products but clearly not milk or cheese) there is a reference to the
environmental safety requirements provided by the Directive 2001/18/EC “[…] to ensure
that all appropriate measures are taken to prevent the adverse effects on human and
animal health and the environment which might arise from the deliberate release of
GMOs”.
Similar to the critical remarks formulated in chap. 2.2.1, deficits can also be identified
here: there is no obligation to analyse specific parameters regarding the health of the
transgenic animal, the preservation of the concept of substantial equivalence, focus on
potential effects on environments by reference to Directive 2001/18/EC, lack of criteria to
ascertain food safety and/or to establish potential adverse effects on human health.
Accordingly, no specific reference to transgenic animals can be found here either, more
specification is certainly necessary.

The guidance document of the European Food Safety Authority (EFSA) for the risk
assessment of genetically modified plants and derived food and feed22 specifies the
requirements in relation to the data which must be submitted in connection with

22
European Food Safety Authority (EFSA), May 2006

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genetically modified plants on the basis of Directive 2001/18/EC and Regulation

1829/2003. The necessary information is explained in detail with concrete plant-specific
examples and a suggestion for the structuring of the application is presented.
This guidance document further codifies the principle of substantial equivalence as the
basis for the risk assessment. After identification of possible differences between the GMO
and a conventional counterpart, the rest of the risk assessment focuses on possible
effects of the identified, intended or unintended, differences in the GMO. Possible points
of criticism of this principle of substantial equivalence have been set out in numerous
publications23, these shall not be repeated in the present study.

Naturally, contentual principles cannot be derived from this guidance document for the
risk assessment of transgenic plants for the case of genetically modified animals or their
products. Nevertheless, this example shows that the existing legislative provisions
contained in Directive 2001/18/EC and in Regulation 1829/2003 manifestly need
substantial specification. If this was already necessary for genetically modified plants,
then all the more so for the field of genetically modified animals, in order to guarantee
risk assessment which is stringent, comprehensive, takes account of the protection
objectives and also is ultimately commensurable.

2.3 FAO/WHO
In the context of the FAO/WHO Codex Alimentarius Commission, two relevant documents
must be mentioned when it comes to the topic of transgenic animals: the “FAO/WHO
Expert consultation on the safety assessment of foods derived from genetically modified
animals, including fish” from the year 2003 as well as the “Proposed draft guideline for
the conduct of food safety assessment of foods derived from recombinant DNA animals”
in the current version of November 2007. As agreed, the description and commentary of
the latter guideline is a core point in this study.

2.3.1 FAO/WHO Expert consultation on the safety assessment

of foods derived from genetically modified animals, including fish
This report from the year 2003 is not a classical, detailed guideline for the risk
assessment of transgenic animals or their products and shall, accordingly, only be
described in brief below.
Basically, it is a general outline of the problem, in which inter alia technical methods,
elements of international regulation, questions regarding surveillance (subsequent to
approval) and ethical aspects are described. In part, relevant criteria for the evaluation of
food safety are defined, often very generally and/or theoretically. Among these are inter
alia:

Assessment of unintended effects depending on integration, number of copies and
expression of the transgene and potentially associated pleiotropic effects

Possible mobility of the transgene within the genome when viral or transposon vectors
are used

Stability of the integration into the animal genome

Existence of undesired DNA sequences, e.g. from marker-genes, bacterial DNA from
the vector, etc.

Studies of feed conversion ratios

Allergenic potential

Toxicity

Analysis of the most important ingredients of animal products

Amount of the food in the average nutritional profile

This document already establishes that substantially the same approach as in the case of
genetically modified plants can be taken for the risk assessment of genetically modified
animals (this point will later be picked up again in connection with the Proposed Draft

23
E.g. IFZ Graz/Federal Environmental Agency 2002, Müller 2004, Spök 2004

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Guideline, see chapter 2.3.2). The starting point is the comparison of the GMO with the
conventional counterpart; the principle of substantial equivalence is also a fundamental
element of the risk assessment. The first step is the comparison between the
conventional and the transgenic animal, which should take the following aspects into
account:

Phenotypical characterisation of the transgenic animal inc. the analysis of animal
health parameters that are not defined in any more detail (also serves the
identification of potential unintended effects)

Details regarding the genetic modification (sequence of the integrated material,
number of copies and location of the integrated transgene, etc.)

Establishment of any potential allergenicity

Analysis of the key components of the respective animal product (compositional
analysis).
Furthermore, a “food intake assessment” is proposed, i.e. an assessment of the amount
of the respective foodstuff contained in the average human diet. This should be followed
by a toxicological evaluation and an assessment of the dietary-physiological
consequences which might arise from the novel foodstuff. Each of these sometimes very
generally described steps can necessitate further analyses and investigations. Therefore,
substantial equivalence would form the basis for a risk assessment under this approach.

Aspects concerning the environment are only touched on insofar as they are directly
related to food safety. The main question in this context is whether and if so how a
transgene can enter the human food chain via the environment. This is relevant in
particular for genetically modified fish and to a lesser extent for genetically modified
poultry, where escape is possible and/or likely.

The majority of the criteria and contents described in this FAO/WHO document are also in
the “Draft Guideline for the conduct of food safety assessment of foods derived from
recombinant DNA animals” and shall be commented on in detail in the following chapter.

2.3.2 Proposed draft guideline for the conduct of food safety

assessment of foods derived from recombinant DNA animals
In 1999, the FAO/WHO Codex Alimentarius Commission set up a Task Force on Food and
Biotechnology, the so-called Ad Hoc Intergovernmental Task Force on Foods derived from
Biotechnology (TFFBT). The function of this task force is to assess the safety of such
foodstuffs and to develop standards, guidelines and recommendations on a scientific
basis.

In September 2005 at the 5th session of the TFFBT, the setting up of a working group for
the development of a draft guideline for the conduct of food safety assessment of foods
derived from genetically modified animals was resolved. Over the course of two
sessions24, each over several days, this working group developed a proposal for a “Draft
Guideline for the conduct of food safety assessment of foods derived from recombinant
DNA animals”. In addition, an expert consultation was carried out in March 2007 on
specific questions regarding antibiotic marker-genes and non-heritable constructs (DNA-
sequences which are not inherited). The results of the working group and the expert
consultation were subsequently discussed at the 7th session of the TFFBT from 24
September to 28 September 2007 (in Japan) and the proposal was finalised. This
proposal is now at the International Codex Alimentarius Commission for final adoption at
its 31st session (30.6.-5.7.2008).

The “Proposed draft guideline for the conduct of food safety assessment of foods derived
from recombinant-DNA animals” in the version valid in November 2007 (hereinafter the
Proposed Draft) will now be described and analysed, the complete text of the Proposed
Draft is in Annex I.

24
Most recently from 30.5.-1.6.2006 with participation by the author

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Besides all the general provisions on scope, definitions and principles of food safety
assessment, section 4 of the Proposed Draft contains detailed requirements for the
criteria subject to analysis. The Proposed Draft distinguishes thereby between the
animals respectively relevant in the process, i.e. differentiates between

Recipient animal (prior to the genetic modification)

Donor organism (unless a synthetically produced nucleic acid sequence is
involved)

initial rDNA animal and

the rDNA animal ultimately used for food production
This increases, on the one hand, the extent of the information to be submitted and thus
the probability of being able to encompass possible risks, but hampers, on the other
hand, to some extent the transparency and comprehensibility of what is actually required
in which case.

In accordance with the principles this Proposed Draft is based on, whereby a healthy
animal results with great probability in a healthy food (i.e. a food without any adverse
affects), by far the largest part of the provisions are devoted to the various, above-
mentioned categories of animals.
The information which is to be submitted in respect of the foodstuff itself is scanty and
relates to the estimation of possible allergenic potential, the analysis of the composition
and/or some ingredients and possible effects from processing and/or storage.
Sometimes, provisions relevant in connection with food are found in other sections of the
Proposed Draft, for example, information on the “effect of feed, exercise and growth
environment on food products” is required for the description of the recipient animal. The
concentrations of the newly expressed protein and/or other metabolites in the food
product (“… in the edible tissue and other derived food products …”) must be described
(section on the description of the genetic modification carried out on the food-product
animal).

2.3.3 Analysis
The Proposed Draft developed by the working group is at present the most
comprehensive document in comparison to the other instruments analysed in relation to
the risk assessment of food products from genetically modified animals. In particular for
the assessment and evaluation of the different animals involved, comprehensive
requirements and criteria are set out.

Modelled on the “Codex Guideline for the conduct of food safety assessment of
food derived from rDNA plants”25 (Plant Document)

Upon deploying the working group, the Task Force decided to use the Plant Document as
a basis and to formulate the Proposed Draft in a manner closely based thereon. This
meant, on the one hand, that inappropriate terminology was taken over, on the other
hand, it became clear that certain passages of the Plant Document no longer reflected the
current state of the art and science. A further consequence of this rigid dependence
manifests itself in the adoption of only those provisions in the Proposed Draft which are
specific to animals. General aspects of risk assessment that are necessary, but not
considered in the Plant Document, could therefore per definitionem not be taken up in the
Proposed Draft for transgenic animals. Ultimately this results, for example, in the
establishment of possible toxicity and/or allergenicity as hitherto by identification of
possible sequence homologies of the expressed protein, the risk assessment focuses on
isolated single substances.

25
FAO/WHO Guideline Document CAC/GL 45-2003

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Scope

The risk assessment focuses on aspects of food safety, “safety and nutritional aspects of
foods”. Questions of animal protection, ethical or socioeconomic aspects, possible
environmental risks, and the safety of transgenic animals as feedstuff are firmly
excluded. The current formulation of the scope - unlike other versions discussed -
deliberately avoids the question of whether this risk assessment can/should also apply to
genetically modified animals which serve purposes other than food, e.g. in the field of
gene-pharming.
Parts or remains of such animals can certainly end up in the food chain, by
contamination, over disposal routes (also unintentionally as the example of the
transgenic pigs in Canada shows) or via the processing of animal waste as feedstuffs. To
leave these animals out of the present risk assessment is to miss out on an opportunity.
The Task Force, which took this decision at their last session, also recognises this “The
Task Force noted that […] the document would remain silent as to whether the guideline
could be applied to the safety assessment of foods derived from rDNA animals intended
to non-food use […] … entirely up to member countries to decide on the most appropriate
approach.”26

The approval of transgenic animals, whose products are intended for non-food use, has
been rejected out of safety concerns for example by the Royal Society Canada: “The
panel recommends that approvals should not be given for GM products with human food
counterparts that carry restrictions on their use for non-food purposes (e.g. crops
approved for animal feed but not for human food). Unless there are reliable ways to
guarantee the segregation and recall if necessary of these products, they should be
approved only if acceptable for human consumption.”27

Non-Heritable Constructs

The term Non-Heritable Constructs (NHC) covers applications in which recombinant

nucleic acids are transferred into somatic cells. These NHC can remain episomal or be
integrated into the chromosomes of the somatic cells, but are not passed on. Examples
thereof thus include the use of genetically produced vaccines, DNA-vaccines and
transgenic probiotic bacteria (lactic acid bacteria) as vectors and similar.
As it remained unclear throughout the discussions whether NHC have a different risk
potential and thus require specific consideration in the Proposed Draft, the Working
Group of the TFFBT developed a questionnaire on this topic, as it also did for the ARM
genes (see further below). This was discussed at a WHO/FAO Expert Consultation
between 26.2. and 2.3.2007 in Geneva. One significant result of this consultation was the
finding that in relation to possible risks at a qualitative level, there was no difference
between heritable and non-heritable nucleic-acid constructs, when these are
chromosomally integrated. Quantitative differences can arise as a result of the differing
expression patterns in each case. In the course of the 7th session of the TFFBT, a
supplementary footnote on paragraph 1 was conclusively resolved in order to clarify that
this Proposed Draft “..had been developed primarily for animals bearing heritable
recombinant-DNA constructs.”. A further footnote (paragraph 7) established that
additional, specific criteria may be necessary for the risk assessment of NHC.

Principle of substantial equivalence

The principle of substantial equivalence has established itself in most international

regulations as a binding concept in the context of risk assessment. Its foundations were
developed in the course of classical plant breeding. With respect to the question as to
necessary tests for genetically modified plants, the system of comparison with the

26
FAO/WHO Codex Alimentarius Commission, Report of the sixth session, 2007
27
The Royal Society of Canada 2001

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conventional counterpart was subsequently integrated into precisely this principle of

substantial equivalence, which thus reflects the approach of classical breeding.

Substantial equivalence also provides a basis for the present Proposed Draft: indirectly in
paragraph 4 and directly in paragraphs 13 and 14. This is rationalised inter alia by the
difficulties of transferring principles from the classical risk assessment of potential toxic
single substances to whole foodstuffs. The concept of substantial equivalence is labelled a
“key step”, at the same time paragraph 14 points out that “safety assessment in itself” is
not concerned but rather a “starting point”. Theoretically, this neither limits nor more
closely describes the extent of possibly necessary experimental tests. It is important to
stress this, because many years of experience in approval processes of genetically
modified plants and/or derived products under Directive 2001/18/EC or Regulation (EC)
1829/2003 have shown that the principle of substantial equivalence and/or the
establishment thereof is often seen as the endpoint of a risk assessment. The area within
which a GMO is deemed to be substantially equivalent is construed very widely. The
conclusions drawn therefrom by the applicants have mostly been the same: on the basis
of the finding of substantial equivalence at the beginning of a risk assessment (insofar
therefore really used as a starting point), possible further experimental tests have been
argued to be unnecessary. The subsequent steps of the risk assessment consequently
focussed on the newly expressed protein. These hitherto common, somewhat
reductionist, approaches should, however, be avoided for the purposes of precautionary
risk assessment.

The Royal Society Canada takes a critical stance regarding the principle of substantial
equivalence because of its unclear definition and superficial application: “However, the
panel also concluded that, for the purposes of the safety assessment of GM foods for
human consumption, “substantial equivalence” should be considered to have been
achieved only if, to the point of scientific certainty, there is equivalence in the genome,
the proteome and metabolome of the GM food as compared to that of the native food.”28

Antibiotic Resistance Marker (ARM) Genes

The topic of ARM genes is somewhat complex. In the discussion regarding ARM genes
there are very diverging views on whether these are technically necessary and thus
indispensable or whether their use really gives cause for safety concerns.

On the one hand, existing alternatives to these marker genes are regularly mentioned.
Thus, in a report by the DEFRA29 in the chapter on “Alternative Markers to Antibiotic
Resistance Genes” it is pointed out that a series of other systems is already available in
the case of plants. These are precisely listed complete with their respective advantages
and disadvantages. On the other hand, even experts critical of genetic engineering, for
instance Cummins and Ho, in their text “Genetically modified food animals coming” note
that there are scarcely alternatives whose “safety to humans in food products” has
sufficiently been demonstrated. As early as 1998, the British Royal Society gave a
recommendation that ARM genes be replaced by alternative marker systems as soon as
this be possible. This recommendation was repeated in 2002. Likewise, in 2001 the Royal
Society Canada already pointed to available alternatives, with the additional remark that
the biotechnology industry (without further specification) would not develop any more
plants with ARM genes and that similar trends are likewise to be expected in connection
with transgenic animals.30

28
The Royal Society of Canada 2001
29
Department for Environment, Food & Rural Affairs 2001
30
The view that the cause for bacteria’s increasing resistance is more likely caused by the wide
general use of antibiotics in feedstuffs and in human therapy and less likely to lie in the danger of a
possible gene transfer from genetically modified organisms is supported thereby.

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The most recent Austrian research work, “Risk assessment of antibiotic resistance marker
genes in genetically modified organisms. A comprehensive report”31, evaluates the
possible risks arising from the use of ARM genes in transgenic plants on the basis of the
most newly available scientific findings. The afore-mentioned study develops a detailed,
critical argumentation in relation to the EFSA GMO Panel’s classification of the use of
certain ARM genes (for example npt II) as risk-free. Significantly different country-
specific patterns regarding the qualitative and quantitative use of antibiotic treatments,
their respective clinical relevance (local significance) as well as the background exposure
existing in each case are documented in detail. Consequently, no broad categorisation of
ARM genes can be sustained. The rating of the npt II gene as simply inactivating clinically
irrelevant substances (e.g. neomycin, kanamycin or paramomycin) cannot be applied to
all European countries in the same way according to this most recent study, although
neomycin is only used in rare cases. This line of argumentation is also followed
substantially by the European Medicines Agency (EMEA), which rates neomycin and
kanamycin as relevant substances in veterinary and human medical treatment. Penicillin
and derivatives of tetracycline are still a routine part of clinical treatments.
In relation to possible alternative systems, the report explains that these are not yet
ready for the market and furthermore imply other intrinsic risks, which can hardly be
assessed. On the basis of the described differences and of the lack of representative data,
Wögerbauer ultimately emphasises the necessity of an evaluation on a case-by-case
basis upon the application for the deliebrate release or placing on the market of a GMO
with ARM genes.

The working group of the TFFBT developed a questionnaire on this topic, as also for the
non-heritable constructs, which was discussed at a WHO/FAO Expert Consultation
between 26.2. and 2.3.2007 in Geneva. The results of this consultation brought no
significant new findings in relation to ARM genes. It was established that at the present
time there is insufficient knowledge as regards the safety of food products from
transgenic animals with ARM genes. The Expert Consultation finally comes to the
conclusion that alternative systems do not yet have the efficiency of conventional
systems, that very little information is available about them and that what is available
does not necessarily indicate a lesser potential for risk (in comparison to ARM genes). In
the case of one possible alternative, GFP (green fluorescent protein), information from
tests with transgenic plants is available, whereby a possible potential for cytotoxicity was
established (in situ testing, not administered orally). However, the Expert Consultation
recommends the advancement and development of further, new alternative systems as
desirable.
Consequently, at the end of September 2007, during the course of the 7th session of the
Task Force, no changes were made to the provisions in paragraphs 64-67.

Unintended effects

It is important that possible unintended effects resulting from a genetic engineering

procedure be considered theoretically at many different levels. Paragraphs 15 and 16
make detailed reference to the different levels and even contemplate unintended effects
resulting from the further breeding of rDNA animals. The formulation – “Safety
assessment should include data and information to reduce the possibility that a food […]
would have an unexpected, adverse effect on human health.” – does not specify,
however, which criteria are to be imposed. It also remains unclear when and how exactly
these possible unintended effects must be assessed.

31
Wögerbauer 2007

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Miscellaneous

Some formulations seem unclear or are open to ambiguous interpretation.

Paragraph 27, Description of donor organism or other source(s)

Which detailed information must be submitted in case of a synthetically produced
DNA-sequence?

The formulation “It is particularly important to determine whether the rDNA sequence
impart pathogenicity [...]” appears problematic. It must be emphasised that merely a
finding that pathogenicity can be imparted, is not enough. In this case, concrete
information must be submitted, the possible effects on food safety must be described,
etc.

Paragraph 30, Description of the genetic modification(s) including the construct(s) used
[...]

Must information about the primary sequence of the rDNA only be made available if
this is of synthetic origin?

Characterization of the genetic modification(s) in the rDNA animal [...]

Paragraph 37, under point A) not only the potential for “mobilization or
recombination” should be established but also the possible consequences resulting
therefrom for the animal and for food safety

Details on the number of integrated copies and their integration sites are missing

Paragraph 39 A and E: here too, the consequences resulting from these findings
should be described

Paragraph 55, Food storage and processing

Here too, it must be noted that the consideration of possible effects (“should also be
considered”) and the description of the processing processes do not provide enough
information for a risk assessment. The description and evaluation of possible
consequences is necessary.

Safety assessment of the recombinant-DNA animal ultimately used for food production,
Paragraphs 40-62

As has already been mentioned, this Proposed Draft operates mostly on the principle
that a healthy animal in all probability yields healthy (i.e. without adverse effects)
food. This derives from the premise that substantial equivalence is proven, i.e. the
comparison of the transgenic animal with its conventionally bred counterpart. Thus, if
a genetically modified animal is substantially identical with one of the same type and
race which has been cultivated through conventional breeding, substantial
equivalence is postulated

Thus, there are few comprehensive provisions on the concrete assessment of the
product per se

The analysis of the composition of the food product only concerns comparing the
concentrations therein with that of the conventional counterpart. A particular problem
is posed in this respect by the possible range of these parameters, which, apart from
the genetic modification and the effects resulting therefrom, vary greatly with the
breeding conditions, the feedstuffs administered and other similar factors. The
question of what criteria are required to determine the suitability of an appropriate,
conventional counterpart for comparison purposes has not yet been solved

The consequences of the heavy dependence on the Plant Document are also visible
here. From the assessment of allergenicity to the compositional analysis, the
principles familiar from the requirements for genetically modified plants are taken
over in this Proposed Draft. The primary orientation on the establishment of sequence
homologies does not seem adequate in this connection, the same goes for the focus
on tests with the isolated new protein. No tests with the whole foodstuff are foreseen

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2.4 Countries
Here, those countries will be introduced for which it was possible to obtain reasonably
usable information with reasonable efforts. For possible further details, targeted (but also
more involved) research in China, Cuba, perhaps also India, Korea or Malaysia could be
conducted.

2.4.1 USA
In the USA, food/-products are regulated by three different authorities. The Food and
Drug Administration (US FDA) is responsible for food and feedstuffs from genetically
modified organisms. The Department of Agriculture (USDA) regulates meat and poultry
products and release attempts (also with genetically modified plants). Finally, the
Environmental Protection Agency (EPA) comes into play when genetically modified plants
display resistance against weed killers or pesticides.

Pursuant to the “Federal Food, Drug, and Cosmetic Act” foods can be placed on the
market without prior approval as long as it cannot be proven that they are injurious to
health. The FDA has the final decision on whether a product can be rated as “generally
regarded as safe” (GRAS), i.e. the assessment of food safety consists in the evaluation of
the end-product independent of the production process. Thus, the principle applicable
hitherto has been that products derived from genetically modified organisms do not
require any special risk assessment or separate regulation.

The following information about possible changes in the law in connection with
genetically modified animals comes from different sources.32

The US FDA as the authority with main responsibility has no up-to-date information
regarding this topic on its website and did not reply to an email request in this matter.
Neither are any references to the approval process currently running in respect of the
company Aqua Bounty’s transgenic salmon to be found. The US FDA is presently (August
2007) – probably as a result of the increasing pressure, which has now also been
articulated by industry and research players – working for the first time on the
development of rules for transgenic animals and derived products. As, however, the FDA
has not yet issued any direct statements on the matter, the exact objective being
pursued must for now remain unclear. This would be of particular interest in connection
with the FDA’s statements at the end of 2006, which classified food from cloned animals
as harmless, safe and therefore not necessitating any extra regulation.
An approval should be required for each genetically modified animal at any rate if
products derived therefrom should end up in the food chain. According to a report in the
New York Times, the existing law on veterinary medicines, the “New Animal Drug Rule”,
should be used to this end. An additionally integrated gene would be treated as a
pharmaceutical thereunder and a special guideline should be developed in order to define
the application of the rule to the transgenic animal as well as the information which must
be submitted. This would, then, not be a regulation specific to food products.
AquaBounty draws the following conclusions from experiences in the course of the
approval process thus far: “We expect the new approach to be risk-based and to include
detailed studies covering
(A) the molecular characterization of the transgene construct and its expression in the
animal,
(B) studies of the transgenic phenotype, including gene expression levels, behaviour,
health and welfare of the host animal,
(C) studies of the long term stability of the transgene over time, life history and
multiple generations,
(D) food and feed safety, including direct and indirect toxicity measures,
(E) a demonstration of efficacy, and

32
e-Mail communication J. McGonigle/AquaBounty, Article in the New York Times, Website of the
Union of Concerned Scientists

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(F) an assessment of the potential for environmental impact and possible mitigation
measures that could remove, reduce or modify any identified impacts.”33

The website of the Union of Concerned Scientists has the following interpretation: if the
protein newly expressed in the animal is substantially a pharmaceutical, then the
transgenic animal will be evaluated and approved pursuant to the above-mentioned Drug
Rule. If this new protein were a conventional food ingredient, then evaluation and
approval would ensue pursuant to the already existing regulations in these areas, e.g. for
additives, etc. Under this approach, AquaBounty’s transgenic salmon, which seeks
approval as a food product, would fall under the law on veterinary medicine, because
growth hormones are classified as pharmaceuticals.

At the beginning of 2007, the USDA set up a special department in the field of transgenic
animals in order to define the USDA’s role in future processes. The duration and direction
of this development in the USA is at present not foreseeable.

2.4.2 Canada
In Canada, responsibility in relation to genetically modified animals is spread across
several authorities, Health Canada (federal department), Environment Canada (federal
department) and the Canadian Food Inspection Agency (CFIA).34 A risk assessment must
be conducted prior to every deliberate release or approval of a transgenic animal or a
derived product as well as prior to any import, the applicant must submit a great deal of
information to the authorities for this purpose.

Transgenic animals are classified under the Canadian Environmental Act (CEPA) and the
“New Substances Notification Regulation” as “new substances”. Environment Canada is
responsible for the risk assessment with respect to possible consequences for the
environment. In order to specify the generally worded requirements for the risk
assessment in relation to environmental effects, the CFIA developed a comprehensive
document, the “Notification guidelines for the environmental assessment of BT animals”
(see annex II).
Inter alia the following information is required:

Information about the transgenic animal inc. details on cell lines, oocytes, parent
animals, methods for further breeding of the transgenic animals

Description of the genetic modification, information on the vector, on the resulting
genotypic and phenotypic changes

Description of unintended effects in the transgenic animal

Number of copies of transgenes inserted, integration sites, genetic material possibly
knocked out or modified by the insertion

Possibility of horizontal gene transfer

Behaviour, interaction, reproductive behaviour in the environment

Possible ecological effects of the transgenic animal or residues/remains, descriptions
of habitats, pathogenicity, toxicity, possible invasiveness, effects on biodiversity, etc.

Potential adverse effects on human health, likely exposure routes (not specified
exactly)

All other information which may be relevant for the assessment of possible risks for
human health or the environment

33
e-mail communication J. McGonigle/AquaBounty
34
In Canada, the term “Biotechnology-derived animals” is used. This includes far more than just
genetically modified animals, the following further categories are included:
“Clones of animals derived by nuclear transfer from embryonic and somatic cells.
Chimeric animals that have received transplanted cells from another animal.
Interspecies hybrids produced by any method.
Animals derived by in vitro cultivation such as maturation or manipulation of embryos.”
www.inspection.gc.ca/english/anima/biotech/bioteche.shtml

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Health Canada evaluates the safety of food products from transgenic animals on the basis
of the Novel Food Regulation (see Annex III).35 The notification must include inter alia the
following information:
“[…] (a) common name under which the novel food will be sold;
(c) a description of the novel food, together with
(i) information respecting its development,
(ii) details of the method by which it is manufactured, prepared, preserved, packaged
and stored,
(iii) details of the major change, if any,
(iv) information respecting its intended use and directions for its preparation,
(v) information respecting its history of use as a food in a country other than Canada, if
applicable, and
(vi) information relied on to establish that the novel food is safe for consumption;
(d) information respecting the estimated levels of consumption by consumers of the
novel food; […]” B.28.002.(2)

A comprehensive guideline was also developed for this, the “Guideline for the Safety
Assessment of Novel Foods” (Health Canada, June 2006). This describes in detail the
requirements for the application documents for the assessment of food safety, as yet,
however, only for genetically modified plants and micro-organisms. At present work is
being done to provide the same for transgenic animals (novel foods derived from
animals).

The expertise of the CFIA will be drawn on in order to evaluate aspects of animal health
in particular. The CFIA has also created a guideline, the “Animal health risk analysis
framework for biotechnology-derived animals” (see Annex IV), which deals with risk
assessment exclusively from the perspective of animal health and animal protection.

The approval decision is ultimately taken by Health Canada and/or Environment Canada;
each decision is taken on a case-by-case basis. The precautionary principle that is seen
as an element of risk management comes into play when within the context of a
necessary decision there is a risk of serious or irreversible damage and “full scientific
certainty” is not given. The Department of Fisheries and Oceans is responsible for
transgenic fish.36

Up till now (status as of 2 September 2007)37 not one transgenic animal has been
approved in Canada, either for release attempts in the environment or for the production
of foodstuffs.

Comment

In summary, it can be said that Canada has developed very detailed rules for the
production, approval and import of transgenic animals and derived products. For both
risk assessment in relation to environmental effects of genetically modified animals and
for such in the field of food safety, detailed guidelines and requirements either exist or
are being developed. The status accorded to animal health and welfare within the
regulatory system is a special feature of the Canadian system.

In 2001 the Royal Society of Canada developed recommendations for the adaptation of
the regulatory system and of risk assessment in order to be better able to take into
account and assess health and environmental aspects in connection with food products
from genetically modified animals. In general, because of the numerous scientific
uncertainties in relation to the risk assessment of genetically/produced foodstuffs, an

35
Foodstuffs from genetically modified animals are per definitionem novel food
36
The detailed interplay of these authorities is not completely transparent “from the outside”, in
particular because as yet there has been no approval, i.e. the process for transgenic animals in
realita has yet not been run through
37
Canadian Food Inspection Agency: www.inspection.gc.ca/english/anima/biotech/bioteche.shtml

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approach applying the precautionary principle is considered necessary. The principle of

substantial equivalence is described as ambiguous and as too imprecisely delineated.
Further, there is criticism that, in common risk assessment practice, this principle is
mostly interpreted as an argument contra the necessity of further and/or more
comprehensive tests and not as a possible point of departure for further investigations.
The report recommends carrying out rigorous analyses of the possible consequences by
“direct testing for harmful outcomes” in lieu of said principle. In each case, clear proof
that there is no risk in connection with new technologies is required (“ […] unless there is
a reliable scientific basis for considering them safe.”). The CFIA is called upon to develop
its own guidelines in relation to the approval process for genetically modified animals,
which also take into account both behavioural and physiological parameters in the risk
assessment. In the case of transgenic fish, a moratorium in relation to breeding in farms
on Canadian coastlines is called for, or the tying of approvals for transgenic fish to
obligatory breeding in so-called “land-based facilities”.

In response to this report, the Canadian government has developed an action plan to
implement the recommendations contained therein. In the meantime, the “Guideline for
novel foods derived from plants and micro-organisms” has been revised. And, as already
mentioned, a new guideline for the risk assessment of food products from transgenic animals
and fish is being developed.

2.4.3 Argentina
Argentina is one of the few further countries which have issued special statutory
regulations – on the one hand for the field of transgenic animals per se Rule Nº57/03,
the relevant annex to which was gratefully received by the author of this study in an
English version, on the other hand for vaccines produced by genetic engineering and
similar products, which are used for animals (Rule Nº656/92).38

In the Annex to Rule Nº57/03, “Application for permit for experiments with and/or
release into the environment of genetically modified animals” (see Annex V), the
requirements in terms of documentation to be submitted upon application for the
carrying out of experiments in “controlled conditions”, for deliberate releases and also in
the case of the import of genetically modified animals, gametes or embryos are set out in
detail and relatively comprehensively. This information simultaneously represents the
relevant criteria for the risk assessment for the authorities, whereby molecular
characterisation of the “transformation event” and aspects of biosafety are especially
central. The risk assessment is conducted case-by-case. The studies can only be
commenced after positive feedback from the authorities. Each approval contains inter alia
measures regarding “biosafety” and regarding the frequency and details of inspections as
well as risk management. Genetically modified animals and/or their products must fulfil
not only the requirements of these provisions but also those of the “Animal Health
Regulation” (Law N°130636/49) (“to prevent risks to human and/or animal health or the
environment”). In the following cases the authorities must be notified within 24 hours:

In the case of unintended release or escape of animals

In the event that unexpected characteristics appear in the transgenic animal

In any “abnormal” situation, for instance sharply increased mortality rates, illnesses
or other unforeseen effects on other organisms.

The information which must be submitted focuses on the genetic information and
functions and on the possible effects and measures in relation to environmental safety.
The data required include (the usual) details like sequences of the construct to be
integrated, the marker-gene, the introns and promoters, the vector, details about the
donor and recipient organism, as applicable details about the site of the intended release,
etc. Further, a detailed description of such information as has been considered in advance

38
e-mail communication Dr. M. Burachik, Coordinador General Oficina de Biotecnología, Secretaría
de Agricultura, Ganadería, Pesca y Alimentos (Ministry for Agriculture, Livestock Breeding, Fisheries
and Food)

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for the prevention of any contamination, also of the environment, as well as any
consequent measures is necessary, e.g. description of:

Isolation and biosafety measures

Confinement conditions

Methods to control potential vectors

Techniques to detect gene transfers from the transgenic animal to the biotic
environment

Distance to closest roads and heavily travelled areas.

