Überschrift 1 - Bundesministerium für Gesundheit und Frauen

Transcription

Transgenic Animals
Developments regarding transgenic animals since 2007 including
risk assessment and status-quo in respect of cloned animals
Impressum
Herausgeber, Medieninhaber und Hersteller:
Bundesministerium für Gesundheit, Sektion II
Radetzkystraße 2, A-1030 Wien
Für den Inhalt verantwortlich:
Dr. Ulrich Herzog, BMG
Autorin:
MMag. Alice Schmatzberger, Gumpendorferstraße 63b, 1060 Wien
Titelbild:
Image Source / Digidas
Druck:
Kopierstelle des BMG
Bestellmöglichkeiten:
Telefon: +43-0810/818164 (Ortstarif)
E-Mail:
broschuerenservice@bmg.gv.at
Internet:
www.bmg.gv.at
ISBN 978-3-902611-58-1
Erscheinungsjahr: Februar 2012
CONTENT
INTRODUCTION ........................................................................................................................................5
1
TRANSGENIC ANIMALS ......................................................................................................................7
1.1 Livestock ..................................................................................................................................... 7
1.2 Fish ............................................................................................................................................ 13
1.3 Insects / Arthropodes ............................................................................................................... 19
2
GENE PHARMING .............................................................................................................................28
3
CLONING OF ANIMALS .....................................................................................................................34
4
SUMMARY........................................................................................................................................41
ZUSAMMENFASSUNG ............................................................................................................................46
REFERENCES ...........................................................................................................................................51
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Page 4 of 54
INTRODUCTION
Transgenic animals are being developed for various reasons, e.g. to serve as model organism in basic
research, as faster growing farm animals, for being disease resistant, with altered compositions for
food products or within the production of pharmaceutically relevant proteins. Cloning of animals is
mainly used for spreading certain features identified as being beneficial in breeding. Progeny of such
animals are derived through sexual reproduction and are being potentially intended for food uses.
The successful development of a genetically modified animal is a lengthy process. Despite the already
long-running and extensive research work done, transgenic animals have up till now attained rather
little 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 complex biological backgrounds. Most of the
characteristics interesting in the context of agricultural animals are conditioned by more than one
gene, a further factor that makes concrete implementation more difficult. Molecular mechanisms for
the integration of new DNA sequences in mammalian genomes are also still the object of on-going
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) - resulting in a rather low rate of success in the creation of transgenic animals.
Therefore, numerous projects on the production of transgenic animals are directed in particular at
the augmentation of scientific knowledge and the development of efficient methods. The same
applies to efforts of cloning of animals.
Within the present expert opinion the most recent developments in this field have been investigated
and analysed to provide an overview over the status-quo with specific regard to the following topics:
 Transgenic animals as food resources (i.e. farm animals, fish).
 Transgenic animals used for the production of pharmaceutically interesting proteins.
 Genetically modified insects used for vector control concerning the transmission of human
diseases.
 Cloning of farm animals.
Furthermore, focus has been laid upon recent developments of and experience with the regulatory
framework concerning questions of risk assessment (food safety and environmental assessment),
thereby looking especially at activities of the European Food Safety Authority, the USA, and if
appropriate the OECD or FAO.
The following topics are outside the scope of this report:
 Transgenic animals as model organisms in basic research.
 Organs from transgenic animals for use in xenotransplantation.
 Genetically modified or cloned pets or animals used in sports.
 Industrial fields of application, such as e.g. transgenic spiders producing specific silk threads
of transgenic sheep with specific wool fibre.
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The principal constraint regarding the development of this report laid in a quite limited time frame as
the period from the commissioning until the deadline spanned over only six weeks. Therefore,
specific approaches towards dealing with the potential enormous amount of information have been
adopted. Genetic modifications of animals have been topical for many years, research on and use of
genetic methods in the context of agricultural animals or concerning gene pharming is performed on
every major animal species. In fact, there is such an abundance of publications available that a
complete overview of on-going research is hardly possible. Moreover, as this the vast amount of
scientific literature is mostly dealing with only very specific parts of a problem it barely enables a
concrete assessment of the respective current status-quo or of potential so called pipeline-products.
As an example the specific scientific reports commissioned by the European Food Safety Authority
may be pointed to: each of these comprehensive reports covers only one topic (i.e. fish, mammals &
birds, and insects respectively) but in order to create such a review several hundreds of scientific
publications had to be screened for each species.
In order to be able to nonetheless develop an overview of tangible recent developments within the
framework of the present expert opinion, recourse was taken especially to scientific reviews, reports
from competent authorities, information and pipeline analyses of relevant companies, and critical
analyses from international NGOs, as these represent the involved stakeholders with each one of
them focusing at various stages of the development of transgenic animals as well as revealing
different points of information. Within the several chapters of this study there is neither a general
introduction into the respective topic nor a discussion of the scientific background, methods and/or
techniques. Likewise, a quantitative description of all theoretically possible species and traits has
deliberately been avoided, as such a list does not allow for a statement on potential products ready
for application in the near future.
The most important point was to assess the respective probability as well as to anticipate future
developments out of this quantity of information. Equally important was the exercise of
contextualising these findings with regard to the level of the European Union and the tasks of the
Austrian Federal Ministry of Health likewise. Related scientific questions arising especially in relation
to risk assessment (tackling food safety as well as environmental safety) are pointed out with regard
to the existing instruments in this context (appropriate regulatory framework, guidelines).
This overview should enable the Federal Ministry of Health to especially qualitatively evaluate those
developments and assess what applications for the approval of a genetically modified animal or a
food/-product from a transgenic or (a progeny of) a cloned animal are to be expected probably in the
near future as well as to define any potential resulting need for action.
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1
TRANSGENIC ANIMALS
1.1
Livestock
Farm animals such as cattle, pigs or chicken are being genetically modified for various reasons e.g.
enhanced growth, resistance towards stressors or diseases, improved feed conversion ratio or lower
emissions to the environment. These are not specifically related to genetic engineering as traditional
breeding has very similar goals, supported already through a set of assisted reproductive techniques
(e.g. insemination, selection through genetic diagnostics). Another set of goals focuses on altered
food qualities such as more muscle protein within meat or modified composition of proteins in cow´s
milk.
As already stated in 2007 within the study “Transgenic Animals Status-quo in relation to risk
assessment and the state of research“ a lot of different research and development activities are
being undertaken with yet very few transgenic animals approaching commercialisation in spite of the
already long-running and extensive work done. There are several reasons for this, mainly the limited
fundamental knowledge about the relevant biological/genetic processes and structures. There is still
rather low rate of success in the creation of transgenic animals.
Potential products
The most advanced example of a genetically modified farm animal intended to be used as food /
product is the transgenic pig developed by the University of Guelph/Ontario. In conventional
breeding feed for pigs needs to be supplemented by either mineral phosphate or commercially
produced phytase, as the animals are not able to digest plant phytate in their feed. The so-called
Enviropig is a genetically modified Yorkshire pig with the capability of breaking down the normally
indigestible phytic acid to readily metabolised phosphate as these transgenic pigs produce the
enzyme phytase in the salivary glands. This enzyme is active in the acidic environment of the
stomach, degrading indigestible phytate in the feed that accounts for 50 to 75% of the grain
phosphorus.1 This distinctly reduces the content of phosphor in the manure which normally causes
adverse environmental impacts especially in freshwater. At the same time it reduces costs for feed.
The Guelph University has received approval to develop a herd of transgenic pigs exclusively for
research purposes. The transgene has been proved to be stable over eight generations.
Whereas the environmental advantages with relation to the manure are quite obvious, further
potential impacts, such as e.g. potential effects of escaped animals, have to be considered.2 Scientific
data concerning the food safety as well as risk assessment in this context also have to be discussed.
Commercialisation of these pigs is clearly intended, “Regulatory submissions have been made to
both the Food and Drug Administration in the United States and to the Canadian Regulatory
Authorities“ in 2007 and 2009 respectively, including information on swine health and welfare, tissue
composition, toxicology, allergenicity and performance characteristics.3
1
http://www.uoguelph.ca/enviropig/ (8.12.2011)
The Enviropig is one of the theoretical case studies that have been discussed within the study commissioned
by EFSA.