Finally information on possible interbreeding partners, the potentially altered selection

pressure and inheritance patterns but also on the wellbeing of the animals and any toxic
or other adverse effects inter alia on human health must be provided. Possible further
details in relation to risk assessment with respect to human health and/or food safety
could not be ascertained up to the time of project completion.

According to information provided by the competent authority, as yet (29.06.2007) no

applications have been made in Argentina for the approval of a genetically modified
animal, either for the field of gene-pharming or for food use. Applications for
experimental releases for research purposes have been submitted and approved after a
corresponding risk assessment. These concerned cattle and sheep that express
pharmaceutical substances in their milk (human growth hormone, bovine growth
hormone and modified human insulin). The transgenic animals did not get outside of the
controlled conditions; the tests took place under strictly confined conditions in the
laboratory. The offspring of such animals are also subject to legal provisions in Argentina.
An application for experimental releases for research purposes of transgenic sheep
(expression of a reporter gene) has been submitted, a further application in relation to
cattle is expected very soon. An inspection system has been set up in Argentina in this
connection.

2.4.4 Other countries

Australia
In spite of over 20 years of ongoing research with respect to the production of genetically
modified animals, no transgenic animal has been approved outside of the research field
to date in Australia (or in New Zealand). Work in these countries is focussing on fish,
cows with an additional gene for β- and κ-casein (between 20 and 100% more casein)
and sheep (focus on wool). In the evaluation of the food safety of a product from a
transgenic animal, the principle of substantial equivalence is also of central significance
in these countries.

The Australia New Zealand Food Standards Code39 is a food law for Australia and (in
many parts) for New Zealand; chapter 1.5.2, “Food Produced Using Gene Technology”40,
deals with genetically produced or modified foodstuffs. It contains definitions and
labelling requirements as well as the requirement that such undergo an approval process
and a risk assessment (which, however, is not further specified here) in the area of food
safety. Products which have already been approved, e.g. various genetically modified
plants, are listed in a register here. The Food Standards Australia New Zealand, which is
responsible for the carrying out of the risk assessments, created in June 2005 a 60-page
booklet on the topic of risk assessment of genetically modified/produced foods, “GM
Foods. Safety Assessment of Genetically Modified Foods”.41 The necessary criteria include
for example:

Information on the donor and recipient organism, information on which parts have
been used as food up till now

Description of the genetic material and the methods used for the integration, e.g.
source, function, regulation elements of the genetic material, primary sequence, how

39
www.foodstandards.gov.au/thecode/foodstandardscode.cfm
40
www.foodstandards.gov.au/_srcfiles/Standard_1_5_2_GM_v92.pdf
41
www.foodstandards.gov.au/_srcfiles/GM%20Foods_text_pp_final.pdf

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often and where it has been integrated, possible consequences resulting therefrom,
etc.

Any “effects of any new genes on human health” must also be described in connection
with the above, there is particular reference to antibiotic-resistance-marker-genes
and the associated question of a possible transfer of the resistance to bacteria in the
human digestive system

Characterisation and expression of the new protein, possible toxic or allergenic
characteristics of the protein, information about feeding tests carried out with it

Differences between the novel and the conventional food, in particular as regards ash
content, moisture, protein, fat, carbohydrate, amino acids, vitamins, minerals

Toxic or allergenic potential of the new food

Nutritional value in comparison to the conventional food, final intended use, any
directions for processing

Risk assessments in the environmental field, also in the case of intended releases, are
carried out in Australia by the Department of the Environment and Heritage as well as by
the Office of the Gene Technology Regulator (OGTR) in the Department of Health and
Ageing, the main principles – for instance the obligatory performance of a risk
assessment – are anchored in the gene technology law.42 A separate advisory committee
has been established in connection with ethical questions, the Gene Technology Ethics
Committee. The OGTR has specified the requirements a risk assessment must fulfil when
it comes to intended release or placing on the market in a 118 page document called
“Risk Analysis Framework” (January 2005).43 Interestingly, this document is only
indirectly addressed to applicants, as it expounds those principles according to which the
authority (the Regulator) conducts a risk analysis44, “The Risk Analysis Framework
describes the principles of risk analysis used by the Regulator to protect human health
and safety, and the environment, in accordance with the Gene Technology Act.”

The risk assessment pertinent in connection with the present study is treated in chapter 3
of the above-mentioned framework. However, in contrast to comparable documents from
other countries, hardly any concrete criteria are listed, rather there are numerous
fundamental explanations and descriptions about what might theoretically present a
danger, how adverse effects can be grouped and so on. The rationalisation: “No list of
generic criteria would be sufficient for all cases. Therefore the properties of the GMO, its
location(s), the types of dealings and the management conditions employed will all be
important in deciding which people and what particular local environmental attributes are
most susceptible.” Individual, concrete details named include:

The possibility of harmful effects on humans and other organisms and/or ecosystems
and non-target organisms

Horizontal gene-transfer to other organisms

The possible propagation and/or persistence of a GMO in the environment

Possible selection advantages

Toxic, allergenic or pathogenic effects on other organisms

Unintended effects or secondary effects
As also seen in other cases, the explanatory examples in this guideline are taken
exclusively from the plant field.

Japan
In Japan, all food obtained from genetically modified organisms must undergo a risk
assessment by the "Food Safety Commission” and subsequently be approved by the
competent Ministry for Health (Ministry of Health, Labour & Welfare; risk management
body).

42
www.frli.gov.au/ComLaw/Legislation/ActCompilation1.nsf/0/0A2F6253DBF1CBE7CA257313000E8
674/$file/GeneTechnology2000_WD02.pdf
43
www.ogtr.gov.au/pubform/riskassessments.htm
44
In this context, risk analysis means the combination of risk assessment, risk management and
risk communication

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According to the competent authority45, special standards have been developed for the
risk assessment of genetically modified plants. In the meantime (June 2007), almost 80
genetically modified cultivated plants have been approved under these standards. On the
other hand, there are no separate guidelines or standards for transgenic animals, and up
till now there have been no applications for the approval of such; there have also been no
requests by scientific or private economy institutes. The authority is aware, however, that
numerous experimental projects of this type are carried out in Japan.

European countries
Most of the competent authorities surveyed in European Union countries have no national
regulations or recommendations with respect to genetically modified animals that go
beyond Directive 2001/18/EC and Regulation (EC) 1829/2003. The measures formulated
in Directive 2001/18/EC (see chapter 2.4.2) are mostly perceived to be sufficient for the
present (at least until such an application for approval must be processed for the first
time), some point to the anticipated guideline from the FAO/WHO Codex Alimentarius
Commission (see chapter 2.4.3) as a further important basis.

Germany points additionally to those criteria for risk assessment which are set out in the
German Statutory Regulation on the Safety of Genetic Engineering
(Gentechniksicherheitsverordnung). Annex 1 on “risk groups of donor and recipient
organisms/general criteria for the safety evaluation” contains criteria like

Information about the donor and recipient organism, e.g. type and characteristics of
the vectors contained, interaction with others and effects on other organisms in the
environment including anticipated competing or symbiotic characteristics

Description of the genetic modification, such as source of the genetic material,
methods used, stability of the organism in relation to the genetically modified traits

Health considerations, e.g. toxic or allergenic effects of the genetically modified
organisms and/or their metabolic products, product risks (not further specified),
possible pathogenicity

Environmental considerations, e.g. factors which influence the survival, the breeding
and the dispersal of the genetically modified organisms in the environment;
description of the ecosystems to which the organisms may be unintentionally
dispersed; known or foreseen effects on plants and animals
These rather general criteria may be able to provide a starting point as occasion arises,
but do not contain by any means all the necessary aspects and information required in
connection with the risk assessment of genetically modified animals.

In the Netherlands, every genetic modification of animals (including cloning) requires

special approval in advance from the Ministry of Agriculture, Nature and Food Quality.
These requirements, set out in the "Animal Health and Welfare Act”, also apply to all
research institutes. Every application is additionally subjected thereby to an ethical
evaluation, on the one hand in relation to the effects on the animal itself, on the other
hand in relation to the ethical evaluation of the objective of the intended modification
(see also the discussion in the excursus “Ethical Aspects”). These specific regulations
were introduced subsequent to the public debate concerning the genetically modified bull
“Hermann”. Authorisation is also necessary from the Minister of Housing, Spatial Planning
and the Environment, which in each case assesses possible adverse consequences for
humans and the environment. Up till the end of this study, no details on this specific
national risk assessment in the case of research projects were available in the English
language.

In Great Britain, the authority mainly responsible for health questions is the Health and
Safety Commission/The Health and Safety Executive. The HSE has developed jointly with
the “Scientific Advisory Committee on Genetic Modification” guidelines for projects using
genetically modified organisms, the fifth chapter of which deals with genetically modified

45
Dr. K. Fukushima, Office of International Food Safety, Ministry of Health, Labour & Welfare

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animals.46 It contains the information considered necessary by the authorities for a risk
assessment with a focus on “contained use” projects. Possible risks for the environment,
e.g. in the case of a transgenic animal escaping (availability of cross-breeding partners,
survival capability, potential for horizontal gene transfer, etc.), and for health of workers
are centred on – this necessitates, for example, an assessment of the allergenic or toxic
potential of an animal. Ultimately, a semi-quantitative assessment of the risk under
investigation must be made (severe, modest, minor, negligible).

In 2002, the Agriculture and Environment Biotechnology Commission issued a report

entitled “Animals and Biotechnology” on genetically modified animals. The AEBC
advocates that genetically modified, cloned and conventionally bred animals be handled
so far as possible within the same legal framework. In the field of animal protection,
legislative amendments are viewed as necessary in this respect. Because of the currently
inassessable risks in connection with the possible ecological effects of genetically
modified fish, it is recommended that these not be kept in open and/or coastal waters. As
customary in the English speaking countries, “public engagement”, i.e. public discussion
and the participation and involvement of all socially relevant stakeholders in the
discussion process, is accorded great importance.

46
The SACGM Compendium of Guidance:
www.hse.gov.uk/biosafety/gmo/acgm/acgmcomp/part5.pdf

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Excursus: ethical aspects

Ethical questions in connection with the genetic modification of animals shall be outlined
here in a short excursus. Accordingly, this is not an exhaustive representation of all
possible or usual arguments, the corresponding counter-arguments and the theoretical
foundations thereof47, but rather an overview of the discourse field with those of its main
ethical aspects associated with the subject of this study. This proceeds in principle from a
value system which – to greater or lesser degrees – does not call animal protection per se
into question.

Science ethics

Scientific and technological developments and changes bring in general, along with their
intended effects, also unintended effects/consequences, which may for instance be of a
social, ecological, economic or ethical nature. Scientific ethics is concerned in this
connection inter alia with the possible consequences of scientific activity or scientific
findings for society as a whole. It attempts thereby to define criteria and parameters for
the evaluation of new technologies (as result of a scientific development) or current
research (as institutional science) as ethically imperative, ethically desirable or ethically
objectionable. Equally, aspects such as the freedom and limits of research and their
implementation, questions of scientific responsibility or the value system this is founded
on and the “right thing to do” are discussed.48

The question of the potential risks posed by a technology or method is not an ethical
subject in itself, but rather more so is the question of its justification. The more severe
and long-lasting the extent of the interference, the more rapidly its justification is
questioned. Ethical concerns and arguments are always based on an individual or societal
value system. In this context, ethics is the culture-related, normative basis for human
action. A multidimensional interbraiding of current developments, opinions, values, fears
and perceptions exercises a subliminal influence thereby: a fast-growing basis of
knowledge with technological possibilities, the constant change resulting therefrom,
globalisation, the dominance of the economy and at the same time less state and
supposedly less regulative and/or public control; and correspondingly: diffuse unease,
scepticism, mistrust of public institutions, increasing significance of eco-topics, fair-trade
products and similar developments.49

In any case, a distinction must always be made between general scepticism and concerns
on the one hand, and concrete ethical questions on the other. Ethical aspects are very
diverse depending on the societal and cultural context, the arguments made are very
different and based inter alia on changing value systems. Which risk is justifiable in which
case and why? How can/must this be dealt with? Who bears the costs, who the risks, who
profits? What significance do the rights and interests of an individual have as opposed to
a society (or a social group)? An evaluation in the sense of “right” or “wrong” must be
decided by a society, sometimes as the occasion arises and time and time over anew.

47
There are numerous different ethical and ethical-philosophical approaches, e.g. theoretical
ethics, normative ethics or discourse ethics, utilitarianism or deontology and also different
interpretations of whether results or actions are subject to ethical examination. All these
theoretical approaches and strategies ultimately affect the formulation, evaluation and weighting of
ethical concerns, but shall however not be further dealt with here
48
Schicktanz 2000
49
McDonald 2000

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Animal ethics

In relation to the field of genetically modified animals, similar questions can be asked:
from an ethical point of view, what suffering, what harm is it reasonable to cause to
animals, is justifiable? What advantage balances what risk? Aspects of animal health and
species-appropriate husbandry as well as animal welfare considerations are the main and
at the same time the minimum criteria from the ethical perspective.

In general, it may be observed that the higher the animal is, i.e. the closer it is to
humans taxonomically speaking, the more critically work on the animal is viewed. Hence,
society grants the right to a greater degree of animal welfare measures more readily to
vertebrates for example (as opposed to say earthworms), as a capacity to suffer and
sensitive faculty are ascribed to vertebrates. In particular in Switzerland, a more
advanced approach is taken on this, centred on the term “the dignity of the creature”.
This calls for a definite rejection of anthropocentric animal protection, according to which
animals are only to be protected insofar as this benefits humans. “Dignity of the
creature” thus means protecting animals for their own sakes. Their worthiness for
protection does not depend thereby on their degree of proximity to humans but rather
consists in being and in being allowed to remain an animal of a particular type under
comprehensive consideration of their physical and psychological integrity.50
In this connection, the concept of an animal’s “telos” is also relevant; this is used in
particular in English language literature. The telos of an animal means its nature, its
being, its specific needs, wants and interests on the basis of its belonging to a particular
species – i.e. “the pigness of a pig, the dogness of a dog”. 51 Thus, this term concerns
much more than the absence of pain, it also concerns social aspects of animal husbandry
and the animal’s psychological capacity to suffer. This argumentation approach is of
particular significance in the context of the potentialities of genetic modifications, where
questions regarding the possible changing of the telos must be discussed.

Animal ethics & genetic engineering

The genetic modification of animals is either evaluated fundamentally sceptically to

negatively (intrinsic rejection) or on the basis of the consequences resulting specifically
from the technology (extrinsic rejection).52 In the case of intrinsically motivated rejection
there is little room for discussion; such can only be addressed with highly restrictive
legislation (should this be so desired).
As already mentioned, the Swiss standpoint is formulated fairly categorically:
“A normative limit must be applied to the technological dealings of humans with animals.
Dignity is indivisible. Genetic engineering procedures fundamentally violate dignity with
their specific deviation from natural living contexts and evolutionary laws”. The authors
base a call for a “general ban on the genetic manipulation of agricultural animals” on the
ethical concerns formulated.53 This approach puts the intrinsic value of the animal in the
foreground, regardless of its usefulness to humans.54

Ethically motivated questions arise from the above-mentioned concept of telos. Should
this be absolutely respected? May it be changed? If so, within what limits? To follow the
pathocentric approach, the development of transgenic animals which – e.g. in the case of
non-appropriate husbandry – no longer feel any suffering could be argued positively.
Suffering would be the sole ethically relevant criterion thereby; on the other hand, the
telos of the animal would be changed. Further arguments could be religiously motivated,
pick up on the unnaturalness of the genetic engineering procedures or the possible

50
Amman 1999
51
Thompson 2000, Straughan, Pew Initiative 2005
52
Straughan
53
Amman 1999
54
On possible deviations from this approach see further below in this chapter, details of the legal
regulation in Switzerland

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severity of the interference. Especial potential for conflict seems to arise when it is
necessary to decide between animal ethics and human health.

Spectrum of the arguments

The different critical ethical arguments and/or aspects invoked in connection with the
genetic modification of animals all lie within these poles. They are summarily represented
below without any kind of prioritisation or valuation.

Interference in divine order

Interference with natural conditions, because existing species boundaries are
overridden

Man forces what cannot come about through evolution

The speed in achieving breeding goals is outside that of evolutionary timeframes

Injury of the natural integrity, dignity, identity and telos of an individual

Evaluation of the possibility of adapting animals by genetic modification to breeding
and husbandry conditions which are not deemed species-appropriate, e.g. in order to
thus reduce susceptibility to stress or sickness; i.e. this would involve, on the one
hand, diminishing the capacity to suffer, on the other hand it would involve
interference in the telos and/or genetic integrity

Genetic engineering exchange of genetic information takes a purely utility-oriented
approach

Mechanistic or utilitarian approach in dealing with animals, increased
instrumentalisation

Twofold burden on transgenic animals through genetic modification on the one hand,
and existence as a laboratory animal for experiments on the other, i.e. there is more
(qualitative and/or quantitative) suffering than with conventional laboratory animals

Genetic modification causes numerous potentially detrimental side-effects, sometimes
unforeseeable damage

The crude inefficiency of the methods results in numerous “useless” animals (e.g.
because the transgene is not expressed at all or only very weakly), which are then
slaughtered

Unexpected suffering, deformations, pain, impaired health because of new,
sometimes strongly expressed genes, at times foreign to the species, because of
coincidental integration or pleiotropic effects; negative physiological condition,
independently of whether a genetic engineering procedure also has a phenotypic
effect

Genetic modification of animals to obtain pharmaceuticals increases the pressure on
animals to have longer lactation phases, thus they are milked more frequently and for
longer; this unnatural procedure causes additional pain

Specific argumentation in connection with such transgenic animals as are used in
basic research as so-called model animals, in order to deliberately develop specific
disease symptoms

Growing research possibilities resulting from genetic engineering lead to an increase
in the animals used in research

Question as to the ethical consequences in the case of potential restriction of a
technology which in the middle-term may potentially be able to reduce or prevent
human suffering

Transfer of pig genes, for instance, into specific food plants might result in food which
is forbidden or ought to be avoided by certain (not only religious) groups

Escape of transgenic animals into the environment or entry - unintentionally – into
the human food chain

Potentially possible reduction of the genetic pool

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Magnitude of the consequences, i.e. not only the consideration of the transgenic
animal itself but also the impairment of the surrogate mother animal and/or the
progeny

Each of the arguments cited here could be further differentiated and/or countered or
qualified. This would go beyond the scope of this excursus.

Country-specific

Ethical questions and arguments in connection with the genetic modification of animals
do not generally find expression in legal regulations, also not in the European
authorisation procedure for transgenic animals. In the Anglo-American countries and in
Switzerland there is a lively stream of publications on ethical matters in which
governmental bodies and similar are also involved. Some country-specific aspects as to
ethics are sketched out below.

As already mentioned in chapter 2.4.2, animal health and animal welfare are accorded a
special significance in Canada within the regulatory context, there must be a separate
risk assessment under the aspect of animal health. This does not consider ethical
evaluations for themselves alone but integrates them into the process as a whole.
McDonald calls for a further-reaching approach, ethical evaluations should not be one
aspect among others, but be seen as a complete appraisal in their own right: “It is itself
an “all-things-considered” judgement, which takes into account all relevant factors.”

In Great Britain, animal protection traditionally enjoys great importance. Various

national studies and reports consider the topic and regularly formulate calls for the
adaptation of legal regulations to take into consideration the requirements resulting from
the genetic modification of animals. “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.”55

Further information is available for the Netherlands. Pursuant to the Animal Health and
Welfare Act, every experiment with animals in connection with genetic engineering
methods must fulfil a catalogue of ethical criteria, whereby both a justification for the
project and the lack of suitable alternatives must be demonstrated. This applies both to
work on the animal itself as also to animal embryos. The competent Ministry56 may then
issue an approval when the project is not associated with any “inacceptable
consequences” for the health of the animal, when there are no further ethical concerns
and the possible benefit, e.g. for human health, is preponderant. The following criteria
are drawn on for the evaluation:57

The biotechnological project must be carried out for serious purposes

An alternative method must not be available

The biotechnological project must not adversely affect the animal’s health or welfare

The impact on the animal’s integrity must be ethically acceptable (Here a distinction
is made between impact on phenotype (i.e. appearance, behaviour and self-
sufficiency) and impact on genotype (genetic make-up)

Gains and importance of the project are balanced against the potential impact on the
animal’s health, welfare and integrity
It is also emphasised by the authority that there is no consensus on the meta-level in the
Netherlands as to what is ethically acceptable and what is not. This is decided on a case-
by-case basis.

Switzerland has extensive and also relatively specific requirements on animal

protection. The explicit recognition of the notion of “dignity of the creature” is anchored
in the Federal Constitution. This “ethics of co-createdness” means that animals are to be

55
Straughan
56
Ministry of Agriculture, SAEBC
57
e-Mail communication J.B.F.C. van den Assum

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protected for their own sakes, regardless of their proximity or use to man. In the Swiss
Gene Technology Law (GTG), the above constitutional provision finds expression in the
definition of animal dignity as a protection objective, which encompasses all animals, i.e.
agricultural animals as well as house pets and others. The question of whether genetic
modifications infringe the dignity of the creature must be decided on a case-by-case
basis. According to the Swiss GTG, the possible impairments of the animal must always
be weighed up against the described human interests worthy of protection – like human
and animal health, the securing of sufficient food, reduction of ecological damage,
augmentation of knowledge, etc. Transgenic animals with the exclusive object of
increased performance are clearly prohibited. The Ethics Committee for Animal
Experimentation has developed a guidance document “Ethische Güterabwägung bei
Tierversuchen” (ethical balancing of interests for animal experiments), which can be used
by researchers for critical self-assessment in relation to the weighing up of interests.

The European Union regulations on gene technology, especially Directive 2001/18/EC

and Regulation (EC) 1829/2003, do not contain any concrete criteria in connection with
animal protection or in relation to ethical questions. However, under article 29 of the
afore-mentioned Directive, there is a possibility to have ethical questions discussed by a
special committee. Provisions which deal with animal protection in general (e.g. Directive
86/609/EEC on the protection of animals used for experimental and other scientific
purposes) do not contain any criteria dealing with genetically modified animals and the
specific issues associated therewith. The Animal Health and Animal Welfare Panel
(AHAW), a scientific panel of the European Food Safety Authority (EFSA), is concerned
with animal protection, species-appropriate husbandry, specific slaughtering methods for
different species and similar issues, but explicitly excludes the handling of ethical aspects
in its work. The EU Community Action Plan on the Protection and Welfare of Animals
2006-201058 of January 2006 also deals with general animal welfare initiatives; it calls
for the reduction of animal testing as well as for the creation of alternatives thereto and
the upgrading of “existing minimum standards for animal protection and welfare [...] as
well as possibly elaborating specific minimum standards for species [...]” in line with new
scientific findings, but does not comment on ethical subjects.

The objectives defined in paragraph 1 of the Austrian Genetic Engineering Act59 (GTG)
do not mention ethical values explicitly, but line 5 of the principles listed in paragraph 3
does define an ethical principle: “[...] 5. In the case of genetic analyses and gene
therapies on humans, attention must be paid to the safeguarding of human dignity; the
responsibility of humans for animals, plants and ecosystems must be taken into account
(ethical principle).” This formulation allows the conclusion that animals – in particular
higher animals which can be expected to feel pain and have heightened powers of
perception – should at any rate be considered entitled to a species-appropriate existence
without the infliction of severe suffering.60 Finally, paragraph 63, social unsustainability,
should be mentioned. In this connection an “irreversible interference in [...] value
systems also with respect to other human and animal living creatures, etc.”61 can
constitute a so-called “unbalanced burden on society”, which in end effect could serve as
an argument for the social unsustainability of a product. In this context, it must be
pointed out that the provisions of paragraph 63 have never yet been applied since their
coming into effect in 1995.62

58
Communication of the Commission to the European Parliament and the Council
59
Federal Act, which regulates work on genetically modified organisms, the release and placing on
the market of genetically modified organisms and the use of gene analysis and gene therapy on
humans (Gene Technology Law – GTG) and changed the Product Liability Law; BGBl. 1994/510 in
the versions BGBl. I 1998/73, I 2001/98, I 2002/94, I 2004/73, I 2004/126 and I 2005/127
60
Kerschner, Lang 2007
61
Wagner 2007, p.229
62
ibid

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Résumé

In summary, it can be said that the ethical arguments and questions cited in connection
with the genetic modification of animals are not always specific to gene technology. That
means the perception and evaluation of such projects and developments often do not
differentiate between problems of conventional animal breeding, ethical questions
relating to experiments on animals in general, cloning on the one hand and specific
aspects of gene technology on the other. In relation to genetic engineering methods, it is
sometimes the process itself which takes centre stage (i.e. modifications of animals by
conventional methods would be acceptable) and/or the respective result striven for
and/or the associated speed en route to this objective. Concrete discussions should
therefore distinguish between specific features of genetic engineering procedures and
those of conventional practices and methods.

Animal protection as such has been on the agenda for decades, in particular in
connection with intensive farming and battery farming methods and the diseases
associated therewith, with modern animal breeding and with laboratory animals for
research. The most various studies and reports show that human dealings with
agricultural animals in the context of modern agriculture generally tend to create unease
and thus a need for discussion. Nevertheless, the general exploitation of animals by
human is seldom raised as a problem, rather the focus is always on specific applications,
like animal experiments in the cosmetics industry or indeed possible genetic engineering
modifications. In general, animal experiments, including genetic engineering
experiments, are the more easily accepted the more they have to do with medical
research and thus are potentially associated with human health.

The risk assessment of genetically modified animals or food products derived from them
is a process which is substantially based on scientific facts and/or findings. The topic of
the transgenic animal as a whole is, however, much farther-reaching. The societal need
for the discussion of ethical aspects and concerns should also be taken into account in
this connection; it should not be seen as a hindrance. Various food scandals, the
occurrences around the commercialisation of genetically modified plants and similar
happenings have sensitised the public in recent years and helped create a principle of
scepticism with regard to the scientific-political decision-making processes. General
societal discussions on ethical questions would also seem necessary if socially robust, i.e.
socially accepted, forms of application for genetic engineering on animals are to be found.

LIST OF REFERENCES
The references listed below are by no means exhaustive. They represent only those
studies, guidelines, etc., which were easily accessible during the course of the research in
connection with this study.

Agriculture and Environment Biotechnology Commission: Animals and Biotechnology;

AEBC, September 2002
www.aebc.gov.uk/aebc/pdf/animals_and_biotechnology_report.pdf

Ammann D., Goetschel A.F.: Die Verfassungsnorm der Würde der Kreatur. Konsequenzen
für die Zulassung genmanipulierter Tiere; Schweizerische Arbeitsgruppe Gentechnologie,
SAG – Studienpapier B2, Juli 1999
www.gentechnologie.ch/papiere/wuerde99.pdf (12.4.2007)

Amman D., Cimerman Z.: Bio- und Gentechnik an Tieren; Zürcher Tierschutz, Zürich
Februar 2007

Einsiedel E.F.: Public perceptions of transgenic animals; Rev. sci. tech. Off. Int. Epiz.,
Vol.24 (1), S.149-157, 2005

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European Food Safety Authority: Gutachten des wissenschaftlichen Gremiums für

Tiergesundheit und Tierschutz (AHAW) zur Biologie und zum Wohlergehen von Tieren, die
für Versuchszwecke und andere wissenschaftliche Zwecke verwendet werden; rev.
Version Jänner 2007
www.efsa.europa.eu/de/science/ahaw/ahaw_opinions.html

European Science Foundation: Use of animals in research; Policy Briefing, August 2001
www.esf.org

Kerschner F.: Kommentar zum Gentechnikgesetz; Wien 2007

McDonald M.: Biotechnology, ethics and government. A synthesis; The Canadian

Biotechnology Advisory Committee, Project steering committee on incorporating social
and ethical considerations into biotechnology, Ottawa October 2000
http://cbac-cccb.ca/epic/site/cbac-
cccb.nsf/vwapj/GovEthics_McDonald_e.pdf/$FILE/GovEthics_McDonald_e.pdf (17.7.2007)

Pew Initiative on Food and Biotechnology (Hg.): Exploring the moral and ethical aspects
of genetically engineered and cloned animals. Summary of a multi stakeholder workshop;
Rockville/Maryland 24.-26. Jänner 2005
http://pewagbiotech.org/events/0124/proceedings.pdf (25.5.2007)

Schicktanz S.: Ethik in den Wissenschaften. Wege der Urteilsbildung am Beispiel

„Transgene Tiere“; in: Hüsing B., Zimmer R., Schicktanz S.: Reproduktions- und
Gentechnik bei Tieren; Biotechnologie-Agentur Baden-Württemberg, Fraunhofer Institut
für Systemtechnik und Innovationsforschung, S.99-121, Karlsruhe September 2001

Sherwin S.: Towards an adequate ethical framework for setting biotechnology policy; The
Canadian Biotechnology Advisory Committee, Stewardship Standing Committee, Ottawa
January 2001 http://cbac-cccb.ca/epic/site/cbac-
cccb.nsf/vwapj/BioPolicy_Sherwin_e.pdf/$FILE/BioPolicy_Sherwin_e.pdf (17.7.2007)

Straughan R.: Ethics, morality and animal biotechnology; Biotechnology and Biological
Science Research Council, Swindon/UK o.J.
http://www.bbsrc.ac.uk/tools/download/ethics_animal_biotech/ethics_animal_biotech.pd
f (17.7.2007)

Thompson P.: Food and agricultural biotechnology: incorporating ethical considerations;

The Canadian Biotechnology Advisory Committee, Project steering committee on
incorporating social and ethical considerations into biotechnology, Ottawa October 2000
http://cbac-cccb.ca/epic/site/cbac-
cccb.nsf/vwapj/FoodAgric_Thompson.pdf/$FILE/FoodAgric_Thompson.pdf (17.7.2007)

Waßmuth R.: Literaturstudie zum aktuellen Stand der Anwendungen von Gentechnik und
Genanalytik in der Tierproduktion; Thüringer Landesanstalt für Landwirtschaft, Thüringer
Ministerium für Landwirtschaft, Naturschutz und Umwelt, Jena April 2006

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3 Transgenic animals. Examples

Countless articles in scientific literature report on new methods, findings and applications
concerning the genetic modification of animals. In fact, there is such an abundance of
publications that a complete overview of the status-quo or of the respective relevance of
the individual papers is hardly possible. Time and time again case-studies and possible
applications are announced and cited, are then suspended and later again revived
perhaps with new details and published anew. In the area of pharmaceuticals in
particular, which sees regular mergers, takeovers and corresponding renaming of
companies, it is practically impossible to discern any continuity in the various approaches
without continuous and detailed research. In order, nevertheless, to be able to create an
overview within the framework of this study, recourse was taken especially to reviews
and literature studies. According to Waßmuth, a complete overview would also require
research and analysis of the pertinent patent literature.

Animals have been used by people for agricultural and similar purposes for centuries, and
also continually developed by means of breeding. The objectives pursued thereby have
always been increased production, changes in proportion of meat or other desired
attributes. Since scientists first succeeded in genetically modifying the genetic makeup of
an animal (a mouse) in 1980, genetic engineering methods have also been used on
agricultural animals. Genetic engineering picks up directly from previous developments,
admittedly with entirely new possibilities. The objectives from the year 1990 for the
application of genetic engineering methods in animal breeding listed by Waßmuth in his
literature study in 2006 are more or less unchanged today and, moreover, little different
from those of conventional breeding. Central objectives are the improvement of synthetic
and productive capacity, acceleration of growth, better feed conversion ratio, decreased
emission of pollutants (e.g. less phosphorous in excretions), resistance to disease,
change in the agricultural end-products, production of pharmaceutically relevant
substances or adaptation to environmental conditions.

In spite of the already long-running and extensive work done, genetically modified
animals have up till now hardly attained readiness for the market. There are several
reasons for this, e.g. the limited fundamental knowledge about the relevant
biological/genetic processes and structures, the causes of which are especially constituted
in the considerably more complex, as compared to plants, biological backgrounds. Most of
the characteristics interesting in the context of agricultural animals are conditioned by
more than one gene, a further factor which makes concrete implementation more
difficult. Molecular mechanisms for the integration of new DNA sequences in mammalian
genomes are also still the object of ongoing intensive research. Just as problematic is the
attainment of stability in the expression of the gene and in the passing of such on to the
progeny (mostly different integration sites, i.e. each animal thus represents its own line).
And finally, the hitherto extremely low rate of success in the creation of transgenic
animals also plays a significant role, efficiency lies at a maximum of 2-3%. Therefore, the
development work is laborious and extremely costly; numerous projects on the
production of transgenic animals are currently directed in particular at the augmentation
of scientific knowledge and the development of efficient methods.