3
http://www.uoguelph.ca/enviropig/commercialization.shtml;
http://www.uoguelph.ca/enviropig/technology.shtml (8.12.2011)
2
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Concerning cattle, successful developments of disease resistance to mastitis have been reported as
well as still on-going work related to altered composition and/or content of casein in milk. As
mentioned also below, there are on-going activities especially in Latin America as well as in some
Asian countries that awaits further screening. Besides Argentina (June 2011, National Institute of
Agricultural Technology, Buenos Aires)4 also China (China Agricultural University, Beijing)5 is reported
to have cloned a transgenic cattle that produces milk (insertion of genes coding for two human milk
proteins) very similar to human breast milk.6 The objective behind these efforts to enrich cow´s milk
with antibacterial proteins such as Lysozyme or Lactoferrin. This milk is intended to be processed into
milk powder that is then used as baby foods.
The Roslin Institute at the University of Edinburgh developed genetically modified chickens to
prohibit the transmission of avian influenza (bird flu), a common problem in poultry production and
subsequently to human health. The transgenic chicken may get infected but is not able to pass the
infection further on within a flock. For the time being, “these particular chickens are for research
purposes only and are not intended for consumption.“7 This purpose is yet not excluded for the
future.
The scientific study commissioned by EFSA (see discussion below) concerning environmental risk
assessment criteria for genetically modified mammals and birds mentions more or less the same
examples of genetically modified farm animals intended potentially as food / product: chicken, cattle,
pigs.8
To get the whole picture especially concerning future developments a thorough screening of on
going activities has to focus on South American and Asian countries, which are economically and
geopolitically of increasing importance. Quite some scientific research and development of
transgenic animals is going on e.g. in China, India, Argentina, Brazil, or Singapore. E.g. in September
2011, the first international workshop on the food and environmental safety assessment of
genetically modified animals - organized inter alia by the Argentinian Ministry for Agriculture, the
International Centre for Genetic Engineering and Biotechnology and the United Nation´s Programme
for Biotechnology in Latin America and the Caribbean - took place in Buenos Aires City.9 The focus of
interest lay upon transgenic agricultural animals for food purposes as well as cloned animals,
including also questions of food and environmental safety.
A report of the FAO10 focusing on livestock biotechnologies in developing countries states that China
produced the first transgenic buffalo in 2004, India followed in 2009. A main topic especially in Asian
countries may be transgenic or cloned pets, e.g. the now famous ornamental fish „GloFish“ has
originally been developed by the National University of Singapore as a model system in research.
Sources in English language such as e.g. Bio Spectrum Asia Edition could also provide useful
overviews over current activities and issues. An article of October 2011 mentions a focus on medical
research as well as on drug development from transgenic animals.11
4
http://www.inta.gov.ar/ins/en/englishvers.htm; search is only possible in Spanish
http://www.cau.edu.cn/cie/en/aboutus/index_cau.htm (only limited information available in English)
6
http://www.plosone.org/article/info:doi/10.1371/journal.pone.0017593 (10.12.2011)
7
http://www.roslin.ed.ac.uk/news/2011/01/13/gm-chickens-that-don%27t-transmit-bird-flu-developed/
(8.12.2011)
8
This study commissioned by EFSA deals with a broader range of mammals of birds, but most of these are used
within fundamental research, for proof of concept or as pets. These examples are outside the scope of this
opinion.
9
http://www.agrobiotecnologia.gov.ar/gmanimal2011/ (12.12.2011)
10
FAO March 2010.
11
http://www.biospectrumasia.com/content/041011OTH17213.asp
5
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Regulatory aspects / Risk assessment
European Union
The European regulatory framework for genetically modified organisms has initially been developed
with mainly genetically modified crops in mind.12 Taking these developments into account, the
European Food Safety Authority (EFSA) has already developed several specific guidelines for the risk
assessment of genetically modified organisms and/or their products during the last years, e.g.:
 Guidance Document for the risk assessment of genetically modified plants containing stacked
transformation events (2007)
 Guidance on the environmental risk assessment of genetically modified plants (2010)
 Guidance document for the risk assessment of genetically modified plants and derived food
 Guidance on the risk assessment of genetically modified microorganisms and their products
intended for food and feed use (2011)
Such guidance documents provide information for potential applicants defining in detail
requirements for scientific information for an application submitted under Regulation (EC)
1829/200313 on genetically modified food and feed, and Directive 2001/18/EC on the deliberate
release into the environment of GMOs. As the requirements in Annex II of Directive 2001/18 are
accurate mainly for genetically modified crops, specification of this annex has been undertaken
already several times through such guidance documents. Equally, Regulation 1829/2003 needs
detailed supplemental requirements.
As various applications of genetic engineering such as gene pharming through animals or the
development of transgenic insects emerged it appeared that the existing regulations could not
provide satisfying guidance in this field, neither for an applicant nor for the competent authorities. So
far, no applications for an approval of a genetically modified animal have been made in the European
Union. As a provident measure, in February 2007 the European Commission has asked the EFSA to
develop a comprehensive risk assessment guidance on the food, feed and environmental safety
assessment of genetically modified animals, taking also into account animal health and welfare.
Therefore, several related activities have been conducted: EFSA commissioned three different socalled scientific/technical studies related to the environmental risk assessment of various genetically
modified animals which have been delivered in 2010.14 In addition, specific working groups have
been set up, dealing with environmental risk assessment of genetically modified fishes, of genetically
modified insects and genetically modified mammals and birds respectively. Another working group is
dedicated to transgenic animals as such, another one concerned with human health risk assessment
of genetically modified animals, is commissioned with developing a guidance for the molecular
characterization and the food and feed safety assessment of products derived from genetically
modified animals. Existing guidelines such as e.g. the FAO/WHO Codex Alimentarius Guideline on this
subject, are also taken into account.
These activities undertaken by EFSA will result in two different guidelines. In August 2011 a „Draft
Guidance on the risk assessment of food and feed from genetically modified animals including animal
health and welfare“ developed by EFSA’s Panel on Genetically Modified Organisms and the Panel on
Animal Health and Welfare has been released for public consultation in August 2011 which ended
September 30th 2011.15
12
This is also true for similar activities e.g. within the Cartagena Protocol on Biosafety or with regard to the
USA.
13
Regulation (EC) No 1829/2003 of the European Parliament and of the Council of 22 September 2003 on
genetically modified food and feed.
14
I.e. for mammals and birds; insects; and fish respectively.
15
http://www.efsa.europa.eu/en/consultationsclosed/call/110810.htm (7.11.2011)
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The draft document outlines specific data requirements and methodologies for the risk assessment
for food and feed derived from transgenic animals that may be placed on the market within the
framework of Regulation (EC) N° 1829/2003. It follows the common approach of comparing the
genetically modified animal and derived food / feed with their respective conventional counterparts.
Specific requirements include information about the molecular characterisation of the insert, the
stability of the trait/s, a compositional analysis, the toxicological and allergenicity assessment of the
novel protein/s as well as of the whole food, and concerning nutritional aspects. Furthermore, the
methodology required for the comparative assessment of health and welfare aspects of such animals
is described. The last part is dedicated to post-market monitoring stating somewhat vaguely: „Where
appropriate a Post Market Monitoring (PMM) programme should be performed for GM animalderived food/feed. The appropriateness of performing a PMM is indicated by findings in the premarket safety assessment.“16 Acknowledging existing knowledge gaps this draft guideline includes
several recommendations, e.g. concerning „the limited amount of background data available on, for
instance, the composition of the broad variety of different animal-derived food and feed products“.
Therefore, data collection, the establishment of databases as well as the development of consensus
documents on the composition of food and feed derived from different animal species is being
recommended.17 The final guidance is expected to be ready for adoption at the end of 2011.18
The second guidance document will be developed by EFSA´s GMO Panel and address issues
concerning the environmental risk assessment (ERA) of genetically modified animals used for food
and feed purposes. „The guidance takes a species-by-species approach to ERA, focusing on GM fish,
GM insects, and GM birds and mammals. To help define the criteria for ERA of GM animals, EFSA
launched external calls for data for the three categories. The information received is being
considered by EFSA’s Working Group preparing the guidance document.“19
One of the above mentioned scientific reports is dedicated to transgenic mammals and birds,
„Defining environmental risk assessment criteria for genetically modified (GM) mammals and birds to
be placed on the EU market“.20 The authors of this comprehensive study evaluated scientific data
with regard to potential hazards and adverse effects, endpoints, as well as potential receiving
environments and compiled a database of species to provide an overview over on-going research
activities in this field (relevant species are mentioned above, see Potential products). On the basis of
several theoretical case studies detailed criteria - categorized in risk of introduction, risk of
establishment, risk of dispersal, risk of impact, and management - to be considered when conducting
an environmental risk assessment have been developed. Due to the limited data available a case-bycase approach is recommended.