The following chapters contain a number of concrete examples from more recent
literature in the field of agricultural animals, applications with fish, on gene-pharming
and in relation to house pets. The lists and tables found in numerous publications shall
not be reproduced here, as these mostly just summarily compare possible application
areas and animal species used. Generally speaking, these do not enable any conclusions
to be drawn as regards concrete, actually current ongoing research and development
projects.

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3.1 Agricultural animals, fish

The specific objectives for agricultural animals encompass primarily general increase of
production (especially via additional genes for growth hormones), more targeted
selection, reduced resource-input and/or better feed conversion ratios, less
environmental pollution, resistance to diseases (inc. BSE, TSE, etc.) and to infections,
reduced fat content in meat and increased muscle mass (means higher meat content),
and the altered composition of food products such as milk, cheese or meat. Work is being
done on all agriculturally relevant animals, but cattle, pigs, chicken, sheep and fish take
centre stage.

3.1.1 Cattle
The first transgenic bull was “Herman”, who was developed by the enterprise Gene-
Pharming (the Netherlands, USA; today: Pharming). The original objective was cows that
produce human lacto-ferrin in their milk, which in turn was to be used as an additive in
baby food. Only one living animal developed from the genetically modified embryos, the
above-named bull.63 Herman was sexually mature in April 1992, artificial insemination
using his sperm was allowed from 1993. A total of eight female transgenic offspring were
born, five of these attained sexual maturity. However, these produced only small
amounts of human lacto-ferrin. In March 1996 these offspring of Herman in turn gave
birth to calves. From then on the scent seems to be lost; apparently no information about
the later years is available. According to an article in the magazine Science from the year
2002, the enterprise suspended the work around the mid 1990s.64

Lacto-ferrin plays a direct role in the field of food. The above-mentioned enterprise
Pharming continues to produce human lacto-ferrin obtained from the milk of transgenic
cows. This lacto-ferrin is used for its bioactive protective function (potential protection
against infections in the gastro-intestinal tract) for instance in the form of food
supplements (functional food)65 or as additives to infant food. Japan in particular is seen
as a promising market; bovine lacto-ferrin is currently widely used as an additive or food
supplement there. As the studies conducted by the enterprise showed no adverse effects,
no genotoxicity or allergenic potential, a so-called GRAS (Generally Recognized As Safe)
notification was delivered to the US Food and Drug Administration.

In general, resistance to diseases is a hotly pursued objective, as high costs are involved.
Work continues to be done on cattle with additional lacto-ferrin genes, both human and
bovine.66 The increased amount of lacto-ferrin is expected to strengthen the animal’s
general defence mechanisms against diseases – and thus also against mastitis. In 2005
there were reports on Jersey cows which exhibited resistance to mastitis because of a
gene from the bacteria staphylococcus simulans (related to the s. aureus which mostly
causes the infection) that codes for the protein lysostaphin. Nonetheless, these cows do
contract mastitis from other pathogens, e.g. e. coli or streptococcus uberis. As the
transgene is expressed in the milk, the scientists working on the project reckon with
serious reservations among the public should a commercialisation at some point be on
the table.67
Further work is being done on cows (and sheep) in connection with the prevention of
transmissible spongiform encephalopathies, like BSE and TSE, by inactivating specific
genes.

Numerous objectives are pursued in relation to milk: increased yield, less fat content,
less/no lactose, hypoallergenic milk (inactivation of the gene for beta-lactoglobulin),
increased proportion of unsaturated fatty acids, increased similarity to human breastmilk,

63
ILSI 1995, Selig 2004, Waßmuth 2006
64
Science 18 January 2002, Vol. 295. no. 5554, p.437
www.sciencemag.org/cgi/content/short/295/5554/437a
65
www.pharming.com/index.php?act=prod&pg=11, Waßmuth 2006
66
van Berkel 2002, Hyvönen 2006, Waßmuth 2006
67
Wall 2005, Rainard 2005

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faster coagulation for cheese production or increased casein content (to yield more
cheese from the same amount). Caseins, which constitute almost 80% of the milk
proteins, have a particularly central role.68 Cows with modified casein content can be
resistant to mastitis69; increased casein content means greater yields in cheese
production70; more κ-casein would mean finer emulsions and make processing easier;
more β-casein can increase the milk’s calcium content.71 The understanding of the
physiological factors and processes which ultimately regulate the amount of milk
produced within the animal in the mammary glands is still limited at present.72

The modification of milk quality has functioned hitherto above all in mice and has shown
unexpected adverse effects thereby. Lactose-reduced milk (α-lactalbumin) has been
tested in transgenic mice. Because of the increased viscosity of the milk, the mice were
no longer able to suckle their young.73 According to other publications, the development
of transgenic cows with an additional gene for β-casein or κ-casein was already
successfully accomplished in 2001/2002, the milk yielded by these cows did accordingly
have a greater content of the respective casein. The next challenges are seen to lie in
improving the efficiency of the production methods and strategies for the production of
an economically relevant, i.e. correspondingly large, herd.74

The Scottish Roslin-Institute does work on the genetic identification and utilisation of
agronomically relevant attributes in cattle within the framework of a long-term publicly
funded project.75

3.1.2 Pigs
The first genetically modified pigs were developed in the USA in 1988.76 As has often
been reported, these pigs with an additional gene for a growth hormone suffered from
numerous illnesses like arthritis, kidney failure and stomach ulcers, similar problems
were observed again and again in experiments into the late 1990s.77 The largely
unexpected side-effects were traced especially to the fact that under natural
circumstances the growth hormone was only produced during a particular, time-limited
development phase, but in the case of the transgenic pigs continually.

One combined goal is the increased efficiency in feed conversion ratios and at the same
time reduced environmental pollution. In Canada, transgenic pigs (EnviropigTM) with a
phytase gene originating from e. coli were developed to absorb and convert phosphorous
better from feed. 78 Currently, the phytase enzyme is generally added to pig-feeds.
Subsequently, this leads to a reduction in phosphate excretion of approx. 60-80% and
thus to diminished pollution of the environment by manure or dung; however, the
phytase activity decreased with the increasing age of the pigs. The pigs were developed
in collaboration between the University of Guelph/Toronto, the University of
Aarhus/Denmark and the MaRS Landing/Guelph (Consortium of the University of Guelph,
the City of Guelph and enterprises). Approval is being sought for Canada and eventually
the USA; because of the very extensive regulation in Canada (see also chap. 2.4.2) it is
impossible to estimate a possible time-frame at present.79 Carcasses of these transgenic
pigs ended up unintentionally in animal feed at the beginning of 2002. 11 piglets which

68
Brophy 2003
69
Kochhar 2005
70
Karatzas 1997
71
Pew Initiative 2004, Cummins 2006
72
Wheeler 2003
73
Niemann 2005
74
Brophy 2003
75
www.roslin.ac.uk/research/findingGenesTraitsCattle.php
76
ILSI 1995
77
Pursel 1997, Niemann 1998
78
Golovan 2001, Kochhar 2005, Pollack 2007
79
University of Guelph

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were either still-born or died directly after birth were deep-frozen for disposal by
incineration but inadvertently brought to the carcass processing plant.80

For some years there has been work in the USA on pigs that have a modified gene (fat-1
from the worm caenorhabditis elegans) for coding an n-3 fatty acid desaturase. This
results in an increased content of unsaturated fatty acids in the meat of these animals. In
particular the omega-3 fatty acids, which are found especially in fish under natural
circumstances, are deemed to have numerous beneficial effects on human health. Cloning
was commenced last year in order to be able to build up a commercially useful herd of
transgenic animals; this is currently still troubled by the familiar cloning problems.81

In 2002, the transgenic pigs developed at the Kinki University in Osaka/Japan were the
special subject of reports; the meat from these pigs contained about 20% more
unsaturated fatty acids. Their additional gene from the spinach plant codes for an
enzyme (desaturase) that spinach uses to convert saturated fatty acids to unsaturated
linoleic acid. The extremely low success rate, only every 100th piglet survived after birth,
was a problem.82 The current status-quo for the year 2007 is unclear.

Genetically modified pigs which express the gene for α-lactalbumin from cows were
successfully developed in 2002/2003.83 The animals were subsequently used especially in
model studies to improve understanding of the production and composition of milk
proteins.

Selig and Niemann84 report furthermore on pigs developed in Australia by the company
BresaGen with an additional gene for porcine growth hormone. Besides increased rate of
growth, this results in a better feed conversion ratio and a greater proportion of lean
meat, but without the previously observed pathological effects in the phenotype.
According to Niemann, these pigs are already ripe for the market; however, actually
marketing them has been postponed due to lack of acceptance by the public. Internet
research in this connection leaves some questions unanswered: BresaGen operates in the
meantime as Hospira's Adelaide and seems to be active exclusively in the pharmaceutical
field.85

3.1.3 Chickens
Lactose is under discussion as an additive to poultry feed, but cannot be processed, i.e.
metabolised, by these animals. Hence, chickens have been genetically modified to carry a
bacterial lacZ gene. Because of the enzyme this codes for, lactose can be converted to
glucose and galactose and thus may be used as an additional source of energy in feed.86
Corresponding feed experiments should ensue.
In their literature studies, Waßmuth and Amman cite altered meat composition and
general resistance to disease as further objectives in the genetic modification of chickens
but do not mention any specific research projects.87

3.1.4 Sheep88
Genetically modified sheep have been the object of work above all in Australia for about
the last 20 years, for example with an additional gene for a growth hormone.89 These
transgenic sheep were bigger, had leaner meat and faster growing hooves. Wool

80
Campaign for responsible transplantation: www.crt-online.org/20020219.html
81
Lai 2006
82
http://foodsafetynetwork.ca/agnet/2002/1-2002/agnet_january_24.htm, Niemann 2005,
Amman 2007
83
Wheeler 2003
84
Selig 2004, Niemann 2005
85
www.hospira.com/AboutHospira/default.aspx
86
Mozdziak 2003
87
Waßmuth 2006, Amman 2007
88
In the case of sheep, genetic engineering work is aimed especially at qualitative or quantitative
change in wool attributes
89
CSIRO 2003, Kochhar 2005

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production was either increased or decreased depending on the breed. The female
animals had longer lactation periods and produced twice as much milk.90
Here too, Waßmuth and Amman list altered meat composition and disease resistance as
further objectives, again without stating specific research projects.91 Kochhar mentions
experiments aimed towards achieving better feed conversion ratios.92

3.1.5 Fish
The current scientific developments and projects in connection with transgenic fish are
vast and in the meantime quite unsurveyable. Literature citations in this context fill
dozens of pages, and this in spite of the fact that not one of these fish has yet been
approved for food use. And nonetheless, the first food derived from genetically modified
animals will be from fish. Their reproductive biology is much simpler than that of
mammals, the methods are significantly more advanced.

All publications cite the fact that more than 30 different species are being worked on
worldwide at present, e.g. salmon, carp, trout, bass, flunder, pike, catfish, loach and cod
as well as on ornamental fish such as gold fish, zebra fish and spotted medaka. By far the
most work has been done on the Atlantic salmon and the rainbow trout, of this more than
50% concerns the integration of an additional growth hormone.93 The integration of
genes for growth hormones is tested, for example, also in carp, trout, tilapia and loach.94
Further objectives include tolerance to cold, resistance to disease, tolerance of noxious
substances, altered meat quality or changed fat content and deployment as indicator
organisms. According to Tappeser, the work on fish with an additional gene for a growth
hormone and the improvement of cold tolerance (by means of an anti-frost protein) are
furthest advanced.95 Disease resistance is striven towards, for instance, by a gene coding
for lysozym, such work is taking place on the Atlantic salmon.96

For a long time, mainly gene sequences or promoters (often viral) from mammals or
birds were used. Advances in scientific knowledge have since made original fish
sequences available; this enhances the efficiency of the methods, which is significantly
higher for fish than for agricultural animals.97

In this connection, the already much-cited transgenic Atlantic salmon from the US
American concern AquaBounty must be mentioned. This salmon, with an additional gene
for a growth hormone, grows 4-6 times faster than conventionally bred salmon, attains a
marketable size 2 times faster than conventional fish and converts feed better; this
results in 25 and 50% reductions in production costs. The stable integration of the
transgene took four generations.
Besides the increased growth rate, the transgenic salmon was observed to display raised
aggression potential, premature aging, increased oxygen requirements, more intensive
foraging and reduced “antipredator response”. Because of their more aggressive
behaviour and increased need for food, these fish are better predators, one potential
ecological effect would be the displacement of other populations from the traditional
feeding places. These effects arise especially during the juvenile phase, which is
simultaneously the stage at which wild types are most endangered. The consequences
are, according to AquaBounty, the necessary “critical control points” in the ecological risk
assessment, whereby stable physical confinement measures are nonetheless seen as
necessary.

90
CSIRO press release 22 November 2002
www.csiro.au/files/mediaRelease/mr2002/prgmsheep.htm
91
Waßmuth 2006, Amman 2007
92
Kochhar 2005
93
Maclean 2000, Devlin 2001, FAO/WHO 2003, Harper 2003
94
Cummins 2006
95
Tappeser 2000
96
WHO 2005
97
Houdebine 2005

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After a decade long development process, the transgenic salmon has been ripe for the
market for many years. AquaBounty has been engaged in the US Food and Drug
Administration approval procedure for foodstuffs for many years.98 According to current
information further (possibly conclusive) information is at present being compiled for the
US FDA, an approval might be possible in the second half of 2008. In this context it is
emphasised that the said process is by no means predictable, ultimately because of the
lack of official criteria and requirements.99
AquaBounty also did some work on a cold-tolerant fish (anti-freeze protein), however,
the result was a mere 2% increase in tolerance. This work was discontinued.

Besides fish there work is being done on other forms of seafood, e.g. crustaceans and
shellfish (e.g. mussels, oysters, shrimp, crabs, etc.). In these cases the embryonal stage
is particularly difficult to work on, the technologies are not so advanced and there is
hardly any information available. Due to the worldwide depleted numbers of such animals
this field is of great economic interest, the primary objectives here are also faster growth
and resistance to disease.

The greatest ecological concerns are voiced with respect to transgenic fish; in contrast to
agricultural animals these outweigh possible concerns regarding food security as in the
case of fish uncontrolled proliferation resulting from the escape of one single individual
from a breeding farm is very probable. The risk potential lies especially in the possible
proliferation in wild populations, in outcrossing, in possible fitness advantages (in
particular in the case of increased growth hormone) and thus in the potential
displacement of natural species. The superiority of the transgenic salmon with an
additional gene for growth hormone over wild-type populations in certain situations has
already been proven and the necessity for analysis of the “genotype-environment
interactions” has been emphasised in a risk assessment.100

Numerous effects resulting from the genetic modifications in fish are reported:101
pleiotropic and position effects, for instance abnormal gill growth (and consequent
increased oxygen uptake), missing body segments, atrophied neck and caudal parts,
skull malformations, tumours or altered fin and vertebrae and thus altered swimming
behaviour, altered feeding and social behaviour, etc. Equally, stability of the gene
expression with respect to enhanced growth has not yet been attained. Furthermore,
transgenic fish can be “mosaic”, i.e. not all the cells of such modified fish have actually
integrated the transgene. Moreover, there are reports of changed amounts or composition
of amino acids, cholesterol and protein, changed fat and water content in the meat and a
deterioration of swimming ability in the case of transgenic salmon. Possible effects on the
mating behaviour of the transgenic fish, their predatory and competitive behaviour or
eating behaviour must be considered. In the case of genetic modifications promoting cold
resistance, there is additionally the possible effect on ecosystems and their populations
because of the “new” species. Harper evaluates possible pleiotropic effects as operating in
several directions, i.e. not only negatively.102 The potentially higher survival rate and the
altered protein/fat ratio can be seen as positive.

In general, breeders try to counteract these risk potentials by using induced triploidy to
make the transgenic fish sterile, this however results in very various success rates
between 10 and 95%, and moreover impairs growth rates or shows other side-effects.103
Further possible alternatives would be diverse physical or chemical containment
measures.

98
Such a process is made more difficult by the lack of corresponding provisions on genetically
modified animals in the USA, see also chap. 2.4.1
99
e-Mail communication J. McConigle, Vice President External Affairs, AquaBounty, 5.9.2007
100
Devlin 2004, Devlin 2006
101
Maclean 2000, Tappeser 2000, OECD 2006, Devlin 2006
102
Harper 2003
103
Cummins 2002, Harper 2003

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Nonetheless, it must be emphasised in this connection that most of these risk potentials
have up till now merely been theoretically postulated on the basis of experiences with
other ecological occurrences, pertinent extensive scientific studies or findings are scarcely
available at present.104 Because of these imponderables, the British Royal Society calls
upon industry and government to impose a moratorium on the breeding of genetically
modified fish in marine enclosures, breeding should have to be in land-based facilities as
a condition for approval for commercial production.105

The relatively soon-to-be-expected approvals for transgenic fish for food use will likely
depend in part on the evaluation and/or clarification of these ecological problems.

3.2 Gene-pharming
Pharmaceutically/therapeutically relevant proteins are usually produced using bacterial
systems. These function in greater scales, but problems arise because of the different
prokaryotic post-translational modification processes or because of incorrect protein
folding. Similar problems arise when yeast cells or plants are used, the use of
mammalian cells is very limited because of the high costs involved in obtaining high
yields.

The objective of gene-pharming is to produce medicinally and therapeutically relevant

proteins, e.g. anti-thrombin, anti-trypsin, mono- and polyclonal antibodies, albumin,
globine (haemoglobin, myoglobin, neuroglobin), fibrinogen and lacto-ferrin, with the help
of transgenic animals and to harvest such from their milk, blood, urine or sperm.106
Because of the amounts which can be obtained and the existence of proven methods for
the extraction and purification of substances from milk, work centres on expression in the
mammary glands. According to Waßmuth, the production of medicines in the milk of
transgenic animals is being worked on especially in the USA, the Netherlands and
Scotland. Different animals are used depending on the quantity of the protein necessary,
e.g. cattle, goats, pigs, rabbits or hens.

Problems specific to gene-pharming include the possibility of animal-specific pathogens

or viruses being present in the milk and thus in the possible end-products. Often, the
new protein is not only formed in the target tissue but also in other sites in the animal
organism, moreover the expression level of the desired protein cannot be estimated
before the beginning of the lactation phase.

Numerous reviews describe the respective status quo of research and potential
commercialisations very generally, often – because of potentially confidential information
– without precise details, e.g. “more complex proteins, like erythropoietin or human
clotting factor VIII can already be produced in satisfactory quantities”, commercialisation
is imminent107 or “currently at least 33 different drugs in clinical trials”, some of these
already in the decisive last phase.108 Certain pharma concerns, such as Genzyme, PPL
Therapeutics, Pharming, Eli Lilly, Nexia, etc. are active in this area. Specific information
about their activities and the respective status quo is hard to obtain, some information is
accessible on their websites.109 It may be assumed that more data could be discovered by
researching the relevant patent literature, insofar as this is available.

104
Exceptions: Maclean 2000, Howard 2004
105
Royal Society UK 2001
106
This above all because of the significantly larger quantities possible in comparison to production
from cell cultures
107
Niemann 1998, Niemann 2005
108
Lonberg 2005
109
A comprehensive report from January 2006 can be obtained from the information service
Kalorama Information; this describes the current research and development work going on in
gene-pharming and includes extensive profiles of the relevant enterprises. It costs just under
$3,000 www.kaloramainformation.com/product/print/default.asp?productid=1186400

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In the following, some concrete examples from more recent literature shall be described
in greater detail.

3.2.1 Goats
In the summer of 2006, the European Commission approved the first medicine from a
transgenic animal:110 anti-thrombin III (ATryn), which is produced by GTC
Biotherapeutics from the milk of genetically modified goats. ATryn is used in surgical
procedures on hereditary antithrombin deficient patients, in order to prevent problems
resulting from the formation of blood clots in the blood vessels. The application for
approval was submitted in January 2004 and it first received a negative review in
February 2006 by the Committee for Medicinal Products for Human Use (CHMP) of the
European Medicines Agency (EMEA). The reason was, however, not the production
system via transgenic goats but the quality of the clinical studies, a particular critique-
point being that the samples used were too small. Furthermore, the production process in
the studies was criticised as deviating from the one which was intended for ultimate use
and apparently not enough immunobiological tests were performed. At the request of the
enterprise, further information was conveyed by GTC Biotherapeutics and additional
expert opinions obtained. This ultimately led to a positive evaluation.

According to the EMEA’s evaluation report111, the CHMP finally decided that the
advantages of ATryn outweigh the risks, and recommended issuing permission for placing
ATryn on the market. ATryn was approved under “exceptional circumstances”. This
means it was impossible to obtain full information about the medicine because of the
rarity of the disease. On 28 July 2006, the European Commission issued an approval for
placing ATryn on the market in the entire European Union.
Subsequently, negotiations were to be held in each of the Member States, with the
relevant health systems with respect to the financial conditions and then sales and
marketing established.112 The final introduction to the market was planned for the middle
of 2007.
The approval of a recombinant anti-thrombin from transgenic goats had been anticipated
by various publications since at least the year 2000.113

GTC Biotherapeutics is working on numerous other proteins from transgenic goats, e.g.
since 2008 on monoclonal antibodies like CD 20 (used in the therapy of B-cell non-
Hodgkin's lymphoma, B-cell leukaemia and rheumatoid arthritis). It is planned to take up
negotiations for approval with the US Food and Drug Administration from 2010.114

3.2.2 Chickens
In general, chickens are attractive production systems; breeding requires little space,
they have a similar glycolisation pattern to that of humans, there is no problem with
prions, and they grow fast and have short generation times and favourable production
quantities in their eggs.115 Because there are many years of experience in the production
of vaccines in eggs to look back on, eggs are a favoured production option for
pharmaceutically relevant substances. The genetic modification of chicken embryos is
complex, furthermore most chickens only express the new protein in some body cells
(mosaicism).116 More recent research strategies focus on embryonic chicken stem cells
and retroviral vectors.117

110
www.gtc-bio.com/pressreleases/pr022306.html, www.gtc-
bio.com/pressreleases/pr060206.html
111
Summary under www.emea.europa.eu/humandocs/PDFs/EPAR/atryn/058706de1.pdf
112
www.gtc-bio.com/pressreleases/pr080206.html
113
Ziomek 1998, Rudolph 1999, Das 2001
114
GTC Biotherapeutics: www.gtc-bio.com/science/production.html
115
Das 2001, Zhu 2005, Amman 2007
116
Yang 2000
117
Das 2001

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The US enterprise AviGenics Inc. is specialised in the manufacturing of recombinant

therapeutic substances from transgenic chickens, in particular because of the
glycolisation in chickens. The products include, e.g. cytokine, monoclonal antibodies and
fusion proteins, which are planned for use in treating cancer, certain infections and auto-
immune diseases. The clinical studies in phase 1 have been successfully completed for
two of the products, another is currently in phase 1 stage, two further in the development
stage. No more is specified about the particular products.118 By 2002, the stable
expression of β-lactamase in chicken albumin over several generations was successfully
accomplished.119

The production of antibodies in chicken albumin from transgenic chickens for use in
treating cancer or other diseases is the subject of multiple reports.120 Such proteins can
be produced via eggs in a tissue-specific fashion and in the relevant quantities.

3.2.3 Cattle
Research on cattle is complex and thus cost-intensive, moreover specific disadvantages
are seen in cattle as bioreactors in spite of the relatively high milk yield possible: the
effort involved in harvesting zygotes, generally just one calf per pregnancy, lower
pregnancy rates in transgenic cattle (in comparison to conventional cattle), longer time
interval before the first lactation (approx. three years), lower integration rate in
comparison to other animal species.121
Human polyclonal antibodies have been produced in the blood of transgenic and cloned
cattle, which have an integrated “human artificial chromosome”.122 The possible use
spectrum of antibodies reaches for instance from the treatment of specific infections or
cancer, over their use in organ transplantation up to the treatment of autoimmune
disease. Such applications give rise to specific problems due to the interactions of human
antibodies with those of the cattle, for example the possible formation of chimeric
antibodies. In this field as in many other cases, cloning has been used for the rapid
proliferation of animals that have integrated the transgene stably.
The US American enterprise Hematech is working on the production of polyclonal
antibodies from cattle whose own immune system has been shut down.123

Cloned transgenic cattle also produce a recombinant bi-specific antibody which is

intended for use inter alia in cancer therapy (T cell mediated tumour cell killing).124 It
was possible reliably to harvest the antibody from sperm and purify it and test its
activity. It is planned to continue processing the antibody and to submit it for trials in
clinical studies. The same experiments were also performed on rabbits.

3.2.4 Other animals

Pigs
Work is being done on expressing human protein C125 (hinders excessive blood clotting)
and human haemoglobin126 in the blood of transgenic pigs. The latter is, however, not
absolutely identical in function with human haemoglobin. Moreover, only some of the
cells contained and expressed the transgene.
The first transgenic pig that expressed a human protein in its milk was developed in the
mid 1990’s after about 10 years of research.127

118
AviGenics Inc.: www.avigenics.com/index.html
119
Harvey 2002
120
Roslin Institute: www.roslin.ac.uk/research/geneticmodification.php, Zhu 2005
121
Waßmuth 2006
122
Echelard 2002
123
Pew Initiative 2004
124
Grosse-Hovest 2004
125
Cummins 2006
126
Niemann 2005
127
Velander 1997

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Sheep
In the late 1980’s, sheep were the first transgenic animals to express a human
recombinant protein in their milk, the blood clotting factor IX, since then there have
regularly been similar reports.128 The “descendants“ of Dolly, the first animal cloned from
an adult cell, who were developed in 1997, also expressed factor IX in their milk.
α1-anti-trypsin from genetically modified sheep was already in Phase II clinical studies in
1999. 129

Rabbits
In the 1990’s, rabbits were regularly declared to be suitable production systems for
pharmaceutically relevant substances, the advantage being their high and rapid rate of
reproduction. Since then, reports have become scanty. Pharming, a Dutch enterprise, is
currently working on the production of recombinant human-C1-inhibitor in transgenic
rabbits.130 The product is currently in Phase III clinical studies. However, there were
already reports of the forthcoming application for approval in the USA in 2005. 131
Further approaches with rabbits aim, for instance, at the production of vaccines.
Transgenic rabbits can express two recombinant proteins from rota-viruses in their milk,
such can be used for the treatment of viral gastroenteritis in young children.132

3.3 House pets

Genetically modified pets have become topical only in more recent years, in particular in
the USA and Asian countries. At present there are only isolated examples in practice, the
first transgenic pet is an ornamental fish.

3.3.1 Ornamental fish

Asia

Transgenic zebra danio fish (danio rerio) were originally developed for scientific purposes
in the late 1990’s at the National University of Singapore, Department of Biological
Sciences (working group led by Dr. Zhiyuan Gong), as this fish’s rapid development from
egg to larva stage made them suitable as model animals in developmental biology. The
fish were equipped with a green fluorescent protein (GFP) from a type of jellyfish so that
it was easier to observe the development of their internal organs. In a next step, these
transgenic zebra fish were further developed as pollution indicators for heavy metal or
oestrogens: “Such fluorescent-coloured transgenic fish will be able to respond to the
presence of chemicals like oestrogen through the estrogenic promoter and heavy metals
and toxins through the stress-responsive promoter. The fish will immediately display the
colour depending on the type of environment the colour has been specified for. Although
only red and green colours have been produced in the zebra fish, A/P Gong revealed that
he could add up to as many as five colours to the zebra fish, each colour to indicate a
different pollutant. In using such transgenic fish, pollutants can be detected with one
quick look. The fish are also biodegradable and economical to breed. All these factors
make them very suitable pollutant indicators.”133 Work is being done on further
fluorescent types, e.g. carp or goldfish which inter alia could be used as water
temperature indicators.

Subsequently, a fluorescent teleost medaka (oryzias latipes) was developed in Taiwan,

moreover the Taikong Corp., Taiwan’s biggest producer and dealer of aquarium fish,
started marketing the transgenic aquarium fish. Depending on the source, the Taikong

128
Velander 1997, Breekveldt 1998, Rudolph 1999
129
Rudolph 1999
130
Pharming: www.pharming.com/index.php?act=prod&pg=1&more=true (14.8.2007)
131
Niemann 2005
132
Soler 2005
133
National University of Singapore: www.nus.edu.sg/corporate/research/gallery/research12.htm

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Corp enters into an appropriate contract with the University of Singapore or that of
Taiwan, so as to be able to market the transgenic fish through their daughter enterprise
azoo. Since the spring of 2003, TK-1134, a form of the Japanese medaka (oryzias latipes)
and TK-2, zebra danio fish (danio rerio), have been officially available from azoo in the
fluorescent colours green, red, purple and golden. According to an entry in Wikipedia,
approximately 100,000 fish were sold in less than one month at a price per head of about
$18.60.

Taikong has its own research and development department for the development and
breeding of new fish species, new genetically modified variants are being developed
continually:
”Fluorescent Fish has become the representative of Taikong's achievement of Bio-
Technologies. Since the first Fully-Fluorescent Transgenic fish announced in 2001, there
are 10 more new species Fluorescent Fish be announced continuously. In 2005, Taikong
will announce 5 new species Fluorescent Fish at the same time. They are TK1 diamond
series ¡V Emerald night Pearl, Ruby night Pearl, Golden Night pearl and TK2 Platinum
series ¡V Platinum red Leopard and Platinum green Leopard.”135

According to Amman’s 2007 report, the transgenic aquarium fish which have been
available in Taiwan since 2003 are sold under the name “Night Pearls”. They were also
exported to Singapore and Japan, this has since been suspended because of persistent
protests by environmental organisations and the fish have thus become a popular form of
contraband.

USA, Canada, Australia

These transgenic zebra fish have been on the market in the USA136 since the beginning of
January 2004 under the trading name “GloFish® Fluorescent Fish”; the Texan enterprise
Yorktown Technologies has contracted with the National University Singapore to operate
as an importer. In the meantime, the enterprise has developed numerous own (patented)
breeds with the corresponding coral genes from the progeny of the Asian transgenic fish,
these are sold as Starfire Red™, Electric Green™ and Sunburst Orange™.137
Investigations of possible adverse effects on the environment and on wild populations as
well as consultations with diverse US authorities preceded the launch onto the market
according to information on the enterprise’s own website. Ultimately, the genetically
modified breeds are legally available in pet shops in spite of the lack of any actual
approval or official risk assessment. Both the Environmental Protection Agency (EPA) and
the Department of Agriculture (USDA) as well as the Food and Drug Administration (FDA)
declared themselves not to be responsible for a corresponding application by Yorktown
Technologies or declared that they did not see any need for regulatory action.138 The
FDA’s original opinion of 9 December 2003 is posted on the website
“FDA Statement Regarding Glofish: Because tropical aquarium fish are not used for food
purposes, they pose no threat to the food supply. There is no evidence that these
genetically engineered zebra danio fish pose any more threat to the environment than
their unmodified counterparts which have long been widely sold in the United States. In
the absence of a clear risk to the public health, the FDA finds no reason to regulate these
particular fish.” 139 By its own account, Yorktown Technologies is not currently planning to
extend the sale of its transgenic aquarium fish to other countries.

In Canada, the transgenic aquarium fish require approval inc. prior risk assessment
pursuant to the “Environmental Protection Act”, at present no such approval has been
issued.

134
The letters TK stand for Taikong Corp.
135
azoo: www.azoo.com.tw/azoo_en/azoohtml/about.htm
136
Except in California where the sale and possession of all transgenic fish is currently prohibited
137
Yorktown Technologies www.glofish.com
138
Nature Biotechnology 2004
139
US Food and Drug Administration: www.fda.gov/bbs/topics/NEWS/2003/NEW00994.html

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In May 2007, Yorktown Technologies submitted an application for the import and sale of
three variations of these transgenic fluorescent zebra danio fish (danio rerio). In a
preliminary opinion the Australian authorities come to the conclusion that the fish
probably pose no risks to human health or to the environment, the procedure was,
however, still ongoing in September 2007.140 According to the application documents,
GlofishTM is already being sold in Trinidad and Tobago, Mexico and the Dominican
Republic.

European Union

Transgenic aquarium fish have been found in pet shops in European Union countries since
the summer of 2006; according to various sources in Rouen, Paris, the Netherlands and
in Germany.