It remains to be seen to what extent the outcomes and conclusions of the above mentioned three
scientific reports will be included into this guidance on environmental safety assessment. It is
expected to be released for a public consultation in spring 2012, being ready for adoption
presumably in summer 2012.
16
p. 42.
p. 42f.
18
http://www.efsa.europa.eu/en/faqs/faqgmanimals.htm?wtrl=01 (7.11.2011)
19
20
Christine Henry et al. 2010.
17
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USA
Genetically engineered animals are regulated by the U.S. Food and Drug Administration (FDA)21
under the New Animal Drug provisions of the Federal Drug and Cosmetic Act, which went into force
in January 2009, and the National Environmental Policy Act. The rDNA constructs in the resulting
genetically modified animal is regarded as drug that needs to be approved, i.e. the GM animal itself is
not regarded as new drug.
Furthermore, FDA in most cases must also prepare an environmental assessment (EA) for an NADA
approval action. „The EA generally focuses on potential impacts related to the use and disposal of the
GE animal. In general, the EA should describe and discuss the following: (1) the genotype, phenotype
and general biology of the GE animal; (2) potential sources and pathways of escape (or release) and
spread of the GE animal; (3) the types and extent of physical and biological confinement, if any that
will be implemented; and (4) the potentially accessible ecosystems and their characteristics. ... In the
event that the EA results in a finding that a significant environmental impact may result, an
Environmental Impact Statement may need to be prepared.“22 It should be noted here that the US
regulation distinguishes between environmental assessment and environmental impact assessment
(statement), the latter being only necessary if the EA leads to the conclusion that an (adverse) impact
may be expected.
In addition, also in January 2009 FDA has issued a „Guidance for Industry #187, Regulation of
Genetically Engineered Animals Containing Heritable Recombinant DNA Constructs“23 defining
requirements for the application, e.g. proofing the safety of the gene construct, of the bearing
animal, concerning questions of food safety as well as the environmental risk assessment. On page 5
of this U.S. guidance it is emphasized that it does not establish „legally enforceable responsibilities.
Instead, such guidance describe the Agency´s current thinking on a topic and should be viewed only
as recommendations, unless specific regulatory or statutory requirements are cited.“
„This guidance is intended to clarify our requirements and recommendations for producers and
developers ... of GE animals and their products.“24 Requirements for the application are defined, e.g.
measures for animal disposition for ensuring that no edible products enter the food chain, molecular
characterization of the gene construct and of genetically modified animal lineage, phenotypic
characterization of the transgenic animal, issues concerning food safety as well as the environmental
risk assessment. This guidance covers all genetically modified animals, including those for non-food
purposes (e.g. transgenic animals used for the production of pharmaceuticals, see chapter „Gene
Pharming“). It supports a case-by-case approach, approval prior to marketing is mandatory.
FAO/WHO
In 1999 the joint FAO/WHO Codex Alimentarius Commission set up a Ad Hoc Intergovernmental Task
Force on Foods derived from Biotechnology (TFFBT). Its main task consisted in developing on a
strictly scientific basis a guideline for the risk assessment of such foods. A specific working group
under the TFFBT had been constituted in 2005 in order to prepare a first draft, additional expert
consultation on specific topics took place in March 2007. Finally, in 2008 the “Guideline for the
21
U.S. FDA is the competent authority regarding animals used for food purposes. Non-food species are
regulated by other agencies, e.g. APHIS of the U.S. Department of Agriculture for genetically modified insects
for plant pest control (see also chapter „Insects“).
22
U.S. FDA Briefing Packet 2010
23
Pdf-file available at
http://www.fda.gov/AnimalVeterinary/DevelopmentApprovalProcess/GeneticEngineering/GeneticallyEngineer
edAnimals/default.htm; revised in May 2011 only for formal reasons (including table of content, updating
hyperlinks).