In early November 2006, about 1,400 transgenic fluorescent aquarium fish were found in
pet shops in Utrecht/the Netherlands.141 According to a statement by the competent
Netherlands authority, the Ministry of Housing, Spatial Planning and the Environment
(VROM), these were variants of the Asian “Night Pearls” which had been developed in a
fish farm in Malaysia and imported over a dealer in Singapore. Up to this point in time,
400 of the over 1,400 imported transgenic aquarium fish had already been sold. The
remaining unsold fish and those which were returned were sent back to the exporter in
Singapore according to the Netherlands authority.

According to information from the French Agriculture Ministry, transgenic aquarium fish
were also found in France in May 2006; these were destroyed.

In February 2007, transgenic aquarium fish (zebra danio fish) were found in a pet shop in
Kiel/Germany.142 According to the competent authority, these were imports from Poland,
possible trade routes were analysed in order to prevent further imports. Furthermore,
zebra danio fish (danio rerio, under the name “Baerbling Gold”) with striking red
colouring were discovered in a routine inspection by the state veterinary inspection office
in Bavaria.143 According to the Bavarian authority, these transgenic fluorescent fish came
from the Czech Republic and were withdrawn from the market as a result of not having
an approval pursuant to EU law. Under EU law, these transgenic aquarium fish require
authorisation under Directive 2001/18/EC for import, sale and possession and are,
therefore, illegal in the pet market.

Ecological aspects

The potential influence of such transgenic aquarium fish on existing wild populations if
they escape (e.g. over disposal routes like being released in outside bodies of water,
being flushed down the lavatory, etc.) is cited in particular as a possible detrimental
ecological effect. As there has not yet been any official procedure of risk assessment or
anything of the kind in connection with these fish, recourse must mostly be made to the
publications made available by the developing and distributing enterprises and
institutions.

140
Office of the Gene Regulator: www.ogtr.gov.au/ir/dir072.htm
141
VROM, Netherlands Ministry of Housing, Spatial Planning and the Environment:
www.vrom.nl/pagina.html?id=25069
142
Spiegel magazine: www.spiegel.de/wissenschaft/mensch/0,1518,472468,00.html and the
Ministry for Agriculture, Environment and Rural Areas Schleswig-Holstein: www.schleswig-
holstein.de/MLUR/DE/Service/Presse/PI/2007/MLUR__070224__Zierfische.html
143
Bavarian Regional Authority for Health and Food Safety:
www.lgl.bayern.de/gesundheit/zierfische.htm

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Yorktown Technologies makes the following statement in this context: “Stringent testing
will be performed before any fish is made available to the public, with specific emphasis
placed on analyzing growth rates, temperature sensitivities, and mating success. Any line
of fluorescent fish demonstrating increased strengths or successes in these areas relative
to non-fluorescent fish of the same species, or otherwise displaying any characteristic
that poses an environment concern, will not be offered for sale.”144 Both Taikong Corp.
and Yorktown Technologies allege on their websites that all these aquarium fish are
sterile and that hence a proliferation of the transgene in wild populations is not possible.
The British Ornamental Aquatic Trade Association (OATA) 145, a trade group for importers,
breeders and dealers expresses doubt, however, as to whether the sterility functions
100% (as has already been the issue with triploid salmon). The OATA has issued its own
statement in relation to genetically modified aquarium fish in which it calls the
development of transgenic aquarium fish “unwelcome” and declares the range of
aquarium fish naturally available to be sufficient. With respect to possible ecological
effects, it remarks that consequences in this regard should not be detrimental in theory,
at most cold-tolerant tropical fish might pose a problem.146 All in all, both the OATA and
the Netherlands authority are of the opinion that these aquarium fish probably have no
adverse effect on the environment or on human health.

Since zebra danio fish are tropical fish that require temperatures between approx. 16 and
31°C, their survival chances in European winters are estimated to be quite minimal. The
mild winters, especially in Southern Europe, possible results of the climate change and
the good adaptability of these aquarium fish may yet show this estimate to be hasty. An
adapted, newly established fish population would have effects on the predator-prey-
relation, on the food sources available, etc. Furthermore, the question of a potentially
possible passing on of the transgene to wild populations and the resulting consequences
must be asked. A letter from Dr. W. Muir to the CEO of Yorktown Technologies
establishes, as expected, no potential for the passing on of the transgene (“[…] GFP has a
significant net fitness disadvantage, indicating that one would expect natural selection to
eliminate the transgene regardless of where it escaped or was released.”147).

Moreover, comparatively little literature is available on specific questions in connection

with these genetically modified fish, for example the question of any “fitness advantage”
or the effects of fluorescence on hunting or mating behaviour. Zhiyuan Gong, who
developed the first fluorescent aquarium fish in Singapore declares that these fish would
have no reproductive advantage over wild-living fish of the same species, their
fluorescence would probably even be disadvantageous.148 A further publication149 deals
with the question of predator-prey behaviour in connection with red, fluorescent zebra
fish. According to this, the striking colouring has neither an aposematic (warning signal)
effect nor is it particularly attractive in comparison to wild type zebra danio fish. Both are
hunted to the same extent by the relevant predators (here certain types of bass),
predator-prey behaviour is not impacted according to the results of these laboratory
experiments.

3.3.2 Cats
The first genetically modified cats were supposed to come onto the US market in early
2007. Allerca, part of the US American enterprise LIFESTYLE PETS Inc., did work on the
development of a transgenic, sterile cat with a suppressed Fel d1 gene. This gene codes
for a glycoprotein produced in the sebaceous glands, which is considered to be the main
allergen in connection with so-called cat allergies. This protein is distributed all over the
animal’s fur via the saliva. According to Amman,150 animal welfare campaigners and

144
Yorktown Technologies: www.glofish.com
145
Ornamental Aquatic Trade Association: www.ornamentalfish.org/aquanautstatement/gmfish.php
146
OATA: www.ornamentalfish.org/site/about.php
147
http://www.glofish.com/science/Muir%20Analysis%20of%20Fluorescent%20Zebra%20Fish.pdf
148
National University of Singapore: www.nus.edu.sg/corporate/research/gallery/research12.htm
149
Cortemeglia 2006
150
Amman 2007

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veterinarians increasingly criticised this project, alleging it was harmful for the animals’
health and ultimately not destined to be effective, as other cat proteins also trigger
allergy.

In 2006, Allerca developed an alternative strategy. Cats with natural genetic variants of
the Fel d1 gene were further developed by selective breeding into the currently available
hypoallergenic cat, which is not genetically modified. This has a variant of the protein
Fel-d1 with smaller molecular weight, which is harmless to allergy sufferers. The price for
one of these hypoallergenic, castrated cats is US $ 5,950. The demand in the USA is so
great that as of 1.9.2007 no further orders will be taken for a period of 12 months.151
The positive reports on Allerca’s website are contrasted by very different stories.
Extremely critical articles from the San Diego Union Tribune in the year 2006 can be
found under www.signonsandiego.com/uniontrib/20061028/news_1b28brodie.html and
www.signonsandiego.com/news/metro/20060716-9999-1n16allerca.html. These report
on possible criminal activities in particular in connection with financial issues of the
Allerca’s founder; the scientific basis of the work on hypoallergenic cats is also called into
question.

3.3.3 Other kinds of animal

During the course of the research, only a single reference in relation to other transgenic
house pets was found. An article in the Washington Post of 13.3.2004, which treats the
placing on the market of the above-mentioned GloFish into the US market, quotes
Barbara Glenn, Managing Director for animal biotechnology at the industry group
Biotechnology Industry Organization (BIO), as follows: “Other possible creations include
a dog that isn't as susceptible to hip dysplasia, an ailment common among German
shepherds and Labrador retrievers that's associated with over-breeding.”152 Allerca, the
US enterprise that developed the above-mentioned hypoallergenic cats, responds to
numerous requests with the following statement on its homepage: “Because there are
many more allergy causing proteins that are associated with dogs than with cats, we do
not have any plans at this time to breed hypoallergenic dogs (puppies).”153
As of August 2007, the state of affairs is nonetheless that in the USA not one single
transgenic animal has been officially approved. Within the framework of this study it
must ultimately remain unclear whether any enterprises, and if so which, are actually
working on such a project.

151
www.allerca.com/html/pricingreserve.html 20.8.2007
152
Witte 2004
153
www.allerca.com/html/sb/kb.html, 20.8.2007

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4 Conclusions
Risk assessment

Descriptions of the general principles of risk assessment and specific criteria with respect
to genetically modified plants are plentiful in international literature. Concrete
recommendations, guidelines, published articles, etc. referring to genetically modified
animals are only sparsely available up till now.

First, the regulatory frameworks analysed in chapter 2 are summarised as follows with
respect to the risk assessment of transgenic animals and derived food products:

Directive 2001/18/EC is directed very comprehensively at the compilation of possible
parameters in risk assessment with respect to environmental effects. Animal health
plays no role here, likewise animal protection aspects

Regulation (EC) 1829/2003 prescribes general principles and protection objectives to
be fulfilled, with respect to parameters required in the environmental field it points to
the above Directive. However, specific criteria for risk assessment in relation to food
safety are missing. Animal protection and/or ethical aspects are not mentioned.

Like no other of the instruments analysed, the FAO/WHO Codex “Proposed draft
guideline for the conduct of food safety assessment of foods derived from
recombinant DNA animals” differentiates between the different animals that are used
or created in the course of the process and thus provides by far the most extensive
list of criteria in this respect. This increases the scope of the information to be
submitted and thus the probability of being able to assess possible risks. However,
only a few requirements are formulated as regards actual food.

Nothing is stated as to whether this guideline ought also to be applied to those
transgenic animals which are not intended for food use. Hence, this is left up to the
discretion of national states. The Royal Society Canada pleads for just as rigorous a
risk assessment for transgenic animals and derived products intended for non-food
purposes as for those intended for food purposes.

Canada has developed altogether very detailed regulations for the production,
approval and import of transgenic animals and the products derived therefrom.
Detailed guidelines and/or requirements exist or are being worked on both for the risk
assessment in relation to environmental effects and for those in the area of food
safety. The status accorded to animal welfare and animal health within the regulatory
context is a special feature of the Canadian system in comparison to others. These
aspects are not found at either the level of the European Union or in the Draft
Guideline of the Codex Alimentarius Commission.

Australia also has documents on the risk assessment of transgenic animals, both in
relation to environmental effects and with reference to food safety. Ethical aspects are
not explicitly covered thereby.

At present it is completely unclear where developments in the USA and within the
competent authority, the Food and Drug Administration (US FDA), are leading.

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Theoretical Areas covered Principles Applicability to

protection transgenic
objectives animals
Directive environment, environment, case-by-case; + environment
2001/18/EG human health human health in precautionary (+/) - food
part principle
Regulation environment, human health case-by-case; +/- food
(EG) human health, principle of (specification
1829/2003 animal health, substantial necessary)
consumer equivalence
interests
FAO/WHO human health, food safety case-by-case; + food
Propsed animal health principle of
draft substantial
Guideline equivalence
Canada environment, environment, case-by-case; + environment
human health, animal health, principle of +/- food
animal health human health in substantial guideline being
part equivalence; developed
precautionary
principle
Australia environment, environment, case-by-case; + environment
human health, human health, principle of + food
food safety food safety substantial (specification in
equivalence; relation to
uncertainty animals would be
helpful)
Argentina environment, case-by-case; + environment
animal health food safety
unclear

It must be stressed that as yet not one of the instruments analysed in chapter 2 has been
applied in realita to the risk assessment of a genetically modified animal or a derived
food product.154 Thus, there are currently no concrete examples for any actual, finished
risk assessment process for transgenic animals in relation to possible environmental risks
or risks to human health.155 As mentioned in chapter 3.3.1, the transgenic GloFishTM is
presently undergoing the approval process for placing on the market in Australia.

None of the regulatory instruments contains decision trees or like aids for the decision-
finding procedure within the framework of the risk assessment. The question arises as to
whether such uniquely effective criteria can be defined at all in these cases. In most
cases, extensive lists were developed of criteria, which ought to be considered in the
context of the risk assessment or in the subsequent application for approval. The
European Union Regulation 1829/2003 on genetically modified food and feed, which does
not define any specific criteria in relation to the demonstration of food safety is an
exception, it must be demonstrated that there are no “adverse effects on human health,
animal health or the environment”. The individual regulations state that the respective
lists must be applied on a case-by-case basis (i.e. may contain too many or too few
details).

It must be remarked in this context that the examples cited to provide concretization in
the individual instruments derive almost exclusively from the field of transgenic plants.

154
“The challenge is to see whether the existing regulatory model will work […]”, Kochhar 2005
155
Apart from the opinions which have been issued – as required – before the beginning of
experimental work in closed systems

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The focus of this study is genetically modified animals that can be used for food
production or for the manufacture of pharmaceuticals or as pets. Defining or developing a
comprehensive guideline including concrete delimitations regarding transgenic animals
would far exceed the scope of this paper. Nonetheless, this report does summarise for the
first time the main parameters in the risk assessment of transgenic animals and derived
food products. The principles of risk assessment (hazard identification) described here
derive from a synopsis of the assessment of diverse authorities, surveyed scientists and
enterprises, comparative analyses of the existing regulatory instruments, scientific
literature and similar analyses of the risk assessment of genetically modified plants. They
are by no means exhaustive, but serve the definition of the scope as well as the
identification of such points where there is need for further definition and specification in
relation to transgenic animals.

Human health can be negatively affected by the quality of food per se and also indirectly
as a result of environmental effects. The basis for the risk assessment of all applications
mentioned in this paper is the comprehensive description and/or assessment of the
transgenic animal, including the genetic modification thereof. The main criteria for this
include – this is by no means an exhaustive list – descriptions of:

Donor animal (e.g. name, taxonomic data, degree of relatedness between donor and
recipient organisms, pathogenicity, toxicity, allergenicity, previous use as food)

As applicable other sources of the transgene or synthetic sequence

Recipient organism before the genetic modification e.g. name, taxonomic data,
toxicity, allergenicity, previous use as food, etc.

Analysis of the genetic modification:

Molecular characterisation of the construct to be transferred, primary nucleic acid
sequence

Description/characterisation and origin of the vector; viral elements are often used
especially for the development of transgenic animals, it must be clarified whether this
is associated with any specific risk potential

Details of marker genes used

Methods used for the transfer

Details on the protein that is intended to express, e.g. biochemical characterisation,
function, toxic or eco-toxic potential, allergenic potential

Description of the transgenic animal (GMA):

Molecular description of the sequence actually integrated

Insertion site/s plus respective number of copies, identification of the flanking regions
and possible open reading frames

Potential position effects, e.g. activation or inactivation of existing gene sequences,
possible consequences thereof

Analysis/description of the product expressed

Expression pattern, expression site and level, in particular details of expression in
those tissues/organs which later serve as food, details on where any expression that
was unexpected because of the functionality of the promoter nonetheless occurred

The existence or expression pattern of marker genes

Stability of the organism in relation to the new genetic traits, details on stable
inheritance of the transgene

Phenotype, e.g. evaluation of growth rate, morphology, behaviour, aggression
potential, feeding and mating behaviour, etc.

Health of the GMA on the basis of yet to be specified parameters (clinical,
immunological; these are not even specified in the comprehensive FAO/WHO Draft
Guideline)

Pathogenicity; endogenous retroviral activation

Assessment of possible unintended effects, e.g. changes in metabolism resulting from
the expression of a new protein or because of significantly higher amounts of a
hormone, expression of chimeric proteins, etc.

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Within the framework of discussion for the development of the FAO/WHO “Proposed draft
guideline for the conduct of food safety assessment of foods derived from recombinant
DNA animals” on the risk assessment of transgenic animals in the food area (see chapter
2.3.2), it has been shown that there is broad consensus that no metabolites toxic to
humans are formed in the animal organism in general and that in all probability no “silent
pathways” exist whereby toxins are intrinsically produced.156 The literature on the subject
contains no references to concrete toxic danger potentials, however the assessment of
such is repeatedly called for.

In order to be able to assess possible effects on the environment, also in relation to

genetically modified pets, inter alia the following information on the transgenic animal is
necessary:

Possible fitness and/or selection advantage, survival ability, reproductive behaviour,
feeding behaviour, influence of the predator-prey-relation resulting from the genetic
modification

Cross-breeding partners

Habitats

Possible effects on wild populations and/or non-target organisms

Invasivity and persistence, i.e. establishment of the genetically modified type
(dependent on escape and fitness) in the respective ecosystem

Possible horizontal gene transfer to other animals or humans

Possible adverse effects which might result from excretions/faeces or out of the
cadaver of the GMO

Discussion is necessary on whether specific, defined parameters are necessary for fish
because of their particular ecological danger potential

At present there is little concern about the possible negative ecological effects of
transgenic animals. Transgenic animals for pharmaceutical production are generally only
kept in containment conditions. In the case of agricultural animals kept in normal
conditions, escape is rather unlikely; moreover these do not reproduce in an unbridled
fashion, as do plants for instance. The resultant risk depends on the number of the
escaped animals, their mobility and the cross-breeding partners from wild populations
available in the respective ecosystem. Fish are certainly very problematic in this context,
possibly also smaller animals like poultry or rabbits. In such cases the possible ecological
concerns may be greater than those regarding food safety.

The requirements for an assessment of the “delayed environmental impact of the direct
and indirect interactions between the GMO and target organisms (if applicable)” set out
by Directive 2001/18/EC (Annex II D.1) must be specified in connection with genetically
modified animals.

In relation to the assessment of food safety, the general approach is that a healthy
animal very probably yields safe food/-products.157 Together with the application of the
principle of substantial equivalence, this often means that there are only a few criteria for
the evaluation of the food itself. Besides the above-mentioned description of the
genetically modified animal (GMA) and its health, the following further parameters inter
alia are relevant for the assessment of food safety:

Description of the method for obtaining the food/-product from the GMA, for example,
the development of further breeding lines, cross-breeding partners, etc.

Possible allergenic potential of the food, i.e. the assessment of the allergenic potential
of the transgene product (not via a similar syntheticised protein) and possible further
allergens

Assessment of potential toxicity; it must still be discussed which concrete
delimitations would make sense for animal products; see on this the remarks above
regarding toxic metabolites in animals

156
e-Mail communication Dr. M.L. Houdebine, INRA
157
For example in the USFDA, FAO/WHO

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Existence of new or differently expressed proteins in the animal organism and similar,
e.g. growth hormone, vector remnants, remnants of nucleic acids, resistance to
antibiotics, etc.158

Analysis and description of the possible consequences of established unintended
effects at the genetic level on the quality and/or composition of the foodstuff, e.g.
other metabolites, changed concentrations, other/more antinutritiva, etc.

Analysis of the ingredients and/or of main macro and micro-nutrients, minerals,
vitamins and other relevant parameters; see also the remark below in this respect

Changes in the nutritional value and/or content of antinutritiva, possibly details on
amount of consumption or the role of the conventional food in the nourishment of the
respective population

Further discussion of the following relevant questions on the assessment of food safety is
necessary:

Feed conversion studies are not relevant in connection with foodstuffs from animals.
Thus, it must be established what tests might alternatively be necessary.

Definition of parameters for the conventional counterparts suitable for comparison
with transgenic animals, e.g. on the basis of comparable breeding conditions (the
extent of comparability must also be defined), feedstuff, age, body weight, gender,
etc.

Complex food/-products like meat or milk are quite variable in their composition, this
depends heavily on the environment, feedstuffs, breeding conditions and similar
parameters

Thus, within the framework of an analysis of the ingredients, concrete authoritative
parameters must be precisely defined for the individual complex food products, like
meat or milk. Not least in order to be able to further develop the much-criticised
principle of substantial equivalence

In conclusion, the extent of scientific uncertainty and the resultant, potential

consequences must be described within the framework of these assessments. The
precautionary principle should be applied according to the Canadian model, especially in
the case of potentially severe consequences combined with large uncertainty.

Transgenic animals. Example applications

It became apparent that in purely quantitative terms significantly more research trials on
the genetic modification of animals are in progress than was assumed when the study
was begun. In fact, there is such an abundance of publications available that a complete
overview of the fast changing, world-wide activities and/or their respective relevance is
hardly possible any more. Time and time again, case-studies and possible applications
are announced and cited, only to disappear again. Reports like this one can – rather like
a spotlight – light up specific segments, hence the results of diverse studies tend to
complement each other and overlap only in the most seldom of cases.

Genetic modifications of animals have been topical since the 1980’s; research on and use
of genetic methods in the field of agricultural animals or pets is performed on every
major animal species with manifold conceivable goals. But gene transfer methods are still
inefficient, the mostly coincidental integration or interaction of the transgene with the
rest of the genome is still not understood in terms of its processes and consequences.

Significantly more work is being done on the development and production of

pharmaceuticals than for food purposes, where the initial euphoria seems to have worn
off, as the coding genes for the characteristics of interest are obviously difficult to make
available. Thus, transgenic agricultural animals are used at present in particular as model
animals for the purposes of research or methods development. Work on genetically

158
According to Waßmuth there has not y been a conclusive evaluation of the nutritively
conditioned cross-over of foreign DNA into internal organs

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 Conclusions

modified pets has already crossed the threshold to commercialisation in the field of fish,
which are popular above all in Asia. Concrete examples are described in detail in chapter
3.

Deliberate releases

Only one authority, in Argentina, reported on concrete experience with the experimental
release of transgenic animals. These cases involved genetically modified cattle (four
animals) and sheep, which express pharmaceutical proteins (human and bovine growth
hormone as well as modified human insulin) in their milk. It was not possible to establish
conclusively whether these animals were kept outdoors, “release of transgenic animals at
the stage of research or experimentation under strictly confined conditions.” Further
applications are being processed.

The oft-cited transgenic salmon of the US American company AquaBounty can only be
placed in outside bodies of water after the issuance of a permit from the FDA.

According to several other authorities, experiments and projects with and on genetically
modified animals have only taken place under “contained use”, i.e. in closed systems,
e.g. in Great Britain159 or Germany.
There were some references to experiments “under field conditions” registered pursuant
to Art. 11 Directive 2001/18/EC. These concerned animals on which genetically produced
vaccine was being tested and genetically modified mice and rats as environmental
indicators.

Commercialisation

The estimates in scientific publications on when we can expect the commercialisation of

transgenic animals and/or their by-products differ from those of the public authorities
respondent in this study. Whereas among scientists it is usually assumed that
commercial use must be expected soon, representatives of public authorities expect the
first applications in five years at the earliest, on average in 7-10 years. In this
connection, it is often emphasised that tenable estimates are extremely difficult to make
because of the manifold and dynamic developments. Usually it is expected that the first
approvals will be in the USA and South America.

It may be assumed that commercialisations in the field of gene pharming will come
significantly earlier than in the field of food. In particular among scientists, estimates are
optimistic in this context and speak of imminent commercialisation and/or significant
commercialisation within the next five years. Recombinant pharma products from
genetically modified animals are also more probable than the corresponding foodstuffs
because the development costs for a transgenic animal are extremely high and must thus
be linked to the relevant economic perspectives (return on investment).160 This is easier
to secure in the pharmaceutical field, where in addition critical public discussions are
hardly to be expected. Effects of a presently indeterminable nature in this area may be
possible due to developments in the production of pharmaceuticals in genetically
modified plants.

In this connection, the first approval granted for a pharmaceutical substance from a
transgenic animal (a goat) by the European Medicines Agency (EMEA) is pointed out (see
chapter 3.2.1).

In the field of food, significantly longer time-frames are estimated, based inter alia on
the potential lack of acceptance by consumers. The necessary scientific-technical

159
Whether genetically modified sheep, which according to an email source are kept outside in
Scotland, are really included could not be verified by the end of the study
160
For example about US $ 500,000 for the development of a transgenic calf; Yang 2000

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principles and methods come up against – constantly changing – limits. Research and
development on agricultural animals are scarcely carried out in private enterprises due to
the enormous costs associated, but instead mainly in universities and “governmental
research labs”. Success is most likely to be adjudged to those animals which are
genetically modified in such a way as to have positive effects on the environment; for
example those pigs which have significantly lower amounts of phosphate in their
excretions (see chapter 3.1.2). Genetic modifications of this type are significantly easier
to carry out on the scientific-technical level and could encounter less resistance from the
public because of their potential benefits for the environment.

The approval of genetically modified fish is expected relatively soon. The US American
company Aqua Bounty’s transgenic salmon has already been many years in the approval
process in the USA. According to current information,161 further (possibly conclusive)
information and data is being compiled for the competent authorities, the US FDA, and
should be delivered by the end of 2007. It is scarcely possible for the enterprise to assess
whether it will be possible to obtain an approval during the course of 2008 as the
authority has no official catalogue of criteria or specific regulations.

In summary, it may in end effect be assumed that the prospective approval of the
transgenic salmon and the EMEA’s first approval of a pharmaceutical (anti-thrombin)
from a transgenic goat will have considerable significance for future developments, as
through this the further possible economic potential of genetically modified animals and
their by-products can really be exploited. Furthermore, the numerous ongoing scientific
projects worldwide mean corresponding advances, e.g. with respect to the greater
efficiency of the technologies, can be anticipated. The continuing decoding of animal
genomes in particular paves the way for possible further developments. The first
available genome maps, from the year 2004, were those of the cow and the chicken,
currently work is being done inter alia on pigs, sheep and goats. And finally, cases like
that of the transgenic ornamental fish which is already officially available in Asian
countries and in the USA and was also found illegally in several European pet stores,
show that transgenic animals are slowly becoming established outside of the field of
research too.

In view of these developments, we may assume that genetically modified animals and/or
their by-products – at least in the area of gene pharming, as well as fish and possibly
pigs in the food field and also pets – will be a topic for regulatory and approval
authorities in any case within the next five years.

Conclusion and need for further action

The risk assessment of genetically modified plants has long been intensively discussed,
there are numerous models and approaches and just as much criticism and suggestion
for improvements. As regards the risk assessment of genetically modified animals,
however, this report is one of the first outlines of the problem with a synoptic description
of all relevant aspects and instruments as well as identified need for action.

In the course of the research, it was possible to establish that both in international
organisations (OECD, APEC, ILSI, OIE) and in the most various authorities in the
European Union states, the risk assessment of genetically modified animals is not yet
accorded any great significance, regardless of the advances recorded in the meantime in
science and application. Moreover, in comparison with the extent of the ongoing
research, there is all in all a spectacular lack of publications or studies on the risks
connected with genetically modified animals. The numerous publications brought out on
work with and on transgenic animals hardly report at all on side-effects and/or any
unintended effects which arose. The majority of the publications which occupy
themselves with such risks do this on a purely theoretical level and/or in a derivative

161
e-Mail communication J. McGonigle/AquaBounty, 5.9.2007

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 Conclusions

fashion based on the experiences with and findings on genetically modified plants. As yet
there is hardly any practical experience with the existing regulatory instruments.

Numerous provisions apply to the field of risk assessment of transgenic animals in

relation to the environment, Directive 2001/18/EC offers a good basis here, see also the
need for action formulated below. The risk assessment of genetically modified animals
per se should find sufficient criteria here too. The initiative of the FAO/WHO Codex
Alimentarius Ad Hoc Intergovernmental Task Force on Foods derived from Biotechnology
is of special significance for risk assessment in relation to food safety in spite of its
deficits, as it is one of the first comprehensive instruments in the field of food safety. In
this context, the deficits identified in relation to food safety and genetically modified
animals in Regulation EC 1829/2003 are pointed out again, see also in this regard the
need for action formulated below.

Measures should be taken in time to prevent a development like that in the case of
genetically modified plants, where the marketability of the GMO ensued considerably
earlier than the issue was dealt with on a regulatory level. As this experience showed, it
is quite difficult to adapt or supplement existing approval practices in retrospect. The
requirements for the risk assessment of genetically modified animals and/or derived food
products defined in this study are by no means exhaustive but rather serve the definition
of the scope and the identification of those points where there is need for further
definition and specification in relation to transgenic animals.

Accordingly, it may be remarked in the present context, that the Austrian Ministry for
Health, Family and Youth has shown great foresight in commissioning this study.

Hence, open questions and topics requiring further discussion and more detailed analysis
are hereby presented in conclusion:

The risk assessment of genetically modified animals, in particular their by-products in

the field of food, definitely requires specification at European Union level. Guidelines
for example would be conceivable (e.g. a guidance document, development of a
decision tree) to concretise the existing legal framework, i.e. Directive 2001/18/EC, in
particular its Annex IIIA as well as Regulation (EC) 1829/2003 in relation to more
precise requirements for the risk assessment of transgenic animals. Such should
define concrete parameters and delimitations in relation to food safety.

In this context, parameters should also be defined, for example, for the conventional
counterparts suitable for comparison with transgenic animals or the specific
parameters to be applied when it comes to the analysis of ingredients of individual
complex food products, e.g. meat or milk.

This should definitely be called for in discussions at European and international levels,
in order to set corresponding actions in motion.

Tackling the topic of risk assessment of cloned animals162 is considered just as
important. The questions arising from the cloning will be partly identical with those
discussed in this report; but they will also bring their own specific problems. Cloned
animals and their by-products are at present not subject to any regulatory
instrument. If they are also genetically modified they fall within the scope of the
above-described gene technology regulations, which however, do not necessarily
cover the specific risk aspects potentially arising from the process of the cloning. In
general, products from cloned animals (transgene or not) are already anticipated
within the next few years.

162
Animal cloning is especially topical in connection with scientifically or economically relevant
transgenic animals, pets (in particular demand in Asian countries and to some extent in the USA)
and sport animals. Cloning is used as the main means of reproduction for some specific genetically
valuable transgenic animals

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 Conclusions

Dealing with this topic seems all the more imperative since the European Commission
– as a result of the report by the US Food and Drug Administration on the safety of
foodstuffs from cloned products – requested an opinion from the European Food
Safety Authority (EFSA) in March 2007 on the possible “implications of animal cloning
for food safety, animal health & welfare and the environment”. Besides questions of
safety, possible regulation of this food stuff should also be discussed. The EFSA
working group “Animal Cloning” plans to complete and publish a first draft opinion by
December 2007, to then undergo public appraisal and discussion.163

Possibilities for public dialogue, for broad discussions of aspects like ethics and/or
animal protection in connection with genetically modified animals, should be
considered.

Non-heritable constructs (NHC): a risk assessment of animals or their derived
products, which have been administered recombinant nucleic acid products in somatic
cells and/or tissue seems equally imperative in the future. It seems quite unlikely that
the risks and questions in the context of such a risk assessment would be significantly
different from those treated here. The problem consists particularly in the fact that
these applications are currently not subject to any regulatory system and thus
possible risks associated therewith are not assessed. Questions associated with DNA
vaccines in particular ought to be discussed, as was emphasised by the FAO/WHO
Expert consultation. Further questions arise inter alia because of the potential for
horizontal gene transfer (depending on whether the recombinant DNA-construct is
integrated in the genome of the recipient animal or simply episomally present), there
are questions as to the persistence of the DNA, whereabouts ultimately in the animal
product, consequences for food safety and human health.

Finally, relevant risk management questions and potentially necessary risk-
minimisation measures in connection with transgenic animals and/or derived products
must be identified and various possible scopes for action and action strategies must
be developed.

163
http://www.efsa.europa.eu/EFSA/DocumentSet/stakeholders_kleineronclonin_en,0.pdf
(26.11.2007)

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 Annexes

Annexes

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 Annex I

Annex I, FAO/WHO Draft Guideline for the conduct of

food safety assessment of foods derived from
recombinant DNA animals
FAO/WHO Codex Alimentarius Commission: Report of the seventh session of the
Codex ad hoc Intergovernmental Task Force on foods derived from biotechnology;
ALINORM 08/31/34, Appendix II, Oktober 2007

PROPOSED DRAFT GUIDELINE FOR THE CONDUCT OF FOOD SAFETY

ASSESSMENT OF FOODS DERIVED FROM RECOMBINANT-DNA ANIMALS (At Step
5/8 of the Procedure)

SECTION 1 — SCOPE
1. This Guideline supports the Principles for the Risk Analysis of Foods Derived from
Modern Biotechnology. It addresses safety and nutritional aspects of foods consisting of,
or derived from, animals that have a history of safe use as sources of food, and that have
been modified by modern biotechnology to exhibit new or altered expression of traits.164

2. The development, raising and use of animals for human purposes, and in particular,
for use for food, raise a variety of issues beyond food safety. Without prejudice to their
legitimacy or importance, or to whether or how the use of recombinant-DNA methods in
developing animals for food use might affect those issues, this Guideline addresses only
food safety and nutritional issues. It therefore does not address:
• animal welfare;
• ethical, moral and socio-economical aspects;
• environmental risks related to the environmental release of recombinant-DNA animals
used in foodproduction;
• the safety of recombinant-DNA animals used as feed, or the safety of animals fed with
feed derived from recombinant-DNA animals, plants and microorganisms.
3. The Codex principles of risk analysis, particularly those for risk assessment, are
primarily intended to apply to discrete chemical entities such as food additives and
pesticide residues, or a specific chemical or microbial contaminant that have identifiable
hazards and risks; they are not intended to apply to whole foods as such. Indeed, few
foods, whatever their origin, have been assessed scientifically in a manner that would
fully characterize all risk associated with the food. Further, many foods contain
substances that would likely be found harmful if subjected to conventional approaches to
safety testing. Thus, a more focused approach is required where the safety of a whole
food is being considered.