24
U.S. FDA Guidance for Industry #187 2009, p. 4.
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conduct of food safety assessment of foods derived from recombinant-DNA animals” CAC/GL 682008 has been adopted by the Codex Alimentarius Commission.
The latest draft of this guideline has been analysed at length within the report „Transgenic Animals,
status-quo in relation to risk assessment and the state of research“ conducted in 2007. As the final
version does not differ from this last draft no further discussion is necessary here.
Further specific legislation and issues of risk assessment are discussed in the following respective
chapters of this expert opinion.
Summary & Conclusions






So far, no genetically modified livestock intended as use for food has been commercialized
worldwide.
The study “Defining environmental risk assessment criteria for genetically modified (GM)
mammals and birds to be placed on the EU market” commissioned by EFSA compiled a list some
15 species being genetically modified but these also include mice (which are almost exclusively
used as model animals in research), animals used for gene pharming or pets.
The probably first genetically engineered farm animal that will get ready for the market may be
the so-called Enviro-Pig developed by the University of Guelph/Canada.
Another example that may be meaningful to watch closer is the transgenic chicken developed by
the University of Edinburgh.
going activities has to focus on economically and geopolitically emerging countries.
Besides Argentina also China is reported to have cloned a transgenic cattle that produces milk
(insertion of genes coding for two human milk proteins) very similar to human breast milk. The
objective behind these efforts to enrich cow´s milk with antibacterial proteins such as Lysozyme
or Lactoferrin. This milk is intended to be processed into milk powder that is then used as baby
foods.
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1.2
Fish
Fish25 are getting genetically modified with the following objectives: faster growth, improved feed
conversion ratio, increased weight, enhanced tolerance towards environmental conditions (e.g. cold,
salinity) or resistance against specific diseases. It should be noted that these breeding goals are not
specific to genetic engineering but simply may be achieved more easily through this technique.
The most critical aspects related to transgenic fish are potential adverse environmental impacts. In
general, and especially when compared to farm animals, fish have a significant capacity to escape
captivity and become feral. Fish have life stages that can be difficult to contain, and are impossible to
re-capture for all practical purposes. A lot of further issues have to be considered: potential to
interbreed with wild species and reproductive performance (which might happen as sterility is not
working 100%), transgression of genetic constructs, displacement of native wild fish populations,
influence on the predator-prey balance, all of which may lead to a disruption of the respective
ecosystem.
As transgenic fish are intended to be used as food and within food products an in-depth assessment
of their composition, their nutritional quality as well as of potential toxicity or allergenicity is
required. 26
Products
The best-known product is a transgenic salmon developed by the Canadian company Aquabounty
(AquAdvantage® Salmon), which has been working on the development of this animal as well as on
getting an approval for placing on the market at least since the mid-nineties. The genetic construct
consists of a gene from the Chinook salmon coding for a growth hormone in combination with a
regulatory sequence (from ocean pout) for so-called anti-freezing proteins. As this growth hormone
therefore is being expressed perennial, the transgenic fish also grows at low water temperature and
thus twice as fast as conventional salmon. The land-based fresh water egg production facility is
located at Prince Edward Island in Canada. This transgenic salmon is intended to be reared as sterile,
all-female populations in land-based facilities with biological and physical containment in Canada and
Panama, the respective food products should be put on the market in the USA. It would be the first
transgenic animal, which would be utilized as food for human consumption.
Criticism by NGOs and some scientists has mainly centred around issues of potential adverse impacts
on the environment and the narrow approach of the U.S. Federal Drug Administration (FDA) towards
assessing food safety focusing mainly on comparing the nutritional profile of the transgenic salmon
to that of non modified salmon, and screening for known toxins and allergens. FDA itself criticized
Aqua bounty’s statement on the sterility of transgenic fish as potentially being misleading „as ...
sterility has not been explicitly verified in these fish and up to 5% of the eggs sold for grow-out may
be non-triploid and still within release specification. ... We have reason to believe that the population
of triploid, all-female AquAdvantage salmon will be effectively sterile... However, it is recognised that
a small proportion of the fish population, particularly those that are not triploid (i.e., ≤5%), may be
25
Focus of the following considerations is laid upon food fish. Therefore, examples as the transgenic
ornamental fishes will not be covered here.
26
Besides considerations about environmental and food safety also economic issues have been raised, e.g. the
apprehension that the cultivation of these animals could threat the fishing business of wild salmon. These
arguments will not be further explored within this report.
Page 13 of 54
fertile.“27 Aquabounty has therefore been requested to explain in the document the limitations on
interpretation of the term „sterile“.
Another controversial subject is the question of labelling which in the USA focuses solely on the
composition of food products. Therefore, the FDA may not have the regulatory authority to demand
labelling. On the other side arguments in favour of this genetically modified salmon stated that if the
fast-growing fish allows salmon to be profitably grown away from the ocean, where fish farms cause
heavy environmental damage through their waste and escaped charges, it could theoretically present
an environmental advantage for the environment.
Recent developments concerning the approval procedure in the USA are outlined at „Regulatory
aspects/Risk assessment“ (see below). Besides this salmon, Aquabounty is developing growth
enhanced trout and tilapia.28
In quite some report and/or comments a lot of theoretical potential examples of genetically modified
fish have been mentioned. Transgenic fish, e.g. trout, carp and salmon, may presumably be
developed in countries as the USA, Canada, South America, the United Kingdom, Norway and
Japan.29 As many as 16 applications for transgenic fish may be under review throughout the world,
mostly in Asia, although none are known to be yet approved, according to congressional testimony
from the Veterinary Medicine Advisory Committee of the FDA.30 Alas, so far none of these ever have
gained much attention. It seems as if perhaps the long duration of the Aquabounty´s case has slowed
down similar efforts of other companies. At the same time, once the transgenic salmon is decided
upon this definitely will have a signal effect in either ways.
European Union
The European Commission in February 2007 has asked the European Food Safety Authority (EFSA) to
deliver risk assessment guidance on the food, feed and environmental safety assessment of
genetically modified animals. Such guidance documents define in detail requirements for an
application submitted under Regulation (EC) 1829/2003 on genetically modified food and feed, and /
or Directive 2001/18/EC on the deliberate release into the environment of genetically modified
organisms (see also more detailed discussion in chapter 1.1 Livestock, Regulatory aspects/Risk
assessment, European Union). As the requirements in Annex II of Directive 2001/18 have been
developed with mainly genetically modified crops in mind, specification of this annex has been
undertaken already several times through such guidance documents.
Therefore, several related activities have been conducted: EFSA commissioned three different socalled scientific/technical studies related to the environmental risk assessment of various transgenic
animals.31 In addition, within the GMO Unit of EFSA specific working groups have been set up, dealing
with environmental risk assessment of genetically modified fishes, of genetically modified insects and
genetically modified mammals and birds respectively. A separate working group, concerned with
27
U.S. FDA, Briefing Packet 2010, p. 157.
http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/VeterinaryMedicineAdvisoryCommitt
ee/ucm201810.htm (2.12.2011)
28
http://www.aquabounty.com/products/products-295.aspx (1.12.2011)
29
http://www.transgen.de/tiere/143.doku.html; http://www.biosicherheit.de/basisinfo/1301.transgenetiere.html (1.12.2011)
30
http://idealab.talkingpointsmemo.com/2011/10/fda-nears-decision-on-genetically-engineeredsalmon.php?ref=fpb 10.10.2011
31
Page 14 of 54
human health risk assessment of GM animals, develops „guidance for the molecular characterization
and the food and feed safety assessment of products derived from GM animals“. Existing guidelines
such as e.g. the FAO/WHO Codex Alimentarius Guideline on this subject, is also taken into account.
One of the above mentioned scientific reports is dedicated to transgenic fish, „Defining
environmental risk assessment criteria for genetically modified fishes to be placed on the EU
market“.32 This comprehensive report analyses several hundreds of scientific publications and
evaluates in detail potential hazards, exposure profiles, and environmental issues, and describes data
requirements as well as risk assessment concepts and principles. One focus is laid upon the many
possibilities for transgenic fish to escape in freshwater or marine ecosystems. Potential routes have
been analysed in detail which may occur during transportation, loss from research or experimental
facilities, deliberate indiscriminate introductions to improve fishery performance, escape from
commercial aquaculture facilities and perhaps vandalism. The authors concluded that potential
adverse effects depend e.g. on the species used, the trait inserted, reproductive competitiveness,
impacts on the predator-prey balance, presence of wild populations in the receiving aquatic
environment. Specific characteristics of such ecosystems which are of importance for conducting an
environmental risk assessment as well as assessment endpoints have been identified. Upon these
findings, several specific criteria for assessing the potential impact of transgenic fishes have been
developed.