4. This approach is based on the principle that the safety of foods derived from new
animal lines, including recombinant-DNA animals, is assessed relative to the conventional
counterpart having a history of safe use, taking into account both intended and
unintended effects. Rather than trying to identify every hazard associated with a
particular food, the intention is to identify new or altered hazards relative to the
conventional counterpart.

5. This safety assessment approach falls within the risk assessment framework as
discussed in Section 3 of the Principles for the Risk Analysis of Foods Derived from
Modern Biotechnology. If a new or altered hazard, nutritional or other food safety concern
is identified by the safety assessment, the risk associated with it would first be assessed
to determine its relevance to human health. Following the safety assessment and, if
necessary, further risk assessment, the food would be subjected to risk management
considerations in accordance with the Principles for the Risk Analysis of Foods Derived
from Modern Biotechnology before it is considered for commercial distribution.

164
This Guideline was developed primarily for animals bearing heritable recombinant-DNA
constructs.

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 Annex I

6. Risk management measures such as post-market monitoring of consumer health

effects may assist the risk assessment process. These are discussed in paragraph 20 of
the Principles for the Risk Analysis of Foods Derived from Modern Biotechnology.

7. The Guideline describes the recommended approach for the food safety assessment of
foods derived from recombinant-DNA animals where a conventional counterpart exists,
and identifies the data and information that are generally applicable to making such
assessments.165 In assessing the safety of food from recombinant-DNA animals, the
approach should take into account all of the following:
A) the nature of the recombinant-DNA construct and its expression product(s), if any;
B) the health status of the recombinant-DNA animal; and
C) the composition of foods produced from recombinant-DNA animals, including key
nutrients.
While this Guideline is designed for foods derived from recombinant-DNA animals, the
approach described could, in general, be applied to foods derived from animals that have
been altered by other techniques.166

8. A diverse range of animals are used as food or for food production (e.g. mammals,
birds, finfish and shellfish) and may be modified using in vitro nucleic acid techniques.
Because of the combined impacts of their genetic diversity, husbandry, and conditions
under which they are raised or harvested, assessment of food safety must be considered
on a case-by-case basis, with due regard to the framework presented in this
Guideline.

SECTION 2 — DEFINITIONS
9. The definitions below apply to this Guideline:
“Recombinant-DNA Animal” — an animal in which the genetic material has been
changed through in vitro nucleic acid techniques, including recombinant
deoxyribonucleic acid (DNA) and direct injection of nucleic acid into cells or
organelles.

“Conventional Counterpart” — an animal breed with a known history of safe use as

food from which the recombinant-DNA animal line was derived, as well as the
breeding partners used in generating the animals ultimately used as food, and/or food
derived from such animals167.

SECTION 3 — INTRODUCTION TO FOOD SAFETY ASSESSMENT

10. Traditionally, food products derived from animals developed through conventional
breeding or obtained from wild species have not been systematically subjected to
extensive chemical, toxicological, or nutritional evaluation prior to marketing. Thus,
although new breeds of animals are often evaluated by breeders for phenotypic
characteristics they are not subjected to the rigorous and extensive food safety testing
procedures, including validated toxicity studies in test animals, that are typical of
chemicals such as food additives or contaminants that may be present in food. Instead,

165
The approach to the safety assessment of foods derived from recombinant-DNA animals was
first discussed at the 1991 Joint FAO/WHO Consultation on Strategies for Assessing the Safety of
Foods Produced by Biotechnology. Further elaboration of the recommended approach was
undertaken at the 2003 Joint FAO/WHO Expert Consultation on the Safety Assessment of Foods
Derived from Genetically Modified Animals, Including Fish.
166
The food safety assessment of foods derived from animals bearing non-heritable constructs may
require additional specific consideration, e.g. regarding hazards identified in the 2007 Joint
FAO/WHO Expert Consultation on the Safety Assessment of Foods Derived from Recombinant-DNA
Animals.
167
It is recognized that for the foreseeable future, foods derived from modern biotechnology will
not be used as conventional counterparts.

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food derived from an animal of known and acceptable health status has generally been
considered suitable for human consumption.

11. The use of animal models for assessing toxicological endpoints is a major element in
the risk assessment of many compounds, such as pesticides. In most cases, however, the
substance to be tested is well characterized, of known purity, of no particular nutritional
value, and human exposure to it is generally low. It is therefore relatively straightforward
to feed such compounds to test animals at a range of doses some several orders of
magnitude greater than the expected human exposure levels, in order to identify any
potential adverse health effects of importance to humans. In this way, it is possible in
most cases, to estimate levels of exposure at which adverse effects are not observed and
to set safe intake levels by the application of appropriate safety factors.

12. Studies using test animals cannot readily be applied to testing the risks associated
with whole foods, which are complex mixtures of compounds, and often characterized by
a wide variation in composition and nutritional value. Due to their bulk and effect on
satiety, they can usually only be fed to test animals at low multiples of the amounts that
might be present in the human diet. In addition, a key factor to consider in conducting
animal studies on foods is the nutritional value and balance of the diets used, in order to
avoid the induction of adverse effects that are not related directly to the material itself.
Detecting any potential adverse effects and relating these conclusively to an individual
characteristic of the food can therefore be extremely difficult. If the characterization of
the food indicates that the available data are insufficient for a thorough safety
assessment, properly designed studies using test animals could be requested on the
whole food. Another consideration in deciding the need for studies with test animals is
whether it is appropriate to subject test animals to such a study if it is unlikely to give
rise to meaningful information.

13. Due to the difficulties of applying traditional toxicological testing and risk assessment
procedures to whole foods, and based on the experience of assessing the safety of whole
foods, a more focused approach is required for the safety assessment of food derived
from animals, including recombinant-DNA animals. This has been addressed by the
development of a multidisciplinary approach for assessing safety, which takes into
account both intended and unintended changes that may occur in the animal or in the
food products derived from it, using the concept of substantial equivalence.

14. The concept of substantial equivalence is a key step in the safety assessment
process. However, it is not a safety assessment in itself; rather it represents the starting
point, which is used to structure the safety assessment of a new food relative to its
conventional counterpart. This concept is used to identify similarities and differences
between the new food relative to its conventional counterpart168,169. It aids in the
dentification of potential food safety and nutritional issues and is considered the most
appropriate strategy to date for safety assessment of foods derived from recombinant-
DNA animals. The safety assessment carried out in this way does not imply absolute
safety of the new product; rather, it focuses on assessing the safety of any identified
differences so that the safety of the new product can be considered relative to its
conventional counterpart.

UNINTENDED EFFECTS
15. In achieving the objective of conferring a specific trait (intended effect) to an animal
by the insertion of defined DNA sequences, additional traits could, in some cases, be
acquired or existing traits could be lost or modified (unintended effects). The potential
occurrence of unintended effects is not restricted to the use of in vitro nucleic acid

168
The concept of substantial equivalence as described in the report of the 2000 joint FAO/WHO
expert consultations (Document WHO/SDE/PHE/FOS/00.6, WHO, Geneva, 2000).
169
The concept of substantial equivalence was further considered in the context of comparative
safety assessment at the FAO/WHO expert consultation on the Safety Assessment of Foods Derived
from Genetically Modified Animals, Including Fish, 2003.

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techniques. Rather, it is an inherent and general phenomenon that can also occur in
conventional breeding as well in association with the use of assisted reproductive
technologies currently in use. Unintended effects may be deleterious, beneficial, or
neutral with respect to the health of the animal or the safety of the foods derived from
the animal. Unintended effects in recombinant-DNA animal may also arise through the
insertion of DNA sequences and/or they may arise through subsequent conventional
breeding of the recombinant-DNA animal. Safety assessment should include data and
information to reduce the possibility that a food derived from a recombinant-DNA animal
would have an unexpected, adverse effect on human health.

16. Unintended effects can result from the random insertion of DNA sequences into the
animal genome,
which may cause disruption or silencing of existing genes, activation of silent genes, or
modifications in the expression of existing genes. Unintended effects may also result in
the formation of new or changed patterns of metabolites.

17. Unintended effects due to in vitro nucleic acid techniques may be subdivided into two
groups: those that are “predictable” and those that are “unexpected”. Many unintended
effects are largely predictable based on knowledge of the inserted trait and its metabolic
connections or of the site of insertion. As knowledge of animal genomes grows, and
familiarity with in vitro nucleic acid techniques increases, it may become easier to predict
unintended effects of a particular modification. For example, homologous recombination,
where appropriate, allows precise gene placement and so may reduce the occurrence of
unintended effects associated with random integration. Molecular biological and
biochemical techniques can also be used to analyse changes that occur at the level of
transcription and translation that could lead to unintended effects. These should all be
considered on a case-by-case basis.

18. The safety assessment of food derived from recombinant-DNA animals involves
methods to identify and detect such unintended effects and procedures to evaluate their
biological relevance and potential impact on food safety. A variety of data and
information are necessary to assess unintended effects, because no individual test can
detect all possible unintended effects or identify, with certainty, those relevant to human
health. These data and information, when considered in total, provide assurance that the
food is unlikely to have an adverse effect on human health. The assessment of
unintended effects takes into account the phenotypic characteristics of the animal that
are typically monitored by breeders during animal production stock development and
improvement. These assessments provide a first screen for recombinant-DNA animals
exhibiting unintended traits. Recombinant-DNA animals that pass this screen are
subjected to safety assessment as described in Sections 4 and 5.

FRAMEWORK OF FOOD SAFETY ASSESSMENT

19. The safety assessment follows a stepwise process of addressing relevant factors that
include:
A) General description of the recombinant-DNA animal;
B) Description of the recipient animal prior to the modification170 and its use as food or
for food production;
C) Description of the donor organism or other source(s) of the introduced recombinant-
DNA;
D) Description of the genetic modification(s) including the construct(s) used to introduce
the recombinant-DNA;
E) Description of the methods used to produce the initial recombinant-DNA animal171,172
and the processes to produce the recombinant-DNA animal ultimately used as food or
for food production;

170
Not to be confused with a surrogate dam.
171
First animal produced as a result of introducing the recombinant-DNA construct.
172
Sometimes referred to as the founder animal.

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F) Characterization of the genetic modification(s) in the recombinant-DNA animal

ultimately used as food or for food production;
G) Safety assessment:
a. Health status of the recombinant-DNA animal;
b. Expressed substances (non-nucleic acid substances);
c. Compositional analyses of key components;
d. Food storage and processing; and
e. Intended nutritional modification;
H) Other considerations.

20. In certain cases, the characteristics of the food may necessitate additional data and
information to address issues that are unique to the product under review.

21. Experiments intended to develop data for safety assessment should be designed and
conducted in accordance with sound scientific concepts and principles, as well as, where
appropriate, Good Laboratory Practice. Primary data should be made available to
regulatory authorities at request. Data should be obtained using sound scientific methods
and analysed using appropriate statistical techniques. Analytical methods should be
documented.173

22. The goal of each safety assessment is to provide assurance, in the light of the best
available scientific knowledge, that the food does not cause harm when prepared, used
and/or eaten according to its intended use. Safety assessments should address the health
aspects for the whole population, including immunocompromised individuals, infants, the
elderly and individuals with food hypersensitivities. The expected endpoint of such an
assessment will be a conclusion regarding whether the new food is as safe as the
conventional counterpart taking into account dietary impact of any changes in nutritional
content or value. In essence, therefore, the outcome of the safety assessment process is
to define the product under consideration in such a way as to enable risk managers to
determine whether any measures are needed to protect the health of consumers and if so
to make well-informed and appropriate decisions in this regard.

SECTION 4 — GENERAL CONSIDERATIONS

GENERAL DESCRIPTION OF THE RECOMBINANT-DNA ANIMAL

23. A description of the recombinant-DNA animal being presented for safety assessment
should be provided. This description should identify the introduced recombinant-DNA, the
method by which the recombinant-DNA is introduced to the recipient animal and the
recombinant-DNA animal ultimately used as food or for food production, as well as the
purpose of the modification. The potential risk of introducing pathogenic elements (e.g.
elements responsible for transmissible spongiform encephalopathies and other infectious
disease) originating from biological materials used as sources or during the production
should be considered. The description should be sufficient to aid in understanding the
nature and types of food being submitted for safety assessment.

DESCRIPTION OF THE RECIPIENT ANIMAL PRIOR TO THE MODIFICATION AND

ITS USE AS FOOD OR FOR FOOD PRODUCTION
24. A comprehensive description of the recipient animal prior to the modification should
be provided. The necessary data and information should include, but need not be
restricted to:
A) common or usual name; scientific name; and taxonomic classification;
B) history of development through breeding, in particular identifying traits that may
adversely impact on human health;

173
Reference is made to General Criteria for the Selection of Methods of Analysis in the Codex
Alimentarius Procedural Manual (Appendix).

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C) information on the animal’s genotype and phenotype relevant to its safety, including
any known toxicity or allergenicity, symbiosis with toxin-producing organisms,
potential for colonization by human pathogens;
D) information on the effect of feed, exercise and growth environment on food products;
and
E) history of safe use as food or for food production.
25. Relevant phenotypic information should be provided not only for the recipient animal
prior to the modification, but also for related lines and for animals that have made or
may make a significant contribution to the genetic background of the recipient animal
prior to the modification, if applicable.

26. The history of use may include information on how the animals breed and grow, how
its food products are obtained (e.g. harvest, slaughter, milking), and the conditions
under which those food products are made available to the consumer (e.g. storage,
transport, processing). The extent to which the food products provide important
nutritional components to particular subgroups of the population, and what important
macro- or micronutrients it contributes to the diet should also be considered.

DESCRIPTION OF THE DONOR ORGANISM OR OTHER SOURCE(S) OF THE

INTRODUCED RECOMBINANT-DNA
27. Information should be provided:
A) Whether the recombinant-DNA was synthesized and it is not from a known natural
source;
B) If derived from another organism:
i. that organism’s usual or common name;
ii. scientific name;
iii. taxonomic classification;
iv. information about the natural history as concerns food safety;
v. information on naturally occurring toxins, and allergens;
vi. for microorganisms, additional information on pathogenicity (to humans or the
animal) and the relationship to known human or animal pathogens;
vii. for donors of animal or viral origin, information on the source material (e.g. cell
culture) that has been used, and its origins; and
viii. information on the past and present use, if any, in the food supply and exposure
route(s) other than the intended food use (e.g. possible presence of
contaminants).
It is particularly important to determine whether the recombinant-DNA sequences impart
pathogenicity or toxin production, or have other traits that affect human health (e.g.
allergenicity).

DESCRIPTION OF THE GENETIC MODIFICATION(S) INCLUDING THE

CONSTRUCT(S) USED TO INTRODUCE THE RECOMBINANT-DNA
28. Sufficient information should be provided on the genetic modification to allow for the
identification of all genetic material potentially delivered to the recipient animal and to
provide the necessary information for the analysis of the data supporting the
characterization of the DNA inserted into the recombinant-DNA animal ultimately used as
food or for food production.

29. The description of the process of introducing and incorporating (if appropriate) the
recombinant-DNA into the recipient animal should include:
A) information on the specific methodology used for the transformation;
B) information, if applicable, on the DNA used to modify the animal (e.g. genes coding
for proteins used for packaging vectors), including the source, identity and expected
function in the animal;

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1. if viral vectors or known zoonotic organisms have been used, information on their
natural hosts, target organs, transmission mode, pathogenicity, and potential for
recombination with endogenous or exogenous pathogens; and
C) intermediate host organisms including the organisms (e.g. bacteria) used to produce
or process DNA for producing the initial recombinant DNA animal.
30. Information should be provided on the DNA to be introduced, including:
A) the primary DNA sequence if the recombinant-DNA was synthesized and it is not from
a known natural source
B) the characterization of all the genetic components including marker genes, regulatory
and other elements affecting the expression and function of the DNA;
C) the size and identity;
D) the location and orientation of the sequence in the final vector/construct; and
E) the function.

DESCRIPTION OF THE METHODS USED TO PRODUCE INITIAL RECOMBINANT-

DNA ANIMAL AND THE PROCESSES TO PRODUCE THE RECOMBINANT DNA
ANIMAL ULTIMATELY USED AS FOOD OR FOR FOOD PRODUCTION
31. Information should be provided on the various techniques and processes that are
used to introduce the recombinant-DNA to obtain the initial recombinant-DNA animal.
Examples of possible techniques may include transformation of gametes, microinjection
of early embryos, nuclear transfer of transgenic cells.

32. A description of the methods used to demonstrate heritability should be provided,

including descriptions of how heritability is attained (e.g., breeding mosaic animals to
obtain true germ-cell transmissible insertions).

33. Although initial recombinant-DNA animals are generally not intended to be used as
food or for food production, knowledge of the method to generate these animals may be
useful in hazard identification.

34. Information should also be provided on how the initial recombinant-DNA animal leads
to the production of the animal ultimately used as food or for food production. This
information should, if applicable, include information on the breeding partners, or
surrogate dams including genotype and phenotype, husbandry, and conditions under
which they are raised or harvested.

35. The history of use of food products from the animals used to generate the animals
ultimately used for food production from the initial recombinant-DNA animal (e.g.,
breeding partners, surrogate dams) may include information on how the animals breed
and grow, its food products are obtained (e.g., harvest, slaughter, milking), and the
conditions under which those food products are made available to consumers (e.g.,
storage, transport, processing).

CHARACTERIZATION OF THE GENETIC MODIFICATION(S) IN THE

RECOMBINANT-DNA ANIMAL ULTIMATELY USED AS FOOD OR FOR FOOD
PRODUCTION
36. In order to provide clear understanding of the impact on the composition and safety
of foods derived from recombinant-DNA animals, a comprehensive molecular and
biochemical characterization of the genetic modification should be carried out.

37. Information should be provided on the DNA insertions into the animal genome; this
should include:
A) the characterization and description of the inserted genetic materials. This should
include an analysis of the potential for mobilization or recombination of any construct
material used;
B) the number of insertion sites;

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C) the organization of the inserted genetic material at each insertion site including copy
number and sequence data of the inserted material and of the surrounding region,
sufficient to identify any substances expressed as a consequence of the inserted
material, or, where scientifically more appropriate, other information such as analysis
of transcripts or expression products to identify any new substances that may be
present in the food; and
D) identification of any open reading frames within the inserted DNA or created by
insertion with contiguous animal genomic DNA, including those that could result in
fusion proteins.
38. Information should be provided on any newly expressed substances in the
recombinant-DNA animal; this should include:
A) the gene product(s) (e.g. a protein or an untranslated RNA) or other information such
as analysis of transcripts or expression products to identify any new substances that
may be present in the food;
B) the gene product(s)’ function;
C) the phenotypic description of the new trait(s);
D) the level and site of expression in the animal of the expressed gene product(s), and
the levels of its metabolites in the food; and
E) where possible, the amount of the target gene product(s) if the function of the
expressed sequence(s)/gene(s) is to alter the accumulation of a specific endogenous
mRNA or protein.
39. In addition, information should be provided to:
A) demonstrate whether the arrangement of the genetic material used for insertion has
been conserved or whether significant rearrangement have occurred upon integration;
B) demonstrate whether deliberate modifications made to the amino acid sequence of
the expressed protein result in changes in its post-translational modification or
affected sites critical for its structure or function;
C) demonstrate whether the intended effect of the modification has been achieved and
that all expressed traits are stable and are expressed as expected. It may be
necessary to examine the inheritance of the DNA insert itself or the expression of the
corresponding RNA if the phenotypic characteristics cannot be measured directly;
D) demonstrate whether the newly expressed trait(s) are expressed as expected in the
appropriate tissues in a manner and at levels that are consistent with the associated
regulatory sequences driving the expression of the corresponding gene.;
E) indicate whether there is any evidence to suggest that one or several genes in the
recombinant-DNA animal has been affected by the transformation process; and
F) confirm the identity and expression pattern of any new fusion proteins.

SAFETY ASSESSMENT OF THE RECOMBINANT-DNA ANIMAL ULTIMATELY USED

AS FOOD OR FOR FOODPRODUCTION
Health Status of the Recombinant-DNA Animal
40. In contrast to the situation with plants, animals that have a history of safe use as
sources of food generally do not contain genes encoding for toxic substances. Because of
this, the health of a conventional animal has traditionally been used as a useful indicator
of the safety of derived foods. The practice of only allowing animals with known and
acceptable health status to enter the human food supply has been and continues to be an
essential step to ensuring safe food.

41. An evaluation of the health of the animal is one of the essential steps in ensuring
safety of food derived from recombinant-DNA animals. In undertaking this evaluation, it
is important to compare the health status of the recombinant-DNA animal to the health
status of the appropriate conventional counterpart, taking into account developmental
stage.

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42. The evaluation should include the following:

A) General health and performance indicators, including behaviour, growth and
development, general anatomy, and reproductive function, if appropriate;
B) Physiological measures including clinical and analytical parameters;
C) Other species-specific considerations, where appropriate.

Expressed Substances (non-nucleic acid substances)

Assessment of possible toxicity or bioactivity
43. In vitro nucleic acid techniques enable the introduction of DNA that can result in the
synthesis of new substances in recombinant-DNA animals. The new substances can be
conventional components of animal derived foods, such as proteins, fats, carbohydrates,
vitamins, which are novel in the context of that recombinant-DNA animal. New
substances might also include new metabolites resulting from the activity of enzymes
generated by the expression of introduced DNA.

44. It is recognized that the evaluation of the health status of the recombinant-DNA
animals may give information about possible toxicity and bioactivity of the expressed
substances. However, it is still generally expected that the safety assessment will include
evaluation of these substances.

45. The safety assessment should take into account the chemical nature and function of
the newly expressed substance and identify the concentration of the substance in the
edible tissues and other derived food products of the recombinant-DNA animal, including
variations and mean values. Current dietary exposure and possible effects on population
sub-groups should also be considered.

46. Information should be provided to ensure that genes coding for known toxins or anti-
nutrients present in donor organisms, if applicable, are not transferred to recombinant-
DNA animals that do not normally express those toxic or anti-nutritious characteristics.
This assurance is particularly important in cases where food derived from the
recombinant-DNA animal is processed differently from the donor organism, since
conventional food processing techniques associated with the donor organisms may
deactivate, degrade or eliminate anti-nutrients or toxicants.

47. For the reasons described in Section 3, conventional toxicology studies may not be
considered necessary where the substance or a closely related substance has, taking into
account its function and exposure, been consumed safely in food. In other cases, the use
of appropriate conventional toxicology or other studies on the new substances may be
necessary.

48. In the case of proteins, the assessment of potential toxicity should focus on amino
acid sequence similarity between the protein and known protein toxins as well as stability
to heat or processing and to degradation in appropriate representative gastric and
intestinal model systems. Appropriate oral toxicity studies174 may need to be carried out
in cases where the protein present in the food is not similar to proteins that have
previously been consumed safely in food, taking into account its biological function in the
animal where known.

49. Potential toxicity of non-protein substances that have not been safely consumed in
food should be assessed on a case-by-case basis depending on the identity and biological
function in the animal of the substance and dietary exposure. The type of studies to be
performed may include studies on metabolism, toxicokinetics, sub-chronic toxicity,
chronic toxicity/carcinogenicity, reproduction and development toxicity according to the
traditional toxicological approach.

174
Guidelines for oral toxicity studies have been developed in international fora, for example, the OECD
Guidelines for the Testing of Chemicals.

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50. In the case of newly expressed bioactive substances, recombinant-DNA animals

should be evaluated for potential effects of those substances as part of the overall animal
health evaluation. It is possible that such substances may be active in humans.
Consideration should therefore be given to potential dietary exposure to the substance,
whether the substance is likely to be bioactive following consumption and, if so, its
potential to exert effects in humans.

51. Assessment of potential toxicity may require the isolation of the new substance from
the recombinant-DNA animal, or the synthesis or production of the substance from an
alternative source, in which case, the material should be shown to be biochemically,
structurally, and functionally equivalent to that produced in the recombinant-DNA animal.

Assessment of possible allergenicity (proteins)

52. When the protein(s) resulting from the inserted gene is present in the food, it should
be assessed for potential allergenicity in all cases. An integrated, stepwise, case-by-case
approach used in the assessment of the potential allergenicity of the newly expressed
protein(s) should rely upon various criteria used in combination (since no single criterion
is sufficiently predictive on either allergenicity or non-allergenicity). As noted in
paragraph 21, the data should be obtained using sound scientific methods. A detailed
presentation of issues to be considered can be found in the Annex to this document175.

53. The transfer of genes from commonly allergenic foods should be avoided unless it is
documented that the transferred gene does not code for an allergen.

Compositional Analysis of Key Components

54. Analyses of concentrations of key components176 of the recombinant-DNA animal and,
especially those typical of the food, should be compared with an equivalent analysis of a
conventional counterpart grown and bred under the same husbandry conditions.
Depending on the species (and the nature of the modification) it may be necessary to
make comparisons between products from recombinant-DNA animals and appropriate
conventional counterparts raised under more than one set of typical husbandry
conditions. The statistical significance of any observed differences should be assessed in
the context of the range of natural variations for that parameter to determine its
biological significance. However, it should be acknowledged that, particularly in the case
of certain animal species, the available number of samples may be limited and there is
likely to be large variation between animals, even those bred and raised under the same
husbandry conditions. The comparator(s) used in this assessment should ideally be
matched in housing and husbandry conditions, breed, age, sex, parity, lactation, or
laying cycle (where appropriate). In practice, this may not be feasible at all times, in
which case conventional counterparts as close as possible should be chosen. The purpose
of this comparison, in conjunction with an exposure assessment as necessary, is to
establish that substances that are nutritionally important or that can affect the safety of
the food have not been altered in a manner that would have an adverse impact on
human health.

Food Storage and Processing

55. The potential effects of food processing, including home preparation, on foods derived
from recombinant-DNA animals should also be considered. For example, alterations could
occur in the heat stability of a toxicant or the bioavailability of an important nutrient after

175
The FAO/WHO expert consultation 2001 report, which includes reference to several decision
trees, was used in developing the Annex to these guidelines.
176
Key nutrients are those components in a particular food that may have a substantial impact in
the overall diet. They may be major constituents (fats, proteins, carbohydrates as nutrients or
enzyme inhibitors as antinutrients) or minor compounds (minerals, vitamins). Key toxicants are
those toxicologically significant compounds known to be inherently present in the organism, such
as those compounds whose toxic potency and level may be significant to health and allergens. In
animals, the presence of toxicants would be rare, whereas the presence of allergens would be
common in some species.

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processing. Information should therefore be provided describing the processing conditions

used in the production of a food ingredient from the animal.

56. If the modification is intended to change storage or shelf-life, the impact of the
modification on food safety and/or nutritional quality should be evaluated.

Intended Nutritional Modification

57. The assessment of possible compositional changes to key nutrients, which should be
conducted for all recombinant-DNA animals, has already been addressed under
‘Compositional analyses of key components’. However, foods derived from recombinant-
DNA animals that have undergone modification to intentionally alter nutritional quality or
functionality should be subjected to additional nutritional assessment to assess the
consequences of the changes and whether the nutrient intakes are likely to be altered by
the introduction of such foods into the food supply.

58. Information about the known patterns of use and consumption of a food, and its
derivatives should be used to estimate the likely intake of the food derived from the
recombinant-DNA animal. The expected intake of the food should be used to assess the
nutritional implications of the altered nutrient profile both at customary and maximal
levels of consumption. Basing the estimate on the highest likely consumption provides
assurance that the potential for any undesirable nutritional effects will be detected.
Attention should be paid to the particular physiological characteristics and metabolic
requirements of specific population groups such as infants, children, pregnant and
lactating women, the elderly and those with chronic diseases or compromised immune
systems. Based on the analysis of nutritional impacts and the dietary needs of specific
population subgroups, additional nutritional assessments may be necessary. It is also
important to ascertain to what extent the modified nutrient is bioavailable and remains
stable with time, processing and storage.

59. The use of animal breeding, including in vitro nucleic acid techniques, to change
nutrient levels in animal derived foods can result in broad changes to the nutrient profile
in two ways. The intended modification in animal constituents could change the overall
nutrient profile of the animal product and this change could affect the nutritional status of
individuals consuming the food. Unexpected alterations in nutrients could have
the same effect. Although the recombinant-DNA animal components may be individually
assessed as safe, the impact of the change on the overall nutrient profile should be
determined.

60. When the modification results in a food product with a composition that is
significantly different from its conventional counterpart, it may be appropriate to use
additional conventional foods or food components (i.e. foods or food components whose
nutritional composition is closer to that of the food derived from the recombinant-DNA
animal) as appropriate comparators to assess the nutritional impact of the food.

61. Because of geographical and cultural variation in food consumption patterns,

nutritional changes to a specific food may have a greater impact in some geographical
areas or in some cultural population than in others. Some animal derived foods serve as
the major source of a particular nutrient in some populations. The nutrient and the
populations affected should be identified.

62. Some foods may require additional testing. For example, animal feeding studies may
be warranted for foods derived from recombinant-DNA animals if changes in the
bioavailability of nutrients are expected or if the composition is not comparable to
conventional foods. Also, foods designed for health benefits may require specific
nutritional, toxicological or other appropriate studies. If the characterization of the food
indicates that the available data are insufficient for a thorough safety assessment,
properly designed animal studies could be requested on the whole foods.

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SECTION 5 — OTHER CONSIDERATIONS

POTENTIAL ALTERED ACCUMULATION OR DISTRIBUTION OF SUBSTANCES OR
MICROORGANISMS SIGNIFICANT TO HUMAN HEALTH
63. Some recombinant-DNA animals may exhibit traits that may result in the potential
for altered accumulation or distribution of xenobiotics (e.g., veterinary drug residues,
metals), which may affect food safety. Similarly, the potential for altered colonization by
and shedding of human pathogens or new symbiosis with toxin-producing organisms in
the recombinant-DNA animal could have an effect on food safety. The safety assessment
should take the potential for these alterations into account, and where such alterations
are identified, consideration should be given to the potential impacts on human health
using conventional procedures for establishing safety.

USE OF ANTIBIOTIC RESISTANCE MARKER GENES

64. Alternative transformation technologies that do not result in antibiotic resistance
marker genes in foods should be used in the future development of recombinant-DNA
animals, where such technologies are available and demonstrated to be safe.

65. Gene transfer from animals and their food products to gut microorganisms or human
cells is considered a rare possibility because of the many complex and unlikely events
that would need to occur consecutively. Nevertheless, the possibility of such events
cannot be completely discounted177.

66. In assessing safety of foods containing antibiotic resistance marker genes, the
following factors should be considered:
A) the clinical and veterinary use and importance of the antibiotic in question;
(Certain antibiotics are the only drug available to treat some clinical conditions (e.g.
vancomycin for use in treating certain staphylococcal infections). Marker genes
encoding resistance to such antibiotics should not be used in recombinant-DNA
animals.)
B) whether the presence in food of the enzyme or protein encoded by the antibiotic
resistance marker gene would compromise the therapeutic efficacy of orally
administered antibiotic; and
(This assessment should provide an estimate of the amount of orally ingested antibiotic
that could be degraded by the presence of the enzyme in food, taking into account
factors such as dosage of the antibiotic, amount of enzyme likely to remain in food
following exposure to digestive conditions, including neutral or alkaline stomach
conditions and the need for enzyme cofactors (e.g. ATP) for enzyme activity and
estimated concentration of such factors in food.)
C) safety of the gene product, as would be the case for any other expressed gene
product.

67. If evaluation of the data and information suggests that the presence of the antibiotic
resistance marker gene or gene product presents risks to human health, the marker gene
or gene product should not be present in food. Antibiotic resistance genes used in food
production that encode resistance to clinically used antibiotics should not be present in
foods.

REVIEW OF SAFETY ASSESSMENTS

68. The goal of the safety assessment is a conclusion as to whether the new food is as
safe as the conventional counterpart taking into account dietary impact of any changes in
nutritional content or value. Nevertheless, the safety assessment should be reviewed in
the light of new scientific information that calls into question the conclusions of the
original safety assessment.

177
In cases where there are high levels of naturally occurring bacteria which are resistant to the
antibiotic, the likelihood of such bacteria transferring this resistance to other bacteria will be orders
of magnitude higher than the likelihood of transfer between ingested foods and bacteria.

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ANNEX: ASSESSMENT OF POSSIBLE ALLERGENICITY

SECTION 1 — INTRODUCTION
1. All newly expressed proteins178 in recombinant-DNA animals that could be present in
the final food should be assessed for their potential to cause allergic reactions. This
should include consideration of whether a newly expressed protein is one to which certain
individuals may already be sensitive as well as whether a protein new to the food supply
is likely to induce allergic reactions in some individuals.

2. At present, there is no definitive test that can be relied upon to predict allergic
response in humans to a newly expressed protein, therefore, it is recommended that an
integrated, stepwise, case by case approach, as described below, be used in the
assessment of possible allergenicity of newly expressed proteins. This approach takes
into account the evidence derived from several types of information and data since no
single criterion is sufficiently predictive.

3. The endpoint of the assessment is a conclusion as to the likelihood of the protein being
a food allergen.

SECTION 2 — ASSESSMENT STRATEGY

4. The initial steps in assessing possible allergenicity of any newly expressed proteins are
the determination of: the source of the introduced protein; any significant similarity
between the amino acid sequence of the protein and that of known allergens; and its
structural properties, including but not limited to, its susceptibility to enzymatic
degradation, heat stability and/or, acid and enzymatic treatment.

5. As there is no single test that can predict the likely human IgE response to oral
exposure, the first step to characterize newly expressed proteins should be the
comparison of the amino acid sequence and certain physicochemical characteristics of the
newly expressed protein with those of established allergens in a weight of evidence
approach. This will require the isolation of any newly expressed proteins from the
recombinant-DNA animal, or the synthesis or production of the substance from an
alternative source, in which case the material should be shown to be structurally,
functionally and biochemically equivalent to that produced in the recombinant-DNA
animal. Particular attention should be given to the choice of the expression host, since
post-translational modifications allowed by different hosts (i.e. eukaryotic vs. prokaryotic
systems) may have an impact on the allergenic potential of the protein.

6. It is important to establish whether the source is known to cause allergic reactions.

Genes derived from known allergenic sources should be assumed to encode an allergen
unless scientific evidence demonstrates otherwise.

SECTION 3 — INITIAL ASSESSMENT

SECTION 3.1 – SOURCE OF THE PROTEIN
7. As part of the data supporting the safety of foods derived from recombinant-DNA
animals, information should describe any reports of allergenicity associated with the
donor organism. Allergenic sources of genes would be defined as those organisms for
which reasonable evidence of IgE mediated oral, respiratory or contact allergy is
available. Knowledge of the source of the introduced protein allows the identification of
tools and relevant data to be considered in the allergenicity assessment. These include:
the availability of sera for screening purposes; documented type, severity and frequency
of allergic reactions; structural characteristics and amino acid sequence; physicochemical
and immunological properties (when available) of known allergenic proteins from that
source.

178
This assessment strategy is not applicable to the evaluation of foods where gene products are
down regulated for hypoallergenic purposes.

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SECTION 3.2 – AMINO ACID SEQUENCE HOMOLOGY

8. The purpose of a sequence homology comparison is to assess the extent to which a
newly expressed protein is similar in structure to a known allergen. This information may
suggest whether that protein has an allergenic potential. Sequence homology searches
comparing the structure of all newly expressed proteins with all known allergens should
be done. Searches should be conducted using various algorithms such as FASTA or
BLASTP to predict overall structural similarities. Strategies such as stepwise contiguous
identical amino acid segment searches may also be performed for identifying sequences
that may represent linear epitopes. The size of the contiguous amino acid search should
be based on a scientifically justified rationale in order to minimize the potential for false
negative or false positive results.179 Validated search and evaluation procedures should
be used in order to produce biologically meaningful results.

9. IgE cross-reactivity between the newly expressed protein and a known allergen should
be considered a possibility when there is more than 35% identity in a segment of 80 or
more amino acids (FAO/WHO 2001) or other scientifically justified criteria. All the
information resulting from the sequence homology comparison between the newly
expressed protein and known allergens should be reported to allow a case-bycase
scientifically based evaluation.

10. Sequence homology searches have certain limitations. In particular, comparisons are
limited to the sequences of known allergens in publicly available databases and the
scientific literature. There are also limitations in the ability of such comparisons to detect
non-contiguous epitopes capable of binding themselves specifically with IgE antibodies.

11. A negative sequence homology result indicates that a newly expressed protein is not
a known allergen and is unlikely to be cross-reactive to known allergens. A result
indicating absence of significant sequence homology should be considered along with the
other data outlined under this strategy in assessing the allergenic potential of newly
expressed proteins. Further studies should be conducted as appropriate (see also sections
4 and 5). A positive sequence homology result indicates that the newly expressed protein
is likely to be allergenic. If the product is to be considered further, it should be assessed
using serum from individuals sensitised to the identified allergenic source.

SECTION 3.3 – PEPSIN RESISTANCE

12. Resistance to pepsin digestion has been observed in several food allergens; thus a
correlation exists between resistance to digestion by pepsin and allergenic potential.180
Therefore, the resistance of protein to degradation in the presence of pepsin under
appropriate conditions indicates that further analysis should be conducted to determine
the likelihood of the newly expressed protein being allergenic. The establishment of
a consistent and well-validated pepsin degradation protocol may enhance utility of this
method. However, it should be taken into account that a lack of resistance to pepsin does
not exclude that the newly expressed protein can be a relevant allergen.

13. Although the pepsin resistance protocol is strongly recommended, it is recognized

that other enzyme susceptibility protocols exist. Alternative protocols may be used where
adequate justification is provided181.

179
It is recognized that the 2001 FAO/WHO consultation suggested moving from 8 to 6 identical
amino acid segments in searches. The smaller the peptide sequence used in the stepwise
comparison, the greater the likelihood of identifying false positives, inversely, the larger the
peptide sequence used, the greater the likelihood of false negatives, thereby reducing the utility of
the comparison.
180
The method outlined in the U.S. Pharmacopoeia (1995) was used in the establishment of the
correlation (Astwood et al. 1996).
181
Report of Joint FAO/WHO Expert Consultation on Allergenicity of Foods Derived from
Biotechnology (2001): Section “6.4 Pepsin Resistance”.

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SECTION 4 — SPECIFIC SERUM SCREENING

14. For those proteins that originate from a source known to be allergenic, or have
sequence homology with a known allergen, testing in immunological assays should be
performed where sera are available. Sera from individuals with a clinically validated
allergy to the source of the protein can be used to test the specific binding to IgE class
antibodies of the protein in in vitro assays. A critical issue for testing will be the
availability of human sera from sufficient number of individuals.17 In addition, the
quality of the sera and the assay procedure need to be standardized to produce a valid
test result. For proteins from sources not known to be allergenic, and which do not
exhibit sequence homology to a known allergen, targeted serum screening may be
considered where such tests are available as described in paragraph182.

15. In the case of a newly expressed protein derived from a known allergenic source, a
negative result in in vitro immunoassays may not be considered sufficient but should
prompt additional testing, such as the possible use of skin test and ex vivo protocols.183 A
positive result in such tests would indicate a potential allergen.

SECTION 5 — OTHER CONSIDERATIONS

16. The absolute exposure to the newly expressed protein and the effects of relevant food
processing willcontribute toward an overall conclusion about the potential for human
health risk. In this regard, the nature of the food product intended for consumption
should be taken into consideration in determining the types of processing which would be
applied and its effects on the presence of the protein in the final food product.

17. As scientific knowledge and technology evolves, other methods and tools may be
considered in assessing the allergenicity potential of newly expressed proteins as part of
the assessment strategy. These methods should be scientifically sound and may include
targeted serum screening (i.e. the assessment of binding to IgE in sera of individuals
with clinically validated allergic responses to broadly-related categories of foods); the
development of international serum banks; use of animal models; and examination of
newly expressed proteins for T-cell epitopes and structural motifs associated with
allergens.

182
According to the Joint Report of the FAO/WHO Expert Consultation on Allergenicity of Foods
Derived from Biotechnology (22-25 January 2001, Rome, Italy) a minimum of 8 relevant sera is
required to achieve a 99% certainty that the new protein is not an allergen in the case of a major
allergen. Similarly, a minimum of 24 relevant sera is required to achieve the same level of
certainty in the case of a minor allergen. It is recognized that these quantities of sera may not be
available for testing purposes.
183
Ex vivo procedure is described as the testing for allergenicity using cells or tissue culture from
allergic human subjects (Report of Joint FAO/WHO Expert Consultation on Allergenicity of Foods
derived from Biotechnology).

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Annex II, Canada: Notification Guidelines for the

Environmental Assessment of Biotechnology - Derived
Livestock Animals
Health Canada: www.inspection.gc.ca/english/anima/biotech/guidedirecte.shtml

Prepared by:
Harpreet S. Kochhar, BVSc, MVSc, PhD
Animal Biotechnology Unit, Veterinary Biologics Section
Animal Health and Production Division, Animal Products Directorate
Contributors:
New Substances Branch, Environment Canada
Health Canada
Agriculture and Agri- Food Canada
Draft 2.1 January14, 2004

Table of Contents
Scope of the document

Purpose of the document

Legislative authority

Interpretation of biotechnology-derived Livestock Animals

Required technical information for environmental assessment of biotechnology derived

livestock animals

1. Information in respect of the organism

1(a) Identification, current taxonomic name to species or sub-species level, strain,

synonyms, common names and trade names

1(b) Strain history

1(c) Description of any modifications of the organism

1(d) Description of methods that can be used to distinguish and detect the modified
organism

1(e) A description of biological and ecological characteristics of the modified organism

1(f) Identification of patent or other rights, or any application for a patent or other rights

2. Information in respect of manufacture or import of the organism

2(a) The identification of manufacturers, importers or vendors

2(b) Description of the locations of manufacture in Canada

2(c) Description of product containing the organism/Animal

2(d) Description of any recommended procedure for the storage and disposal of the
organism

2(e) Estimation of the quantity of the organism that was or will be imported to or
manufactured in Canada

2(f) Description of method of manufacture and of quality control and quality

assurance procedures

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3. Information in respect of the introduction of the organism

3(a) History of use

3(b) Intended and potential uses of organism and potential locations of introduction

3(c) Description of the mode of action in relation to the intended use

3(d) Description of the procedures for the introduction of the organism

3(e) Description of any recommended procedure for terminating the introduction of

organism

3(f) Description of procedures for disposal of remaining biomass and residues

4. Information in respect of the environmental fate of the organism

4(a) Estimated quantities of the organism in the environment and the estimated
population trends

4(b) Description of habitats where the organism may persist or proliferate

4(c) Identification of other species that are likely to be exposed to the organism

5. Information in respect of the ecological effects of the organism

5(a) Data from a test conducted to determine the pathogenicity, toxicity or

invasiveness of the organism

5(b) Ecological effects of organism residues

5(c) Potential of the organism to have adverse environmental impacts that could
affect the conservation and sustainable use of biological diversity

6. Potential of the organism to be involved in adverse human health effects and the most
likely route of human exposure to the organism

7. All other information and test data in respect of the organism that are relevant to
identifying hazards to human health and environment

8. Identification of other government agencies either abroad or within Canada, that the
person has notified of the manufacture or importation of the organism and the purpose of
the notification

9. Description of test procedures followed in developing the test data, including methods,
reference substance and quality control and quality assurance procedures

Annexure (Definitions)

Scope of the document:

This document has been prepared to assist notifiers responsible for complying with Part
II.I of New Substances Notification Regulations (NSNR) under the Canadian
Environmental Protection Act, 1999 (CEPA, 1999). Schedule XIX of the NSNR, outlines
the general information requirements for organisms other than micro-organisms. These
guidelines will elaborate on the technical information requirements of Schedule XIX
providing supplemental information on biotechnology-derived livestock animals.

These guidelines will be periodically revised and updated to reflect technological

advances and increasing understanding of risk factors associated with animal
biotechnology.

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Purpose of the document:

The Canadian Environmental Protection Act, 1999 (CEPA 1999), promulgated in 1988 and
amended in 1999, provides the federal government the authority to address pollution
issues. It addresses substances ranging from chemicals to living organisms that are
animate products of biotechnology. The Canadian Environmental Protection Act,1999
captures new substances, including animate products of biotechnology, that are not
regulated under other legislation specifically listed in CEPA 1999, Schedules 2 and 4. The
Governor-in-Council makes the determination whether other federal Acts and Regulations
meet the criteria for notice prior to import, manufacture or sale and assessment as
defined in CEPA 1999. Currently captured under CEPA 1999, for example, are terrestrial
animals which are the product of biotechnology such as transgenic animals. These
organisms and a number of terrestrial species would be more appropriately managed by
the Canadian Food Inspection Agency, through its regulatory responsibilities, as the lead
federal Agency for animal health and veterinary public health. In keeping with the
principles of the 1993 Federal Regulatory Framework for Biotechnology, the Canadian
Food Inspection Agency proposes to utilize the authority of CEPA 1999, apply the NSNR
and conduct a CEPA 1999 risk assessment for defined biotechnology-derived livestock
animals.

Legislative Authority:

Currently in Canada, biotechnology - derived animals are regulated through the Canadian
Environmental Protection Act (CEPA 1999) co-administered by Environment Canada
(EC) and Health Canada (HC). The New Substances Notification Regulation (NSNR),
Schedule XIX, section 29.16 of CEPA provides the first regulatory trigger, for import or
manufacture of these organisms, while the Novel Foods regulations under Foods and
Drugs Act administered by Health Canada come into effect if the product is intended for
use as food.

Interpretation of the term ‘biotechnology-derived livestock animals :

Several statutes within the government of Canada define biotechnology as "the

application of science and engineering to the direct or indirect use of living organisms or
parts or products of living organisms in their natural or modified forms". This broad
definition encompasses organisms developed through traditional breeding methods and
newer technologies such as genetic engineering. (For complete list of definitions, please
refer to Annexure)

The term ‘biotechnology-derived animal’ is an extension of the definition of

biotechnology. It refers to animals which have been generated through biotechnological
methods. This term may include, but not be limited to, the following categories of
animals:

1) Genetically engineered or modified animals in which genetic material has been added,
deleted, silenced or altered to influence expression of genes and traits.

2) Clones of animals derived by nuclear transfer from embryonic or somatic cells.

3) Chimeric animals that have received transplanted cells from another animal.

4) Interspecies hybrids produced by in vitro methods.

5) Animals derived from in vitro cultivation, such as maturation or manipulation of

embryos.

It is possible to generate animals with useful novel traits for many purposes, for example,
1) enhanced agricultural productivity and product quality i.e., dairy, meat, eggs, wool, 2)

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reduction or elimination of undesirable by-products or wastes i.e., reduction of

phosphorus levels in swine manure, 3) biomedical research, 4) production of bio-
pharmaceuticals, or 5) production of organs for transplantation to humans
(xenotransplantation). Animals that are near-identical copies of valuable individuals can
be generated or alternately, methods can be employed to modify the animal’s germline
cells by introduction of new genes by transfection, use of retroviral vectors, or
transposons. Genetically modified animals can be further cloned to generate transgenic
progeny which are nearly identical to the parent

The Notification Guidelines for the CEPA 1999 Assessment of Biotechnology-Derived

Animals, addresses the issues related to anticipated risks pertaining to mammalian and
avian livestock species intended for release outside of research and development
facilities. In this context, the hazards related to the technology and its impact on human
health, food safety, animal health and environment are closely inter-related and cannot
be easily addressed individually . The following guidelines are intended to serve as a
baseline for assessing biotechnology-derived animals. However, it must be recognized
that, each genetic modification presents a different set of circumstances and potential
risks, which must be assessed on a case-by-case basis. These guidelines will be
periodically revised and updated to reflect technological advances and increasing
understanding of risk factors associated with animal biotechnology.

Required technical information for environmental assessment of biotechnology -

derived animals

The process of risk assessment is initiated by a request from the notifier to manufacture,
import, or release the animal into the environment. The history and the background, a
full description of the commodity and the proposed release, including production
protocols, volume, quantity, frequency and time frames of the proposed release
(intended use) are all documented

Just to clarify - Subsections 106(1) and 106(2) of CEPA 1999 prohibit the import or
manufacture of any living organisms not listed on the Domestic Substances List. In other
words, the triggers are import or manufacture of a new living organism that is an
animate product of biotechnology, or a new biotechnology-derived animal. The
information to be provided referred to in these subsections is prescribed in the New
Substances Notification Regulations and further elaborated in these guidelines.

The CEPA risk assessment process considers hazard identification and probable exposure.
It is based on the equation: Risk = Hazard X Exposure. In contrast to conventional
animal import risk assessments (such as under the Health of Animals Act and
Regulations) which examine the potential of the organism to harbor infectious agents and
to introduce these agents into Canadian livestock, the CEPA risk assessments also cover
consideration of environmental and human health hazards.

The assessment process identified under CEPA 1999 is thus based on the information that
is required under Schedule XIX of the New Substances Notification Regulations
(information in respect to organisms other than micro-organisms). The following
information will guide notifiers as to the specifics required in order to meet the prescribed
information elements of the Schedule XIX of the NSNR.
1. Information in respect of the organism:

1 a) Identification, or current taxonomic name to species or sub-species level,

strain, synonyms, common names and trade names: The correct identification of the
organism; the taxonomic name, international codes of nomenclature and standard
taxonomic sources, substantiation of the identification, a designation to the species or
subspecies level. If the genus and species are not known or are proposed but not
recognized, then the taxonomic family should also be provided. Experimental

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designation, strain name, variety, trade or common names, if known, should also be
provided. If unknown or there are none, then this should be specified.

1 b) Strain history: Information on the historical record of the organism from named
varieties or strains, experimental designations, or wild sources (e.g., country, region,
accession number, reason for selection) of the strain that is proposed to be introduced,
should be provided. This information should include breeding methods or selection
practices if used to develop the new organism. Information on dam and sire (and their
cell lineages) and the origin of the cells (e.g. somatic or germ line (totipotent)), source of
oocyte (such as obtained from abattoir or live animal), source of sperm (in case of
sperm-mediated gene transfer), source of embryos, and the health status and origin of
surrogate mother should be made available. Details of the methods used to select the
breeding stock and methods to propagate the transgenic animal should be made
available.

1 c) A description of any modification of the organism: A description of any direct

or intentional modifications made to the organism by any means should be provided. If
none has been made, then this should be specified.

1c)(i) the purpose of the modifications: The intended purpose of modification of the
animal in terms of its use, for example, to produce therapeutic proteins (bio-
pharmaceutical purpose), products of industrial importance, organs for
xenotransplantation, and all other uses need to be identified.

1c)(ii) the methods and steps taken to make the modifications: Notifiers should describe
the methods and steps taken to make any direct or deliberate modifications to the
organism either through classical, physical (e.g., natural hybridization), chemical (base
analogues, acridines, nitrous acid, hydroxylamine, alkylating agents), or other
mutagenesis techniques, or through other, e.g., recombinant DNA techniques.

Where the organism has been modified using recombinant DNA techniques, the
description should take into account the following areas:

• DNA cloning strategies and procedures including schematic representations;

• vector construction details, and information on the functional elements contained

within the vector (e.g., promoters and other regulatory elements, replication
elements, structural genes, markers and restriction sites);

• gene transfer methods employed (e.g. nuclear transfer, virus-mediated

transformation, electroporation, microinjection, sperm-mediated gene transfer,
ballistic injection or any other method);

• vector characteristics (e.g., pathogenic, disarmed and whether bacterium or

virus).

• the identities of the reagents and amount of DNA added during each step.

• methods used to verify that no unintended expression (ectopic and pleiotropic)

occurs at any un-intended site.

There should be appropriate references provided on the published scientific literature.

1c)(iii) the phenotypic and genotypic changes that resulted from the modifications: A
description of the phenotypic and genotypic changes known to have resulted from the
modifications to the organism, such as any known changes in physiological characteristics
and biological functions, including unintended changes, should be provided. The
description should include transgene expression levels, cellular and genomic location, and
resulting alterations, additions, or deletions in nucleic acid sequence.

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1c)(iv) the genetic stability of the changes: A description of the stability (inheritance
through several generations, site of integration, effect of selective pressure) of the
phenotypic and genotypic changes known to have resulted from the modifications to the
organism should be provided.

In addition to testing for the presence of transgenes in the transfected cells, the stability
of the transgene inserted should be tested using molecular tools along with the proposed
technique for monitoring the production of the modified product (e.g. a novel protein in
milk). The genetic stability in terms of inheritance should be addressed i.e. whether the
genetic modifications are capable of being transmitted to the next generation through
sexual reproduction, and the transgene activity levels in offspring. The recombination and
the rearrangements of the genes and their possible ill-effects should be gauged. Study of
the transgene stability over 3-4 generations of transgenic animals is recommended in
order to confirm stability.

1c)(v) the nature, source and function of any introduced genetic material: The full
sequence of all the introduced fragments should be made available and the fragment
rearrangement studies need to be done. The location of insert, orientation position and
any hazard characteristic should be elucidated.

• source, description and function of genetic material being introduced

• endogenous genetic material knocked out or modified or silenced as a result of

insertions

• number of copies of each transgene inserted

• location and number of transgene integration sites

• duration of embryos in culture

• identification including the taxonomic designation of all organisms that were a

source of genetic material

• origin of replication, coding and non-coding sequences used

• selection markers (e.g. antibiotics, heavy metals, physiological characteristics)

1 d) A description of methods that can be used to distinguish and detect the modified
organism: This information shall be useful to identify and distinguish the modified
animals from their unmodified counterparts and also from the ones which failed to
express the intended characteristics, incorporate or insert the transgene (non-takes) due
to technical or other problems.

• methods used to confirm the presence of transgene in the modified

embryos/cells/fetuses/animals.

• specific mechanism for transgene integration

• methods used to confirm expression of transgene in the products derived from the
modified animal

• any phenotypic tags/marks used to distinguish modified animals from unmodified

animals

1 e) A description of the biological and ecological characteristics of the organism

1e)(i) The life cycle:

• information on the average life expectancy of the animal

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• detailed description of the life cycle including expected stress triggers and
environmental adaptation needed after genetic modification.

1 e)(ii) The reproductive biology, including the species with which the organism/animal
can interbreed in Canada: For the transgenic animals the assessment of their
reproductive status and health is an important parameter to gauge the effect on the
population of the conventional animals of the same or inter-related species. The following
information should be provided

• reproductive health and status of the animal (e.g. whether the modification leads
to a terminal effect)

• list of all other animal species with which the modified animal can successfully
interbreed

• effect of the reproductive potential of the modified animal on the wild type or
conventional population

• risk of losing genetic stability of the transgene if interbreeding with conventional

counterparts occurs.

1 e)(iii)The involvement in adverse ecological effects, including pathogenicity, toxicity and

invasiveness: Data should be provided for the following concerns

• disease susceptibility of the modified organism (whether altered, increased or

decreased) should include the considerations for endogenous retrovirus replication
etc.,

• increased pathogen load that the animal may shed (in feces, urine or other
secretions) due to the genetic modification,

• effect of the genetic modification on carcass quality, and environmental impact of

aborted fetuses, manure, milk, eggs or proteins.

1 e)(iv) A description of geographic distribution and habitat of the animal/ organism:

• Information regarding the natural habitat and survival of the organisms based on
their distribution in various ecozones

• The geographical barriers including climatic extremes (factor in the spread of the
organism and affects on survival).

1 e)(v) The potential for dispersal of traits by gene transfer: Information on the
possibility of horizontal gene transfer through, for e.g., gut flora, viruses, or other
vectors. Of particular interest are antibiotic gene markers used in transgene construction.
This needs to be addressed in conjunction with the accidental release of the modified
organism into the environment where it can interbreed with conventional counterparts.

• need to be clear what information items would be helpful, e.g. dispersal of traits
by:

o interbreeding with wild populations (probabilities, etc)

o biomaterials released from the organism if released, e.g. manure and

presence of ‘undesirable’ genetic material that could transfer to
environmental microflora

1 e)(vi) Locations and situations where the organism has caused adverse ecological
effects: Notifier should provide any known information on adverse ecological effects on
animals, plants, ecological processes, where the organism was involved.

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In the absence of reports on adverse ecological effects, related reports in this context
may be provided. Related information can help to assess the risk associated with adverse
ecological effects.

1 e)(vii) Involvement in biogeochemical cycling: For example, the potential impacts of

the composted manure spread on the farm or waste product removal on the environment
should be assessed and the data provided.

1 e)(viii) Interactions with other organisms in the environment: Information required on

the aggressiveness, body build-up etc.) have impacts on the feral or native populations
from which the notified organism originates or on other species.

1 e)(ix) The conditions required for survival, growth, reproduction and overwintering:
Information about the survivability, growth and normal reproductive pattern is vital to
judge the ability of the modified organism to survive in the environment after its release
from containment. Information specific to animals such as Information on the seasonal
survival ability, its growth and any seasonality observed in reproductive cycle or
dormancy in growth should be provided.

1 e)(x) Capability of the organism to act as a vector for agents involved in adverse
effects: Information on the ability of the modified animal to act as a vector for agents
involved in creating adverse effects should be provided.

1 e)(xi) The mechanism of dispersal of the organism and modes of interaction with any
dispersal agents: If the animal is in containment or confined, information is required
regarding the possible mode of escape and what mechanism may exist to allow for its
dispersal.

1 f) Identification of patent or other rights, or any application for a patent or

other rights: If the notifier has been granted or has applied for a patent or other right,
the authority under which the patent or other right was issued or applied for should be
provided, as well as the patent or right number or application number. If more than one
has been granted or applied for, then this should be specified.

2. The following information in respect of the manufacture and importation of

the organism:

2 a) The identification of manufacturers, importers or vendors: Name and location

of the facilities where the production of the organism and its modification is done.
Information on the transport or movement of the animals between the production and
maintenance facilities or involvement of a vendor in between is required. Information
provided does not exempt vendors from notification obligations under these regulations if
they subsequently start producing or importing the animal.

2 b) Description of the locations of manufacture in Canada: A description of the

facilities including full address of each production , maintenance, research and
development (R & D) and assessment facilities should be provided with respect to
following details

• details of the location including scale drawings and maps, size of site, slope and
geography

• distance to populated areas and other protected areas like watersheds, farms,
wetlands, watercourses etc.

• facilities and equipments at the different locations

• organizational charts including the personnel working in the facility (names, titles,
duties) and reporting relationship and emergency contacts.

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2 c) Description of product containing the organism/Animal: Data regarding the

product derived from animal are required.

This information item as it is written is not likely relevant to biotechnology-derived

animals. As such, it can be used to either compliment item 3(a) and (c) or the elements
of products generated can be completely captured under these same items. Either way, it
is agreeable to focus on any products derived from the organism and if the organism
itself is the ‘product’, for e.g. in the case of a pet. This can include the reproductive
bodies intended for sale, etc.

2 d) Description of any recommended procedure for the storage and disposal of

the organism: Information regarding the maintenance of the animal(s) at the facilities,
how they are bio-contained in terms of their existence and the possibility of escaping.
The information on handling, identification and tracking methods of genetically modified
animals should be provided. Other information required in context with storage and
disposal of products and by-products is:

• volume / quantity of stored material

• duration of stored material such as hours, days, weeks, months.

• form of storage such as refrigerator, freezer, room temperature or any other.

• location of storage place

• labelling of storage place and equipment.

• disposal of germ plasm such as embryos, semen, oocytes etc.

• disposal of carcasses of euthanized/dead animals such as by incineration,

composting etc.

2 e) Estimation of the quantity of the organism that was or will be imported or

manufactured in Canada: Following information should be provided:

• number of modified animals that are anticipated to be generated during coming

year and subsequent years

• number of animals to be imported or introduced into the nuclear herds (if from the
same line)

• anticipated numbers of the breeding stock (if intended)

• number of animals which are non-takes or do not express the transgene, mosaics,
are of undesired gender, aborted fetuses and non viable animals.

(Note that each transgenic founder animal and its progeny will need a separate
submission in terms of assessment.)

2 f) Description of method of manufacture and of quality control and quality

assurance procedures: the information required should be provided under the following
categories:

• Creation and characterization of the transgenic founder animal (Go) and related
information (Similar to that provided in section 1)

• Establishment of a reliable source of transgenic animals (transgenic procedures,

natural reproduction, or cloning of transgenic animals to produce further
generations of transgenics)

• Maintenance of transgenic animals

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• monitoring health of transgenic animals

• transgenic animal housing and handling facilities

• feeding and animal welfare considerations

• physical containment measures

• Quality control and quality assurance procedures such as

• testing for replication of competent retroviruses in reteroviral based gene transfer

(identifying packaging cell lines, virus titre, potential for recombination, etc)

• Host range/ specificity, tissue tropism and shed/spread capabilities of the viral
vector(s)

• Recommendations for product testing (when and how often to test, methods, etc.)

• Records/documentation of all the experimental work including. Standard

Operating Procedures (SOP) and Good Laboratory Practices (GLP)

• Proof of accredited facility with any animal care organization.

3. Information in respect to the introduction of the organism:

3 a) History of use: A description should be provided of the history of any use of the
animal in Canada or any other country. This description should consider the length of
time the animal has been used. If there is no known history of use, this should be
specified.

3 b) Intended and potential uses of organism and potential locations of

introduction: Information in regards to the intended use e.g. bio-pharmaceutical,
industrial application, food or any other use should be available. The full description of
the regions and the areas where the modified animals will be introduced and their effects
on native population of animals and ecological balance should be provided. Other
information needed would be:

• full address of potential location of introduction

• duration of introduction in potential location

• quantity/ total numbers of animals to be introduced.

3 c) Description of mode of action in relation to the intended use: A detailed

mechanism as to how the genetic inserts will function within the organism e.g. the
molecular processes involved in the secretions of a bio-pharmaceutical in milk. The
notifier should provide information on relevant biochemical breakdown pathways or end
products for the notified organism. The description should indicate whether the organism
functions by altering the physical, biochemical or bio-geochemical environment.

3 d) Description of procedures for the introduction of the organism, including

3 d)(i) method and rate of introduction: Information should be provided about

• how often will the organism be introduced into the environment

• whether the animals will be physically separated from conventional organism or

will be co-mingling with their counterparts that are used as for example, surrogate
dams or animals used for oocyte donations

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3 d)(ii) any activities associated with introduction: All activities associated with the
introduction of the animal should be detailed. These may include the:

• landscaping of site or making it bio-contained

• redirection of streams

• cutting down of trees

• composting of manure

• waste biological material treatment and disposal

• evacuation or elimination of any life form on site

• proper licensing and clearances from local authorities

• import and export regulations regarding germplasm (semen, embryos and

oocytes)

• transportation of animals, animal products and their waste material

• monitoring and tracking of the animals (identification procedures)

3 d)(iii)any recommended procedures for storage and handling and disposal of any
surplus material: Information on how any biological material or tissue samples are
intended to be handled and information regarding the storage and use of the modified
germplasm (semen, embryo etc.) should be provided. Information should also be
provided regarding the fate of mosaics, "non-takes", surrogate mothers and the animals
used for embryo/oocyte donation.

3 d)(iv) any contingency plans for accidental release (and any reproductive isolation
measures: Information regarding the separation of the male and female animals and how
they would be prevented from or allowed to inter-breed. If accidental mixing happens or
the escape of the organism is detected, the procedures used to segregate the organism
or re-introduce it into the herd should be specified.

3 d)(v) resistance to control agents.: Generally not applicable

3 e) Description of any recommended procedure for terminating the introduction

of the organism: Information on the recommended procedures for termination of the
animals (e.g. euthanasia) needs to be provided in detail.

3 f) Description of procedures for disposal of remaining biomass and residues of

the organism: Description of intended procedures, for example, manure composting,
redirection of other wastes such as urine, body fluids, placenta, aborted fetuses etc..
Description of disposal procedures for bio-products derived from the animal such as milk,
semen etc. should be described.

4. Information in respect of the environmental fate of the organism:

4 a) Estimated quantities of the organism in the environment and the estimated

population trends: Details of prevalence of the genetically modified organism with
similar genetic manipulations (if any) already existing in a controlled or open
environment situation need to be provided.

4 b) Description of habitats where the organism may persist or proliferate: The

general profile of the animal’s capacity to exist in a particular habitat or survive with the
environmental conditions related to weather, nutrition, co-existing flora and fauna should
be detailed.

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4 c) Identification of other species that are likely to be exposed to the organism

and other species that are likely to be affected: A list of all species that could be
exposed to the animal is required in detail.

5. Information in respect of the ecological effects of the organism:

5 a) Data from a test conducted to determine the pathogenicity, toxicity or

invasiveness of the organisms: Data to support the absence of any toxic or pathogenic
potential of these hazards should be provided.

• adventitious infectious agent transfer

• endogenous retrovirus activation

• heteroplasmy of mitochondria

• embryo manipulation / use of cell culture

• hazards related to transgene expression

• insertional mutation - disruption of endogenous gene function

• transfer of antibiotic resistance genes to the environment

Duration of test: The time taken for conducting different tests by the company should be
provided.

Control groups: Test organisms subject to treatments and contact with the notified
animal should be accompanied by an appropriate untreated (negative) control group of
test organisms which are not exposed to the notified animal. Control groups should be
used to ensure that any observed effects are associated with exposure to the notified
animal and should be identical in every respect to the treated test animals except for
exposure to the notified animal. For example, the control test animals should be from the
same source, be of the same age, and receive the same nutrition and care as the treated
test animals. To prevent bias, test animals should be randomly assigned to control and
treatment groups.

Wherever possible, notifiers should attempt to establish a positive control group with a
relevant closely related animals to ensure that the test system is capable of detecting an
adverse effect.The company needs to provide us info on all the controls used in their
experiments/projects.

Reporting of data: Notifiers should detail all information for a complete and accurate
description of the test procedures, information, and analysis. This should include a
justification for choosing a particular test species and test method and a statistical
analysis of differences between the test group and control groups.

5 b) Ecological effects of organism residues: Information must be provided on the

residues originating as a result of metabolic and other phenomena like waste,
reproductive secretions or body fluids.

5 c) Potential of the organism to have adverse environmental impacts that could

affect the conservation and sustainable use of biological diversity: This will
require data to support the effect of modified animal on bio-security and bio-diversity
(see details for reference in Annex D). However, the notifier should provide information
on the following:

• Spread of the transgene into indigenous domestic animals or wildlife

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• fitness of the modified animal compared to the conventional animals or wild

counterparts

• changes in adaptability of the modified animal to the environment

• ability to escape, disperse and become feral

6. The potential of the organism to be involved in adverse human health effects

and the most likely route of human exposure to the organism:

In addition to the potential effects of the transgenic material exposure on human health
either through the product of the transgenic animal or by other routes, details are
required. Data on the direct or indirect mechanisms involving intermediate vectors should
be provided.

7. All other information and test data in respect of the organism that are
relevant to identifying hazards to human health and environment:

All aspects of trials and potential risk and benefit information available to the producer
should be made available with the understanding that the privacy of the product
information will be maintained.

All other information and data relevant to environmental and health hazard identification
should be provided, such as:

• experimental data (including negative results);

• summaries of literature reviews

• results of searches from databases

• results of studies of the risk to employees, customers, public, or the environment

(e.g. environmental fate modelling) that may result from the use of the organism
(occupational health and safety data).

Additional information includes information in the person's possession or to which the

person should reasonably have access. "In the person's possession" means information in
the company's offices in Canada or, if the notification was submitted by a foreign
company through a Canadian agent, the offices in the country where the notification
originated. The phrase "to which the person ought reasonably to have access" means
information in any of the company's offices worldwide, or other locations where the
person can access the information.

• Information on possible environmental benefits resulting from the production or

use of the animal should also be provided.

Any additional information may be provided in the language in which the information was
originally prepared.

8. Identification of other government agencies either abroad or within Canada,

that the person has notified of the manufacture or importation of the organism
and the purpose of the notification:

Information should be provided of any known circumstances where the import or

production of the organism has been notified to another agency or government, and the
purpose of such notification.

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• identify which government agencies within Canada have been contacted,

consulted with, or notified and asked for approval for commercialization,
importation, exportation, or R & D.

• identify which government agencies outside Canada have been contacted,

consulted with or notified and asked for approval for commercialization,
importation, exportation, or R & D.

9. Description or specification of test procedures followed in developing the test

data, including methods, reference substance and quality control and quality
assurance procedures:

Complete details as to the purpose of each test, its results, and efficacy of the test
conducted along with the reference standards used to assess the genetic manipulation of
the animal, generation of data submitted for notification.

ANNEXURE
GLOSSARY

Biodiversity: The variety of life and its processes. Biodiversity includes all life forms,
from one-celled fungi, protozoa and bacteria to complex organisms such as plants,
insects, fishes and mammals. It includes processes, pathways and cycles that link living
organisms into populations, ecosystems and landscapes. This variety of life is dynamic
and constantly changing and evolving. It is sensitive to perturbations that may result
from human activity. Biodiversity is generally recognized on three levels:

• genetic diversity - the variety of genetic building blocks found among individual
representatives of a species;

• species diversity - the variety of living organisms found in a particular place; and

• ecosystem diversity - the variety of species and ecological functions and

processes, both their kind and number, that occur in different physical settings.

Biopharm animals: Transgenic animals modified to produce proteins for extraction,

purification and therapeutic use.

Carrier DNA: DNA used to expedite the preparation or the transformation of genetic
material into an organism but which is itself not part of the construct.

Clone: Genetically identical copy of a gene, cell or organism asexually reproduced from a
common ancestor

Coding Region: A DNA sequence which can be translated to produce a protein.

Synonymous with open reading frame.

Construct: An engineered DNA fragment (e.g. plasmid) which contains, but is not
limited to, the DNA sequences to be integrated into a target organism's genome as a
transgene.

Counterpart: The chosen counterpart for use in testing transgenic animals should, if
possible, be the host animals already existing as stable populations (wild or
domesticated) in Canada. In the case of an F1 hybrid, the counterpart must be a similar
genotype/phenotype of the same species. Consideration may also be given to the use of
several counterparts.

Dam: The female parent of the animal especially domestic livestock

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Ectopic gene expression: Expression of a (trans)gene in a tissue where, or

developmental stage when, such expression is not expected.

Electroporation: Introduction of DNA into a cell mediated by a brief pulse of electricity.

Endogenous retrovirus: Integrated retrovirus DNA (provirus) believed to be derived

from infection of the germline of an ancestral animal. All animals are thought to carry
numerous endogennous retroviral genes, some of which were inserted millions of years
ago. Endogenous retroviral genes could produce virions, viral components, or be silent.

Environment: Environment means the components of the earth and includes air, land,
water, all layers of the atmosphere, all organic and inorganic matter and living organisms
and the interacting natural systems that include components referred to above (Canadian
Environmental Protection Act, Section 3). This includes the natural and managed
ecosystems which include agricultural ecosystems.

Environmental Effect: Any significant change that the release of the genetically
modified organism may cause in the environment.

Environmental Risk: Risk is defined in terms of probability of the occurrence of an

effect, multiplied by the hazard (i.e., the degree of harm that results from the effect).

Environmental Safety Assessment: The qualitative and/or quantitative estimation of

the likelihood of adverse environmental impacts that may result from the release of the
modified organism into the environment.

Genotype: The sum total of the genes of an organism, latent or expressed or the genetic
identity of an individual.

Genetically modified: Refers to an organism whose genotype has been modified by

application of biotechnology (e.g. gene transfer or chromosome set manipulation)

Insert: That part of a construct (see above) which is integrated into the recipient
organism's genome.

Micro-injection: The introduction of DNA into the nucleus of an oocyte, embryo or other
cells by injection through a very fine needle

Mitochondria (mitochondrion, singular): Highly pleiomorphic organelle of eukaryotic

cells that varies from short rod-like structures present in high number to long branched
structures. Has a double membrane and the inner membrane may contain numerous
folds (cristae). Houses several copies of mtDNA and a few hundred proteins which carry
on numerous biochemical and energy extraction functions and interact with the cell
nucleus genes. Major function of mtDNA is to regenerate ATP by oxidative
phosphorylation. Mitochondria are maternally inherited.

Non-coding Region: DNA sequences which lie outside of an open reading frame and
which are not translated to become part of a protein. These might include scaffold
attachment regions, promoters, leader sequences, enhancers, introns, terminators, and
any other sequences that are used for gene expression either in the plant or other hosts,
such as origins of replication, transposable elements, DNA borders, lox sequences, etc.

Nuclear reprogramming: Restoration of the correct embryonic pattern of gene

expression in a nucleus derived from a somatic cell and introduced into an oocyte.

Oocyte: The developing female gamete before maturation and release.

Phenotype: The observable characteristics of an organism (including physical,

biochemical or other traits) which may result from the interaction of the organism with its
environment.

Promoter: A regulatory element of a gene that specifies the start site of transcription.

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Retrovirus: An enveloped virus that replicates by reverse transcription of its RNA

genome into DNA, followed by integration of the DNA into the cell genome to form a
provirus (as though it were a cellular gene) that may lead to the production of progeny
virus particles.

Sire: A male parent of the domestic animal

Somatic cell: Usually any cell of a multicellular organism that will not contribute to the
production of gametes, ie. most cells of which an organism is made: not a germ cell.

Surrogate mother: A female that bears a child/ young one on behalf of some one else
who is unable to bear a child. The process is used routinely to bear many embryos
derived from a mother capable of bearing one young one at a time.

Totipotent: Capacity of a cell giving rise to all types of differentiated cells found in ant
organism. A single totipotent cell could, by division, reproduce the whole organism

Trait(s): The phenotypic characteristic(s) of an organism resulting from the interaction

of the organism’s genotype and its environment.

Transfection: Alteration of genome of a cell by direct introduction of DNA, a small

portion of which becomes covalently associated with the host cell DNA.

Transgene: A gene construct introduced into an organism by human intervention.

Transgenics: Organism that has stably integrated one or more genes from another
species ("trans") and can pass them on to successive generations.

Transposase: The enzyme responsible for moving a transposon from one place to
another.

Transposon: A DNA element capable of moving (transposing) from one location in

genome to another in the same cell through the action of transposase.

Vector: An autonomously replicating DNA molecule into which foreign DNA is inserted
and then propagated in a host cell.

Xenotransplantation: the transfer of living cells, tissue and/or organs from one species
to another, (e.g., transplant of a kidney from a pig into a human)

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Annex III, Canada: Novel Food Regulation (Health

Canada)
Canadian Food Inspection Agency:
http://www.hc-sc.gc.ca/fn-an/legislation/acts-lois/fdr-rad/division-titre28_e.html

Division 28 of the food and drug regulations

Novel Foods

Interpretation
B.28.001. The definitions in this section apply in this Division.
"genetically modify" means to change the heritable traits of a plant, animal or
microorganism by means of intentional manipulation. ( modifier génétiquement)
"major change" means, in respect of a food, a change in the food that, based on the
manufacturer's experience or generally accepted nutritional or food science theory, places
the modified food outside the accepted limits of natural variations for that food with
regard to
(a) the composition, structure or nutritional quality of the food or its generally recognized
physiological effects;
(b) the manner in which the food is metabolized in the body; or
(c) the microbiological safety, the chemical safety or the safe use of the food. (
changement majeur)
"novel food" means
(a) a substance, including a microorganism, that does not have a history of safe use as a
food;
(b) a food that has been manufactured, prepared, preserved or packaged by a process
that
(i) has not been previously applied to that food, and
(ii) causes the food to undergo a major change; and
(c) a food that is derived from a plant, animal or microorganism that has been genetically
modified such that
(i) the plant, animal or microorganism exhibits characteristics that were not previously
observed in that plant, animal or microorganism,
(ii) the plant, animal or microorganism no longer exhibits characteristics that were
previously observed in that plant, animal or microorganism, or
(iii) one or more characteristics of the plant, animal or microorganism no longer fall
within the anticipated range for that plant, animal or microorganism. ( aliment nouveau)

Pre-market notification
B.28.002. (1) No person shall sell or advertise for sale a novel food unless the
manufacturer or importer of the novel food
(a) has notified the Director in writing of their intention to sell or advertise for sale the
novel food; and
(b) has received a written notice from the Director under paragraph B.28.003(1)(a) or
subsection B.28.003(2).
(2) A notification referred to in paragraph (1)(a) shall be signed by the manufacturer or
importer, or a person authorized to sign on behalf of the manufacturer or importer, and
shall include the following information:
(a) the common name under which the novel food will be sold;
(b) the name and address of the principal place of business of the manufacturer and, if
the address is outside Canada, the name and address of the principal place of business of
the importer;
(c) a description of the novel food, together with
(i) information respecting its development,

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(ii) details of the method by which it is manufactured, prepared, preserved, packaged

and stored,
(iii) details of the major change, if any,
(iv) information respecting its intended use and directions for its preparation,
(v) information respecting its history of use as a food in a country other than Canada, if
applicable, and
(vi) information relied on to establish that the novel food is safe for consumption;
(d) information respecting the estimated levels of consumption by consumers of the
novel food;
(e) the text of all labels to be used in connection with the novel food; and
(f) the name and title of the person who signed the notification and the date of signing.

B.28.003. (1) Within 45 days after receiving a notification referred to in paragraph

B.28.002(1)(a), the Director shall review the information included in the notification and
(a) if the information establishes that the novel food is safe for consumption, notify the
manufacturer or importer in writing that the information is sufficient; or
(b) if additional information of a scientific nature is necessary in order to assess the
safety of the novel food, request in writing that the manufacturer or importer submit that
information.
(2) Within 90 days after receiving the additional information requested under paragraph
(1)(b) the Director shall assess it and, if it establishes that the novel food is safe for
consumption, notify the manufacturer or importer in writing that the information is
sufficient.

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Annex IV, Canada: Animal Health Risk Analysis

Framework for Biotechnology-Derived Animals
Canadian Food Inspection Agency:
www.inspection.gc.ca/english/sci/ahra/bioanima/bioanimae.shtml

November 2004
Acronyms

AAFC Agriculture and Agri-Food Canada

ABU Animal Biotechnology Unit

AHPD Animal Health and Production Division

AHRA Animal Health Risk Analysis

bp base pairs, referring to nucleotides

BSE bovine spongiform encephalopathy

BVDV bovine viral diarrhea virus

CFIA Canadian Food Inspection Agency

CEPA Canadian Environmental Protection Act

DNA deoxyribonucleic acid

EC Environment Canada

ES embryonic stem

GM genetically modified

GMO genetically modified organism

HC Health Canada

HGT horizontal gene transfer

ICSI intra-cytoplasmic sperm injection

ISH interspecies-hybrid

IVF in vitro fertilization

MI microinjection

M-MoLV Moloney murine leukemia virus

MOS mosaic animals (transgene present, but not in all cells)

mtDNA mitochondrial DNA

NSNR New Substances Notification Regulations

NT nuclear transfer (unmodified clone)

OIE Office International des Épizooties

PCR polymerase chain reaction

PERVs porcine endogenous retroviruses

PERT product-enhanced reverse transcriptase

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RNA ribonucleic acid

RV retroviral

SMGT sperm-mediated gene transfer

TG transgenic

VSV-MoLV vesicular stomatitis virus – Moloney murine leukemia virus

The Animal Health Risk Analysis Framework for Biotechnology-Derived Animals is a

protocol used by the Animal Health Risk Analysis Unit and the Animal Health and
Production Division to conduct risk analyses on animal health. The objective of this
framework document is to provide guidance to perform animal health risk assessments of
animals, and their derived products, regulated by the Animal Health and Production
Division. It is anticipated that the regulated animals will principally include terrestrial
mammalian and avian livestock species intended for release outside of research and
development facilities.

1. Introduction
The Animal Health Risk Analysis (AHRA) group within the Sciences Branch of the
Canadian Food Inspection Agency (CFIA) is responsible for conducting risk analyses and
providing scientific information and advice to the Animal Health and Production Division
(AHPD) of the CFIA in support of the National Animal Health Program. Risk analysis
includes the three interactive processes of risk assessment, risk management and risk
communication (Covello et al., 1993).
The Risk Analysis Framework for Biotechnology-Derived Animals is a protocol used by
AHRA and the Animal Biotechnology Unit (ABU) of the AHPD to conduct risk analyses
from the perspective of animal health. The general design of the document is modelled
after the Animal Health and Production Risk Analysis Framework (AHRA, 2004). The
protocol describes the processes followed for conducting animal health risk analyses and
provides guidelines for risk assessors and managers. The risk management and risk
communication are the responsibility of the AHPD for the animal health and ultimately for
Environment Canada and Health Canada which have legislative authority. However, when
appropriate, all parties participating in the risk assessment should be involved in risk
communication. This framework document will focus on the risk assessment process from
an animal health perspective.

1.1 SCOPE

"The assessment of risk for many genetically engineered organisms may be dauntingly
complex, combining as it does the micro-scale of molecular biology, biochemistry and
physiology with the macro-scale complexity of ecology, population genetics, behaviour,
biogeography, and evolutionary biology." (Scientist’s Working Group on Biosafety, 1998).
This framework is intended for the assessment of biotechnology-derived animal from the
animal health perspective. It is anticipated that the regulated animals will principally
include terrestrial mammalian and avian livestock species intended for release outside of
research and development facilities. For import commodities (biotechnology-derived), the
Animal Health and Production Risk Analysis Framework (AHRA, 2004) may be consulted,
which complements this document.
Biotechnology-derived animals in Canada are, currently, almost exclusively produced
from research and development activities of academic and commercial establishments.
Under CEPA, such animals may be exempted from government regulation that apply to
commercial production establishments, provided there is no release of the organism (or
animal), its genetic material or toxic material from the organism into the environment.
Further development of animal biotechnology research and applications leading to
commercial use of biotechnology-derived animals can be expected in the future. It is

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important for the public to have confidence in regulations which have implications on
animal health. To achieve this goal, regulatory assessments should be based on scientific
knowledge and assessment procedures must be sensible and practical. Therefore, the
need to develop an approach to conduct an animal health risk assessment for
biotechnology-derived animal was addressed by AHRA.
The objective of this framework document is to provide guidance to perform risk
assessments relating to biotechnology-derived animals. Although other considerations
such as human health, environment implications, genetic diversity and sustainability are
mentioned, the principal focus of this document is on the risks to animal health posed by
the production of cloned, transgenic and other animals derived from biotechnology.
Animal welfare considerations are also included in this document, reflecting the
involvement of the CFIA in this area (CFIA , 2002; Doonan, 2002), and consistent with
recommendations made by non-governmental advisory bodies (United States National
Academy of Sciences, 2002).
The risks associated with biotechnology-derived animal must be assessed individually.
This is warranted because of the large number of variables involved, these include:

the species involved,

the health status of the individuals and herds/ flocks involved,

the techniques and materials employed in the production of biotechnology-derived
animal,

the transgene used,

the potential for exposure to the environment (biological and ecological
characteristics of the animal),

the end use of the animal.

1.2 DEFINITION OF "BIOTECHNOLOGY" AND "BIOTECHNOLOGY-DERIVED

ANIMALS"
In several Acts and Regulations of Parliament (e.g. Canadian Environmental Protection
Act, 1999 (CEPA); the Health of Animal Regulations) biotechnology is defined as: "The
application of science and engineering to the direct or indirect use of living organisms or
parts or products of living organisms in their natural or modified forms".
The term "biotechnology-derived animals" is an extension of the definition of
biotechnology. It refers to animals which have been generated through biotechnological
methods. This term may include, but not be limited to, the following categories of
animals (Adlakha-Hutcheon, 2001):

genetically engineered or modified animals in which genetic material has been
added, deleted, silenced or altered to influence the expression of genes and traits,

clones of animals derived by nuclear transfer from embryonic or somatic cells,

chimeric animals,

interspecies hybrids,

animals derived from in vitro cultivation such as maturation or manipulation of
embryos.
Appendix 1 (Introduction to the Generation of Biotechnology-Derived Animals) describes
some techniques that are used to generate biotechnology-derived animals.

1.3 LEGISLATION
Currently in Canada, biotechnology-derived animals, such as transgenic and other
biotechnology-derived livestock animals are regulated under the Canadian Environmental
Protection Act, 1999 (CEPA) and its New Substances Notification Regulation (NSNR).
CEPA is co-administered by Environment Canada (EC) and by Health Canada (HC). Part
II.1 of the NSNR implements provisions of Part 6 of CEPA by prescribing the information
as well as the timelines for notifying Environment Canada of the intent to manufacture or
import such animal or its derived products. Environment Canada and Health Canada then
assess for whether or not the animal is toxic or has potential of being "toxic". The Novel
Foods Regulations under the Food and Drugs Act administered by Health Canada comes
into effect if the product is sold or advertised for sale as food. The CFIA is working in
collaboration with EC and HC to scientific and technical advise, including conducting

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animal health risk analyses. Under the authority of Health of Animals Act and Regulations
and Feeds Act and Regulations the CFIA administers and enforces regulatory controls
over animal health, animal products, veterinary biologics and livestock feeds.
On the basis of the end use for which an animal or its derived products is being assessed,
different government departments may be responsible for the assessment. The end use
of the product determines which department or agency may be responsible for
conducting an assessment. For example (the following list is not exhaustive):

If the animal or its derived products including semen, oocytes and embryos are
going to be imported, the CFIA would be consulted (Health of Animals Act and
Regulations).

If the production of recombinant products from the living animal is intended for
use in animal as veterinary biologic, the CFIA would be consulted for the
assessment (Health of Animals Act and Regulations).

If the production of recombinant products from the living animal is intended for
medical devices, xenotransplantation, therapeutic biologicals, cosmetic, veterinary
drug and industrial chemicals or biochemicals, Health Canada (Food and Drugs Act
and Regulations) and Environment Canada would be consulted for the assessment
(CEPA, 1999 and the NSNR).

If any animal parts, by-products or rendering materials is intended to be used as
livestock feed, or if intended to be used as a fertilizer the CFIA would be consulted
(Feeds Act and Regulations and Fertilizers Act and Regulations).

If any animal parts, by-products or rendering materials is intended to be used in
cosmetics, Health Canada (Food and Drugs Act and Cosmetic Regulations) and
Environment Canada would be consulted for the assessment (CEPA, 1999 and the
NSNR).
Environment Canada, Health Canada and CFIA work together to ensure that both the
food and the environmental safety and the health of the animal and the feed of the final
product are evaluated.

2. The General Process of Conducting a Risk Analysis

Risk analysis is the process of identifying the elements that pose risk, analysing their
likelihood and the significance of impacts, their management, and communicating them
to applicants, stakeholders and the broader community. Risk analysis consists of three
processes; risk assessment, risk management and risk communication. The Animal
Health and Production Risk Analysis Framework (AHRA, 2004) may be consulted for
further details.

3. Risk Analysis Procedures for Biotechnology-Derived Animals from an Animal

Health Perspective
3.1 INITIATION PROCESS
Figure 1 describes the steps of such a risk analysis procedure. The risk analysis process is
initiated by an applicant who makes an inquiry to Environment Canada and Health
Canada. Depending on the end use, the CFIA is then asked to collaborate with EC and HC
by providing scientific and technical advice from an animal perspective as to whether or
not to authorize an animal to be used. Whether the authorization is to consist of a single,
multiple use or on a continuous basis of an animal, the steps followed in the process of
approving the commodity remain the same.
Within the CFIA, the risk analysis process is initiated by a decision of the Director of the
Animal Health and Production Division to conduct a risk assessment. The Animal
Biotechnology Unit (ABU) is responsible of filling a specific form to request a risk
assessment (Appendix 2, Request for an Animal Health Risk Assessment of
Biotechnology-Derived Animals). The request should be endorsed by the Director of the
AHPD and sent to the Director of the Science Division, then on to the National Manager of
the AHRA Unit. Conformity with this process allows AHRA to respond appropriately to the
request. The Animal Health and Production Risk Analysis Framework (AHRA, 2004) may
be consulted for further details of the steps following an inquiry.

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Figure 1

The request form (Appendix 2) includes required information such as the history,
background and description of the commodity, including production protocols, the
volume, quantity, frequency and time-frames of the proposed release. In addition to the
request form, additional information, as described in Table 1 (for further details refer to
Appendix 3, Information Required for Conducting an Animal Health Risk Assessment), is
needed to conduct such assessment. This information will be supplied by EC and HC
through the schedule XIX of the New Substances Notification Regulation
(http://www.ec.gc.ca/substances/nsb/eng/B19ew_e.htm).

Table 1 Summary of Information Required

1. Summary Description of Animal

2. Reason for Production

3. Details of Production

3.1 Source of Genetic Material

3.2 Source of Donor Animals
3.3 Health Status of Donor Animals
3.4 Source of Recipient Animals

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3.5 Health Status of Recipient Animals

4. Cloned/ Transgenic Animal Production

4.1 Sources and Quality Control of Reagents

4.2 Detailed Description of Techniques Employed

5. Characterization of Cloned/ Transgenic Animals

5.1 Health Evaluation of Founder Animals and Subsequent Generations

5.2 Genetic Characterization
5.3 Transgene Product
5.4 Biological and Ecological Characteristics

Note: additional information could be requested if necessary (through EC and HC)

3.2 RISK ASSESSMENT PROCESS

The first step in the animal health risk assessment process is the identification of hazards
associated with the biotechnology-derived animal for which a request has been received.
This process occurs through the collection of evidence, including consultation with
officials both within Canada (CFIA and other Government Departments) and
internationally on a case by case basis.
The risk assessment process involves four other interrelated assessment steps: release
assessment, exposure assessment, consequence assessment and risk estimation. These
steps clarify the stages of the risk assessment, describing them in terms of the events
necessary for the identified potential risk(s) to occur, and facilitate understanding and
evaluation of the outputs. Figure 2 illustrates the processes involved in a animal health
risk assessment.

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Figure 2

Risk assessment principles:

• The risk assessment process should be flexible in order to deal with the
complexity of real life situations. No single method is applicable in all cases. This
is exemplified by the variety of animal commodities, methods and materials used
to produce the animal, the multiple hazards that may be related to the method of
production (biotechnology-derived animal), the different diseases’ epidemiology,
detection and surveillance systems, exposure scenarios and types and amounts of
data.

• Both qualitative and quantitative risk assessments have merit.

• An organizational arrangement that separates risk assessment from risk

management decision-making is encouraged to ensure that the risk assessments
are not influenced to fit prior regulatory conclusions.

• The risk assessment should be based on the best available information that is in
accord with current scientific thinking. The assessment should be well documented
and supported with references to the scientific literature and other sources,
including expert information elicitation (Appendix 4, Source Materials for Use in
Risk Assessments).

• Consistency and transparency in risk assessments should be encouraged to ensure

fairness and rationality, comparison of risks and ease of understanding by all

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interested parties. Consistency may be limited to similar biotechnology-derived

animal and depend on the types and amount of data available. Improvement in
risk assessment methods should supersede consistency.

• Risk assessments should illustrate the uncertainty in the risk estimation output.

• In general, the risk estimate increases with increasing volume or quantity of the
commodity (biotechnology-derived animal) released.

• The risk assessment should be amenable to updating when additional information

becomes available.

3.2.1 Hazard Identification

A hazard is defined as an agent, element or event that poses potential harm, an adverse
event or adverse outcome (AHRA, 2004). Hazard identification is a categorization step
identifying biological agents and genotypic and phenotypic hazards, dichotomously as
potential hazards or not, which could potentially be introduced with a commodity or
activity and for which pathways exist for exposure of the agents to susceptible animals.
The risk assessment is concluded if a hazard identification fails to identify potential
hazards associated with the release.
AHRA is responsible for identifying the hazards associated with biotechnology-derived
animals and their products, and conducting the risk assessment from an animal health
perspective for each hazard. The risk assessment process involves collecting evidence
and information and, on a case by case basis, consulting with experts nationally and
internationally. Often, officials in the CFIA Centres of Expertise and the associated
Biotechnology Testing Centers (Molecular Analysis and Testing Unit / MATU) are
consulted:
Charlottetown Laboratory, Charlottetown, Prince Edward Island
St-Hyacinthe Laboratory, St-Hyacinthe, Quebec
Ottawa Laboratory (Carling), Ottawa, Ontario
Ottawa Laboratory (Fallowfield), Ottawa, Ontario
Sidney Laboratory, Sidney, British Columbia
In contrast to conventional import risk assessments, hazards associated with
biotechnology-derived animals include consideration not only of hazards associated with
infectious pathogens, but also hazards related to the impact of the genetic modification
on animal health and welfare and hazards that have potential impacts on genetic
diversity and sustainability. However, as mentioned previously, the principal focus of this
document is on the risks to animal health posed by the production of cloned, transgenic
and other animals derived from biotechnology. Criteria to identify infectious hazards are
described in the Animal Health and Production Risk Analysis Framework (AHRA, 2004).
Genetic hazards are identified based on the scientific evidence found in the literature. In
the following table (Table 2) an attempt is made to list potential hazards related to the
techniques and methods used (more details are presented in Appendix 5: Hazards
Associated with Biotechnology-Derived Animals). These lists are not exhausted, other
hazards may be added when identified. Because of the broad scope of this document, the
large volume of the literature and the rapid pace of advancement in this field, the
references cited should not be interpreted as all inclusive. In a field as new as animal
biotechnology, genotypic and phenotypic hazards have not been completely identified
and characterized.

Table 2 Hazards Related to the Techniques and Methods Used in production of

Biotechnology-derived animals
1. Technique or Processes-Based Hazards
1.1 Adventitious Infectious Agent Transfer
1.2 Endogenous Retroviral Activation
1.3 Heteroplasmy of Mitochondria
1.4 Embryo Manipulation / Use of Cell Culture

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2. Transgene or Product-Based Hazards

2.1 Transgene Expression

3. Insertional Mutagenesis / Mutation-Based Hazards

3.1 Insertional Mutagenesis Mutation

4. Other Hazards

4.1 Transfer of Antibiotic Resistance Genes from Cells of TG Animals to the

Environment
4.2 Transfer of TG-bearing DNA through the Digestive Tract
4.3 Transfer of TG to Domestic Animal and Wildlife Population and Ecosystems

5. Hazards Associated with Interspecies-Hybrid Animals Produced by in vitro Techniques

The generation of a biotechnology-derived animal represents a sequential series of events

that cannot be viewed in isolation. For a biotechnology-derived animal that is a
transgenic, it begins with the generation of transgenic founder animals and ends with the
production of a group of transgenic animals exhibiting the desired trait. Risk must be
evaluated throughout this process to the production of at least one generations, and
should include consideration of whether or not the transgene is present in a heterozygous
or homozygous state. Cloned animals must be evaluated from the generation of the initial
cloned animal to the production of progeny.
In Appendix 6 (Adverse Effects Associated with Hazards of Biotechnology-Derived
Animals) an attempt is made to identify some adverse effects associated with the
hazards. This appendix also presents the techniques, types of biotechnology-derived
animal which can potentially express the effects, the release and the exposure pathways
associated with the hazards.

3.2.2 Risk Assessment Steps

Release Assessment
Release assessment consists of describing and quantifying the potential of a risk source
(the animal) to release or otherwise introduce a hazard into an environment accessible to
animal population, including the risk to the animal derived from biotechnology itself or its
progeny in subsequent generations.
With respect to the hazards posed by animals derived from biotechnology, release
assessment involves consideration of the prevalence of the hazard, the point at which the
hazard can be detected and the methods used to detect the hazard. The release
assessment typically describes the types, amounts, timing and probabilities of the release
of the hazard. In addition, the release assessment will include consideration of how these
attributes might change as a result of various actions, events or measures.
In a risk assessment for biotechnology-derived animals, the various types of hazards —
infectious, genetic — dictate the variety of inputs that need to be considered in the
release assessment. In addition, any assessment of the release of a hazard from a
biotechnology-derived animal must include consideration of the effects posed by animal
waste products.
Exposure Assessment
Exposure assessment consists of describing and quantifying the relevant conditions and
characteristics of animal exposure to hazards produced or released by a given risk
source. The exposure assessment typically describes the amount, timing, frequency,
duration of exposure, routes of exposure, and the number, species and characteristics of
the animal population that might be exposed.
Detailed information concerning the release and exposure assessment in relation to
identified hazards is presented in Appendix 6 (Adverse Effects Associated with Hazards of
Biotechnology-Derived Animals).
Consequence Assessment

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Consequence assessment consists of describing and quantifying the relationship between

specified exposures of a biological agent and the economic consequences of those
exposures. A causal process must exist by which exposures produce adverse animal
health or environmental consequences. The consequence assessment typically includes a
specification of the impact on health in the animal populations sustained under given
exposure scenarios. In conventional import related risk assessments, consequences are
related to infectious pathogens, and may include, but not be limited to:
• animal mortality and morbidity

• production losses (e.g. decreased reproductive efficiency, feed conversion etc.)

• costs associated with disease control (e.g. veterinary fees, vaccination, antibiotics,
depopulation, decontamination etc.)

• reduced markets (e.g. domestic or export, live animal or products)

• human health implications (e.g. zoonotic disease).

Such consequences still apply with respect to B-D animals. In addition, other
consequences related to unique genotypic and phenotypic hazards, such as the following,
should be considered:
• perinatal mortality and morbidity

• costs associated with genotypic and phenotypic changes in B-D animals (e.g.
immune function effects)

• loss of genetic diversity (e.g. in host and related species)

• costs associated with tracing B-D animals and their products

• effects related to commercial markets and consumer acceptance

• welfare concerns (repetitive invasive procedures, handling and restraint)

(Appendice 7: Animal Welfare in Canada and the Codes of Practice: Backgrounder
and Appendix 8: Welfare Evaluation in Three Successive Stages of a Transgenic
Animal Production Program),

• adverse consequences to the environment, including disruption of ecosystems and

native species extinctions

• costs associated with the control and eradication costs,

• quarantine and isolation costs,

• cleaning and disinfection costs,

• treatment costs,

• vaccination costs.
Risk Estimation
Risk estimation consists of integrating the results from the release, exposure and
consequence assessments to produce quantitative measures of animal health. The final
outputs of this process are estimates of the magnitude of possible adverse animal health
consequences, including a characterization of the probabilities, uncertainties or degree of
confidence associated with these estimates. Therefore, a risk estimation takes into
account the entire risk pathway from hazard identification to unwanted outcome. A
qualitative risk assessment is thus a summation of the findings of the release, exposure
and consequence assessments.
For quantitative assessments, the final outputs may include:

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• estimated numbers of herds, flocks, animals experiencing adverse health and

other impacts of various severities over time,

• probability distributions, confidence intervals and other means for expressing the
uncertainties in these estimates,

• portrayal of the variance of all model inputs,

• a sensitivity analysis to rank the inputs as to their contribution to the variance of

the risk estimation output,

• analysis of the dependence and correlation between model inputs.

3.3 PEER REVIEW
A draft of the animal health risk assessment document is produced and subsequently
distributed for peer review on a case by case basis. The importance of peer review,
particularly for risk assessments related to biotechnology, has been highlighted in several
reports and studies (e.g.: Canadian Biotechnology Advisory Committee, 2002).
The participants in a peer review are selected based upon nature of the risk assessment.
They may include:
• CFIA staff, including those of the CFIA Animal Biotechnology Unit,

• other Government of Canada staff,

• non-governmental specialists in industry and academia.

Comments received from reviewers, when appropriate are incorporated into the risk
assessment document.

3.4 ANIMAL RELEASE PROTOCOL

Recommendations of a release protocol from an animal health perspective for
biotechnology-derived animals are the responsibility of Animal Biotechnology Unit (ABU).
The recommendation are base on the tolerability of the estimated risk provided in the risk
assessment document.
Development of those recommendations protocol may involve further consultation with
CFIA expertise including the ABU, the AHRA Unit, Laboratory staff, Legal Services, etc.
It is important to recognize that, the final decision regarding release into the
environment of a biotechnology-derived animals or animal products is the responsibility
of Environment Canada and Health Canada.
Considerations associated with the release protocol and risk management options may
include, but not be limited to:
• biocontainment requirements for the animal or product (semen, embryo...)

• any breeding restrictions,

• allowable uses for the product,

• domestic or international use,

• requirements for labelling,

• requirements for traceability,

• monitoring requirements – gene stability, health effects, gene expression, etc.,

• effect of release on natural populations and on the ecosystem.

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3.5 ANIMAL HEALTH AND PRODUCTION DIVISION - RISK MANAGEMENT

DECISION
When finalized and approved by the Director of AHPD, recommendations from an animal
perspective to to accept (or not) the release of a biotechnology-derived animal into the
environment are sent to Environment Canada and Health Canada.

4. Risk Management
Options are provided to risk managers to continue in the risk management process. Risk
management comprises a number of measures, however not all are necessarily included
in every risk analysis. The elements of risk management include:
• Risk evaluation: the aspect of risk management concerned initially with the
decision to request a risk assessment, and secondly, with interpreting, comparing,
judging the significance of and deciding the tolerability of the risk as estimated in
a risk assessment document.

• Option evaluation: the process of identifying, evaluating the efficacy and

feasibility, and selecting risk mitigation measures (in addition to those that may
have been considered in the initial risk assessment) in order to reduce the animal
health risk associated with biotechnology-derived animals. The efficacy is the
degree to which an option reduces the likelihood and magnitude of adverse
biological and economic consequences. Evaluating the efficacy is an iterative
process that involves incorporation into the initial risk assessment, which is then
re-evaluated to determine the degree of risk reduction. The evaluation for
feasibility normally focuses on technical, operational and economic factors
affecting the implementation of the risk management options.

• Implementation: proper actions are taken following the risk management decision
on acceptance or refusal of the release.

• Monitoring and review: the ongoing process to observe the release and conduct a
review, if necessary, of the risk assessment, the risk mitigation measures and the
risk management decision.
5. Risk Communication
Risk communication takes place throughout the risk analysis process. The interactive
exchange of information on risk occurs among risk analysts, risk managers and other
interested parties. It begins when a risk analysis is requested and continues after the
implementation of the decision (acceptance or refusal) on the animal. Risk
communication is an integral component of the risk analysis and risk management
process, and should not be considered an "add-on". Risk communication with
stakeholders is principally the responsibility of the Environment Canada and Health
Canada, however risk communication should be carried out by all parties involved in the
risk assessment, when appropriate.
The widespread and deep interest of the public in biotechnology makes it imperative that
risk communication is a priority. In 2001, the CFIA Public and Regulatory Affairs Branch
produced a discussion paper entitled "Risk Communication and Government: Theory and
Application for the Canadian Food Inspection Agency".
Once reviewed and approved, the animal health risk assessment for biotechnology-
derived animal documents will be available via the CFIA website.

5.1 PRINCIPLES OF RISK COMMUNICATION

• The communication of risk should be an open, interactive and transparent

exchange of information that may continue after the decision on release.

• The principal recipients of risk communication include, in addition to the applicant

and the other Government Departments, the authorities and other stakeholders

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such as domestic and foreign industry groups, domestic livestock producers and
consumer groups.

• Peer review should represent a component of risk communication in order to

obtain scientific and analytical critiques, and to ensure the validity of the scientific
data, methods and assumptions.

• The uncertainty in the model, model inputs and the risk estimates of the risk
assessment should be communicated.
REFERENCES
Adlakha-Hutcheon, G., (2001). "Transgenic Animal Safety Assessments: Transgenic
Avian Species / Internal Report", Animal Biotechnology Unit , Animal Health and
Production Division, Internal report, CFIA.

Animal Health Risk Analysis Unit (AHRA), (2004). "Animal Health and Production Risk
Analysis Framework", AHRA, Science Division, CFIA.
(http://www.inspection.gc.ca/english/sci/ahra/rianfrwk/rianfrwke.shtml)

Canadian Biotechnology Advisory Committee, (2002). "Improving the Regulation of

Genetically Modified Foods and Other Novel Foods in Canada." Report to the Government
of Canada, Biotechnology Ministerial Coordinating Committee. (http://cbac-
cccb.ca/epic/internet/incbac-cccb.nsf/vwGeneratedInterE/ah00186e.html#sum)

Canadian Food Inspection Agency, (2002). Draft: "Farm Animal Welfare Infrastructure."
CFIA Performance Measurement and Program Support, Animal Health and Production
Division, CFIA.

Canadian Food Inspection Agency, (2001). "Risk Communication and Government:

Theory and Application for the Canadian Food Inspection Agency." CFIA Public and
Regulatory Affairs Branch. (http://www.inspection.gc.ca/english/corpaffr/
publications/riscomm/riscomme.shtml)

Covello, V.T. and Merkhofer, M.W., (1993). Risk assessment methods: Approaches for
assessing health and environmental risks. Plenum Press, New York, 319 p.

Doonan, G., (2002). "So what does a food inspection agency have to do with animal
welfare?" CFIA Officer Training Program, CFIA.

Scientist’s Working Group on Biosafety, (1998). Manual for Assessing Ecological and
Human Health Effects of Genetically Engineered Organisms. The Edmonds Institute,
Washington DC, (http://www.edmonds-institute.org/manp1os.pdf)

United States National Academy of Sciences, (2002). Animal Biotechnology: Science-

based concerns., Chapter 6, National Academy Press, Washington, DC, USA.

GLOSSARY OF TERMS

Aneuploid: Of nuclei, cells or organisms having more or less than an integral

multiple of the typical haploid chromosome number. (Penguin
Dictionary of Biology (PDB))

Apoptosis: Programmed individual cell death that occurs normally in development,

during aging and in various pathologic conditions. (The University of
Kansas Medical Center: http://www.kumc.edu/instruction/
medicine/pathology/ed/keywords/kw_apoptosi.html)

Blastocyst: Stage of mammalian development at which implantation into the

uterine wall occurs, the inner cell mass spreading inside the blastocoele

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as a flat disc. (PDB)

Chimera: Usually applied to organisms which (unlike mosaics) are comprised of

cells of two or more distinct genomes resulting from experimental
manipulation (e.g. grafting or aggregation) early in development.
(PDB)

Clone: 1) A group of organisms of identical genotype, produced by some kind

of asexual reproduction and some sexual processes.
2) A group of cells descended from the same parent cell.
3) Nucleic acid sequences are said to be cloned when they are inserted
into vectors and then copied along with them within host cells. (PDB)
4) An organism produced asexually, usually by a fusion of a cell
(embryonic or adult) with an enucleated oocyte.

DNA: Deoxyribonucleic acid.

Electroporation: Process by which an electric potential applied across cells in culture

disrupts their membranes sufficiently to create tiny pores, through
which DNA can be taken up.

Epigenesis: In modern terms, relating to those mechanisms by which DNA is

contextualized, controlled and regulated to produce changing patterns
of gene expression in the face of changing environmental signals. A
central tenet is that DNA sequence information, by itself, contains
insufficient information for determining how gene products interact to
produce any kind of mechanism. (PDB)

Epigenetic A factor that influences the phenotype without influencing the

influence: genotype. (Colour Atlas of Genetics [CAG])

Imprinting, Different expression of an allele or chromosomal segment depending on

genomic: the parental origin. (CAG)

Mitochondrion: Cytoplasmic organelle of all eukaryotic cells engaging (mainly) in

aerobic respirations, and the source of most ATP (adenosine tri-
phosphate) in these cells. Plural is mitochondria. (PDB)

Mixoploidy: A tissue or individual having a mixture of cells with a different number

of chromosomes (chromosomal mosaic). (CAG)

Mosaic: Organism comprised of clones of cells with different genotypes derived,

however, from the same zygote (unlike chimeras). (PDB)

Pleiotropy: The ability of allelic substitutions at a gene locus, or a cell product, to

affect or to be involved in the development of more than one aspect of
a phenotype. (PDB)

Position effect: Occurrence of phenotypic change resulting, not from gene mutation as
such, but from a change in position of a piece of genetic material.
(PDB)

Retrovirus: A member of the family Retroviridae, RNA viruses for which the
replication cycle involves the integration of a DNA copy of the virus
genome, produced by reverse transcription, into the chromosomal DNA
of the host cell. This property has been exploited by the use of
retroviral vectors for the insertion of foreign DNA into cells and
organisms.

Stem cell: Undifferentiated cells of either embryonic or adult origin which divide to
produce one stem cell and another which can pass along a specific
differentiation pathway.

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Transgene: Any gene introduced by gene manipulation from one organism into an
organism of a different species (i.e. xenogeneic). Can also be from the
same species under a new promoter (i.e. autogenic).

Zygote: Cellular product of gametic union. (PDB)

Sources:
PDB Thain, M. And Hickman, M. (2000). Penguin Dictionary of Biology, 10th Edition.
Penguin Books, London UK.
CAG Passarge, E. (2001). Colour Atlas of Genetics, Second Edition. Thieme, Stuttgart.

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 Annex V

Annex V, Argentina: Application for Permit for

Experiments with and/or Release into the Environment
of Genetically Modified Animals

(ANNEX to Resolution No. 57/2003)

Application for Permit for Experiments with and/or Release into the
Environment of Genetically Modified Animals

The Permits to Experiments with and/or Release into the Environment of Genetically
Modified Animals will be granted by the Secretary of Agriculture, Livestock, Fisheries and
Food.

REQUIREMENTS

The information in the Application will be used to assess whether granting the permit to
experiment with and/or release into the environment GMAs is within the agricultural
interests. It is absolutely forbidden to experiment with and/or release into the
environment GMAs without proper authorization by the competent authority.

1. Permit to experiment with and/or release into the environment a GMA shall be
requested in the following cases:
1.1. tests with animals in controlled conditions
1.2. field trials
1.3. imports of genetically modified organisms, gametes or embryos

In case of lab-bioterium experiments, including in vitro production of GM gametes or

embryos, the applicant shall describe the experiment for CONABIA to assess the need to
request biosafety conditions.

2. Transformation experiments must have uniform names within the Application and
these should be consistent with those used in the subsequent Applications related to
the same event or events.

3. Any natural or artificial person, hereinafter the Applicant, may request a permit to
release a GMA into the environment.

4. For the processing of the permit, the Applicant shall appoint a Legal Representative to
the corresponding legal effects and at least one Technologist in Charge.

5. The Applicant shall convincingly prove his/her legal personality and the qualifying
powers pertaining to his/her Legal Representative.

6. The information presented by the Applicant or the Legal Representative(s) as part of

the file submitted to request a permit to release a GMA into the environment shall
have affidavit status.

7. The Applicant shall establish his/her legal address within the area of the Ciudad
Autónoma de Buenos Aires and state his/her current address.

8. The Applicant shall submit the Application for a Permit to Experiment with and/or
Release into the Environment a GMA (hereinafter Application) duly completed.

9. The Applicant shall submit the Application, in Spanish, to the SAGPyA. Every page
must be signed by the Legal Representative. The Technologist in Charge must sign
where indicated. FIFTEEN (15) hard copies and ONE (1) electronic copy of the
Application. The Application for permits to experiment with and/or release into the

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environment GMAs, including reproductive material, must be submitted to the

National Agrifood Health and Quality Service – SENASA – with a letter addressed to
the Directorate of International Traffic at Paseo Colón Ave. No. 367, 5° Floor, Front,
1067, Ciudad Autónoma de Buenos Aires, Tel. 0054-11-43316041/9.

10. The remarks on scientific knowledge on the subject matter of the presentation stated
by the Applicant in the documents mentioned in point 8 above shall be accompanied
by bibliographic references. Complete bibliographic references shall be available in
their original language. By request of CONABIA, if the bibliography were in other
language than Spanish, a translation certified by a public translator must be
attached.

11. Any Application for a permit to experiment with and/or release into the environment
GMAs that involves activities connected to the use of genetically modified material,
such as pathogens infection, parasites infestation and material sampling, shall
include the corresponding protocol and the information of the professional in charge
of any such actions.

12. The experiments with and/or releases into the environment of GMAs may only take
place after the Applicant has been notified by SAGPyA about the pertaining approval.
If permit is denied, the competent authority shall determine the destination and
disposition of unused material.

13. The permit to experiment with and/or release into the environment the GMA subject
of the Application granted by the competent authority may be used by the Applicant
only.

14. Failure to comply with the risk management and biosafety conditions agreed upon at
the moment of granting the permit may result in the partial or complete destruction
of the material involved and, eventually, in the withdrawal of the permit.

16. In case of importing test material into the country, such material must comply with
the Animal Quarantine and Health regulations in force.

17. The Genetically Modified Animals and/or its products, including reproductive material,
must comply with the animal health regulations established by the competent
authority to prevent risks to human and/or animal health or the environment (Law
No.130636/49, its norms, and the regulatory framework for veterinary products,
Mercosur Resolution No. 345, dated April 6, 1994.)

18. The Applicant shall at all times be responsible to comply with the risk management
and biosafety conditions stipulated when the permit to experiment with and/or
release into the environment a GMA is granted. The Applicant shall be held
responsible throughout the experiment duration and after its termination as
CONABIA establishes (see point 20) regardless of any modification or alteration to
the natural or artificial person of the Applicant during said period of time.

19. The information on the site where the experiment or the release will take place shall
include maps and the lease agreement, should the site not belong to the Applicant.

20. The Applicant shall be responsible for controlling the access to the site where the
experiment takes place. Personnel in charge of handling the materials and/or animals
involved should be technically qualified and have thorough knowledge of the kind of
material being used.

21. The permit will include a period of time, after the project termination, during which
the Applicant shall be responsible for the site where the experiment took place.

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22. The Applicant shall facilitate the inspections to the site where the Genetically Modified
Animals are and cover the expenses stipulated for each one of them. Inspections
shall be performed by the agents authorized by the SAGPyA to that end, and shall be
as frequent as deemed necessary during the development of the experiment as well
as during the established period after project termination.

23. The Applicant must give immediate oral notification and written notification within
TWNETY-FOUR (24) hours to CONABIA in the following cases:
- Accidental release of the Genetically Modified Animal and/or its products,
- If the Genetically Modified Animal or the associated host organism present
characteristics different from those expected,
- If there is an abnormal situation (excessive mortality, sickness or unforeseen
effects on other organisms.)

24. In case of accidental escape of the GMA, the Applicant must immediately notify the
Technical Coordination at CONABIA at the address provided in point 9 above and
implement the contingency plan proposed in the Application.

25. Should the Applicant desire some information included in the Application remain
confidential, the abbreviation CID184 (Confidential Information Deleted) must be
written on the front of the Application and in the body where the information was
omitted.

26. In the case of Applications with CID, the Applicant shall submit to the Directorate of
International Traffic of SENASA at the address provided in point 9 above in a sealed
and signed envelope, a complete Application in which the information to be kept
confidential (Confidential Information, hereinafter CI) has been highlighted. This
document must be marked “Copy with CI” on the top right-hand corner of every
page. The bibliographical information considered confidential must be submitted with
the rest of the CI.

27. The following information may not be considered CI:

a. Name of transformation experiment
b. Phenotypic characteristics to be inserted into the GMA
c. Name and address of the Applicant, Legal Representative and Technologist in
Charge.
d. Purpose of the requested permit.
e. Location of the experiment.
f. Methods and procedures to control the GMA and to act in case of emergency.
g. Final disposition of biological material.
h. Necessary information for the biosafety assessment.

28. The Directorate of International Traffic of SENASA shall be responsible for the
safekeeping of CI according to the regulations in force.

29. CONABIA shall provide a rooster of experts qualified to assess the document marked
as “Copy with CI”. The Applicant must agree to the review of the documentation by
sending a written notification to the Technical Coordination of CONABIA, at the
address provided in point 9 above. The Applicant shall have the right to choose ONE
(1) primary reviewer and TWO (2) additional reviewers from the rooster as well as to
suggest an expert ad referendum from CONABIA. Both the primary reviewer and
CONABIA may request the CI be assessed by a subcommittee formed by the primary
reviewer and the TWO (2) additional reviewers selected. The Applicant may, in the
same statement of agreement, designate a representative to be present at the
review of the CI.

184
In Spanish “ICE” (Información Confidencial Eliminada).

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30. Those present at the review of the CI shall sign THREE (3) identical copies of the
certificate in which the opinion of the experts is included. ONE (1) copy shall be
delivered to the Applicant.

31. Any request to modify an already approved Application or an Application still at the
assessment stage must be notified in writing to the Technical Coordination of
CONABIA and directed to the address provided in point 9 above to be reviewed by
the Committee. The Applicant may only apply the modification to the experiment
after having received notification attesting a favorable decision.

32. During the established period after project termination, the Applicant must yearly
notify to the Technical Coordination of CONABIA at the address indicated in point 9
above about the use given to the site used for the experiment and about any new
developments that might have taken place. This information shall be verified through
the corresponding inspections.

33. The Applicant must submit to SAGPyA at the address provided in point 9 above a
Final Report, in compliance with the form to that end, within ONE HUNDRED AND
EIGHTY (180) calendar days after the experiment termination. The Final Report must
be signed by the Legal Representative on each page and FIFTEEN (15) hard copies
and ONE (1) electronic copy must be submitted to be assessed by CONABIA. The
Report shall detail the behavior, in compliance with the information requirements
specified when SAGPyA granted the permit.

34. In case of experiments approved for more than ONE (1) year, the Applicant must
submit annual reports during the development of the project to the address provided
in point 9 above. The Legal Representative must sign every page. FIFTEEN (15) hard
copies and ONE (1) electronic copy must be submitted to be assessed by CONABIA.

35. The Applicant must also submit the Final Report in those cases when, for any reason,
the experiments have not been completed. The Legal Representative must sign each
page, and FIFTEEN (15) hard copies and ONE (1) electronic copy must be submitted
to be assessed by CONABIA.

36. The submission and favorable assessment of the reports mentioned in points 33, 34
and 35 above are essential requirements that the Applicant must comply with in
order to request a new permit to experiment with and/or release into the
environment of GMAs.

37. The procedure for requesting a permit will be properly concluded when the correct
management of the authorized experiments has been verified and the reports
required under points 33, 34 and 35 above have been favorably assessed.

Application for Permits for Experimental Release into the Environment of

Genetically Modified Animals under confined conditions

A. SUMMARY

1. Applicant:

2. Organism subject to control:

Scientific name:
Common name:

3. Inserted trait(s):

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4. Identification of the used construct:

Name(s) and/or number(s);

Breeder:

5. Introduced gene(s). Nucleotide sequences.

Main gene(s):
Accompanying gene(s):
Sequences of: markers, promoters, termination signals, introns, others. In case of
inserting large DNA segments in vectors such as artificial chromosomes, a detailed
restriction map should be included if the complete sequence has not been
determined.

6. Type of permit requested (See page 1, point 1):

7. Quantity of GM material:

8. Previous permit(s):
8.1 In Argentina
Date:
Permit No:

8.2 In other countries

Date:
Granting institution:
Permit No:

Application for Granting Permits to Experiments with and/or Release into the
Environment under confined conditions of Genetically Modified Animals

B. APPLICATION FORM

1. This Application for a permit to release this transformation experiment

before the CONABIA is: (check what applies)

( ) New
( ) Renewal. File No:

2. In case of imported material released in another country, indicate:

Country of origin:
Permit No:
Granting institution:
Type of permit granted:

3. If this material is being tested in another MERCOSUR country, indicate:

Country:
Release date:
Permit No:
Granting institution:
Type of permit:

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4. Applicant information:

Name:
Legal address:
Current address:
Phone:
FAX:
E-mail address:

4.1 Legal Representative:

Name:
Current address:
Phone:
FAX:
E-mail address:
Institution:
Position:

4.2 Technologist in Charge

Name:
Current address:
Phone:
FAX:
E-mail address:
Institution:
Position:

4.3 Name and position of any other person, in addition to the Legal Representative
and the Technologist in Charge, that will be responsible for planning, supervising,
monitoring, and safeguarding the experiment with and/or release into the
environment of GM animals.

5. Type of permit requested: (check what applies)

( ) Bioterium

( ) Repetition of bioterium

Place(s) where the previous tests were carried out in Argentina:

Permit or file No:
Date:

( ) First field trial

( ) Repetition of field trial

Place(s) where the previous trials were carried out in Argentina:

Permit or file No:
Date:

6. Purpose of experiment:
In a paragraph, describe the purpose of the experiment subject to this application.

7. Movement of the Genetically Modified Animals:

Describe the mean(s) of transport used to move locally developed animals and/or the
mean(s) used to import them to the country.

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8. Release characteristics (for locally developed animals):

8.1 Number of animals to be released/produced:

8.2 Place and institution of the material origin:
8.3 Movement date(s) within the country:
8.4 Field or bioterium release date(s):
8.5 Destination within the country and/or site where the release and/or handling will
take place:

9. Characteristics of the introduction to the country of genetically modified

animals, gametes or embryos:

9.1 Number of animals/gametes/embryos to be introduced:

9.2 Country, place and institution of origin of the material:
9.3 Import date(s) (introduction to the country):
9.4 Movement date(s) within the country:
9.5 Release date(s) into field or bioterium:
9.6 Port of arrival:
9.7 Destination within the country and/or place where the release and/or handling will
take place:

10.Describe the genetically modified animals, gametes, and embryos.

Complete the following points as appropriate:

10.1 Donor organism(s):

Scientific name(s):
Common name(s):
Other denomination(s):

Genetic elements, whether their function or expression is expected or not:

10.1.1 Main gene(s):
10.1.2 Inserted marker gene(s):
10.1.3 Other accompanying sequences (promoters, etc):

10.2 Recipient organism

Scientific name(s):
Common name(s):
Other denomination(s):

10.3 Vector or vector agent, whether expressed or not:

Scientific name(s):
Common name(s):
Other denomination(s):

10.4 Other means of introduction of the transgene:

11.Brief description of any biological material (such as means and serum)

used for the cultivation of gametes and embryos (if applicable):

12.Detailed description of the biosafety methods and procedures, methods to

eliminate and/or inactivate supposed accidental contaminants and
sterility controls that have been used in the country of origin:

13.Detailed description of the biosafety methods and procedures, methods to

eliminate and/or inactivate supposed accidental contaminants and
sterility controls that have been used in Argentina to prevent the
pollution, release or dissemination into the environment of the GMA

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during each stage of the experiment, as well as each GMA component

subject to control in any type of permit requested:
In this point, the bioterium, the trial fields, the surrounding area and the processing
places should be described.

13.1 Bioterium test:

a) Description of the site and its location. Biosafety level according to the WHO
b) Amount of GMAs to be used
c) Isolation and biosafety measures
d) Proposed methods to control potential vectors of any kind of recombinant genetic
material
e) Techniques to detect genetic modifications in the selected animals
f) Techniques to detect gene transfers from the GMA to the biotic environment

13.2 Field trials

a) Description of site and exact location on a map, including orientation marks

b) Detail size and infrastructure (fences, funnels, etc.)
c) Amount of GMAs to be used
d) Description of surrounding area (animals, geographic accidents, settlements, etc)
e) Lease agreement, should the applicant not owe the field, having the signatures
certified by notary public, the police, or a national public agent.
f) Proposed isolation measures
g) Proposed methods to control potential vectors of any kind of recombinant genetic
material
h) Techniques used to detect the presence of the transgene and its availability within
15 (fifteen) days
i) Techniques to detect gene transfers from the GMA to the biotic environment
j) Confinement conditions
k) Distance to closest roads, to heavily traveled areas and to the field limits

14.Detailed description of the method proposed for the final disposition of

the GMAs and all the material used in the experiment. If antibiotic
resistant genes had been used, the procedures to dispose excreta should
be described:

14.1 Bioterium tests: provide information about the destination of the waste
material and the treatment it will receive
14.2 Field trials: detail the destination of the GMAs after the termination of the
experiment
14.3 In case of accidental escape of the GMA of its confinement conditions, the
proposed control method should be described

15.Submission date:

Application for Granting Permits to Experiment with and/or Release into the
Environment Genetically Modified Animals

C. ADDITIONAL INFORMATION

1. Names, addresses, phone and FAX numbers, e-mail addresses of the

people who developed/provided the GMA(s) and/or the gametes and/or
embryos from which they are derived:

2. Country, city and institution (name, address, phone and FAX numbers and
e-mail address of the responsible scientist) where the recipient organism
and the vector or vector agent have been taken, developed and/or
produced:

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3. Characteristics of the material:

3.1 Regarding the organism subject to control, in this point it should be included
(when applicable):
3.1.1 Scientific name and a brief phenotypic description
3.1.2 Very detailed description of the following points:
a) Recombination and/or crossing probabilities with organisms of the same or other
species
b) From the selective pressure perspective, describe the possible advantages and
disadvantages the modified organism might have over the original species in
natural environments (invasiveness)
c) Possible alterations to the animal’s wellbeing derived from the inserted genetic
modification
d) Hereditary pattern of the inserted trait in the GMAs
e) Information about any toxic or harming effect to human, animal or environmental
health that may occur due to the genetic modification.

3.2 Detailed description of the molecular biology of the donor-vector-recipient system

that has been used or will be used in the production of the GMA subject to control.
In this point, it should be included:
a) Brief description of the donor species gene
b) Identification of the vectors including a map of the plasmid vectors had this
system been used. The vector characteristics, such as marker genes and
promoters, should be described and the genes expression levels should be
indicated. The nucleotide sequences homologies with pathogens such as viruses
should be identified, and a supported assessment of the probabilities and
expected consequences of an eventual genetic recombination that may generate
pathogens (such as the generation of new pathogen breeds) should be submitted.
If large DNA segments have been inserted into vectors such as artificial
chromosomes, a detailed restriction map should be included if the complete
sequence has not been determined.
c) Identification (when known) of the genetic product and the affected metabolic
pathway
d) Description of the effect(s) the genetic product has on the host organism or on
those organisms that it may accidentally reach. Include description of the
secondary metabolites to assess the components that may enter the food chain.
e) Include background information on the gene transfer to the same or other species

3.3 In case of organisms with deletions of insertions that modify and/or add any
function, it should be included:
a) Description of the added and/or modified function
b) Effects on the modified organisms regarding their physiologic, biochemical, etc.
characteristics
c) Transmission mechanisms of the genetic modification, resistance method and
persistence in the environment and the host
d) Possible interactions of the GMA with other organisms in the ecosystem where the
experiment and/or release is carried out. Analyze, in particular, the probabilities of
successfully competing with the original species in different ecosystems
e) Hereditary pattern of the inserted trait in the GMA
f) Information on any toxic or harmful effect to human, animal or environmental
health that may occur due to the presence, contact, manipulation or processing of
the GMA or products derived from it.

4. Detailed description of the purpose of the experiment and the proposed

schedule of the procedures carried out on the GMA:

In this point, the background and the results of experiments conducted in the country
and abroad that have not been described in point 6 of the Application should be

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included.

5. Detailed description of proposed destination:

a) Include the final destination as well as intermediate destinations

b) Uses and/or distribution of the GMA, products and subproducts as well as all the
material used in the experiment
c) Specify whether the material will be exported. In such case, indicate the
destination port, country and town
d) If the genetic material of the GMA (embryos, gametes or somatic cells) will be
kept, indicate the site and the biosafety conditions in which it will be kept and the
use it will be given.

6. Transportation

In this point, the proposed method of transportation to locally move the GMA to its
final or intermediate destinations should be specified for both locally developed and
imported animals.

Signature of the Legal Representative Signature of the Technologist in Charge

Print name Print name

Application for Granting Permits to Experiment with and/or Release into the
Environment Genetically Modified Animals

E. FINAL REPORT

1. Name of the institution:

2. Common and scientific name of the organism subject to control

3. Identification of the transformation event(s):

4. Tested material(s) (gametes and somatic cells):

5. Inserted trait(s):

6. Location of experiment (including province, town, name of

institution or settlement):

7. Purpose of experiment:

8. Start and Termination dates:

9. Final design of experiment:

10.Experiment results on inserted trait(s):

11.Studies and/or analysis on the GMAs, some of them or their

subproducts:

12.Expected results of the experiment and/or release:

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13.Unexpected results of the experiment and/or release that might be

observed:

14.Final disposition of the genetically modified material:

15.Final disposition of the materials connected to the project (excreta,

secretions, tissue among others):

16.Method used in the final disposition of the elements used in the

experiment:

17.Compliance with the biosafety conditions set by CONABIA for lab,

bioterium and /or field after the experiment termination:

18.Observations:

19.Final Comments:

Signature of the Legal Representative Signature of the Technologist in Charge

Print name Print name

WE HEREBY STATE on our own and on behalf of our principal

....................................................................................

1) That we know and accept the terms of this Norm.

2) That the information included in this Application is complete and accurate. We

acknowledge that false or inaccurate information or any forgery of the documentation
will result in the rejection of the Application or the withdrawal of the issued permit, if
already granted.

3) That we will execute the directives of the competent authority and that failure to
comply with the biosafety conditions established by the SECRETARIAT OF
AGRICULTURE, LIVESTOCK, FISHERIES AND FOOD and/or by CONABIA will result in
the withdrawal of the issued permit for the File No ……………………… of the Register of
the NATIONAL AGRIFOOD HEALTH AND QUALITY SERVICE.

4) That failure to comply with what has been stated in the preceding paragraph, in case
of withdrawal of the permit, shall result in the destruction of the material related to
the granted permit and that the company will remain ineligible to obtain permits
related to genetically modified materials the following year.

5) That we are to be held entirely responsible for the management of the GMA at all
stages of its handling and we assume complete civil and commercial responsibility.

Signature of the Legal Representative Signature of the Technologist in Charge

Print name Print name

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With respect to risk assessment regarding
genetically modified animals, this report is
one of the first with a synoptic representa-
tion of relevant aspects and statutory in-
struments as well as identified need for ac-
tion.
The focus lies on questions of risk assess-
ment regarding genetically modified agri-
cultural animals including fish intended for
use as food as well as on animals that have
been genetically modified in the course of
so-called gene pharming, furthermore, ex-
amples of genetically modified pet animals
have been compiled.

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