These activities undertaken by EFSA will result in two different guidelines. In August 2011 a „Draft
Guidance on the risk assessment of food and feed from genetically modified animals including animal
health and welfare“ developed by EFSA’s Panel on Genetically Modified Organisms and the Panel on
Animal Health and Welfare has been released for public consultation in August 2011 (which ended
September 30th 2011). This draft is briefly outlined in chapter 1.1. of this opinion (see Regulatory
aspects/Risk assessment, European Union), the final guidance is expected to be ready for adoption at
the end of 2011.
The second guidance document will be developed by EFSA´s GMO Panel and will address issues
concerning the environmental risk assessment (ERA) of genetically modified animals, taking a
species-by-species approach focusing besides on genetically modified fish also on genetically
modified insects, and genetically modified birds and mammals. It remains to be seen to what extent
the outcomes and conclusions of the above mentioned three scientific reports will be included into
this guidance on environmental safety assessment. It is expected to be published for a public
consultation in spring 2012, being ready for adoption presumably in summer 2012.
USA, recent developments in the case of Aquabounty´s salmon
Genetically engineered animals are regulated by the U.S. Food and Drug Administration (FDA) under
the New Animal Drug provisions of the Federal Drug and Cosmetic Act and the National
Environmental Policy Act.33 The rDNA construct in the resulting genetically modified animal is
regarded as drug that needs to be regulated, i.e. the genetically modified animal itself is not
regarded as new drug and not as novel food.
Furthermore, FDA typically must prepare an environmental assessment (EA) for each NADA approval
action. „The EA generally focuses on potential impacts related to the use and disposal of the GE
animal. In general, the EA should describe and discuss the following: (1) the genotype, phenotype
and general biology of the GE animal; (2) potential sources and pathways of escape (or release) and
spread of the GE animal; (3) the types and extent of physical and biological confinement, if any that
will be implemented; and (4) the potentially accessible ecosystems and their characteristics. ... In the
32
33
I. G. Cowx et al. 2010.
U.S. FDA, Briefing Packet 2010.
Page 15 of 54
event that the EA results in a finding that a significant environmental impact may result, an
Environmental Impact Statement may need to be prepared.“ It should be noted here that the US
regulation distinguishes between environmental assessment and environmental impact assessment
(statement), the latter being only necessary if the EA leads to the conclusion that an (adverse) impact
may be expected.
In addition, FDA has issued a „Guidance for Industry #187, Regulation of Genetically Engineered
Animals Containing Heritable Recombinant DNA Constructs“, defining requirements for the
application, e.g. proofing the safety of the gene construct, of the bearing animal, concerning
questions of food safety as well as the environmental risk assessment (this U.S. Guidance is outlined
briefly in chapter 1.1 Livestock, Regulatory aspects/Risk assessment, USA).
In the beginning of 2009 the approval procedure for the genetically modified salmon developed by
Aquabounty has been resumed by the FDA. The requirements mentioned in the regulations above
have been met by Aquabounty by the middle of 2010 including the submission of an Environmental
Assessment.34
FDA concluded in August 2010 that the company has provided sufficient proof that there is no risk
for human consumption and that the transgenic salmon is not expected „to have a significant impact
on the quality of the human environment“35, neither in the U.S nor in foreign nations not involved in
the action. Simultaneously, FDA stated that the decision on whether an Environmental Impact
Statement has to be provided by the company will only be made after having received experts
comments on the environmental assessment.
The FDA then convened its Veterinary Medicine Advisory Committee (VMAC) to further consider this
application. An expert meeting took place in September 2010 with the objectives of „... receive an
orientation on both general scientific issues surrounding genetically engineered animals and the
statutory and regulatory constraints under which the agency must operate“ and „...consider issues
regarding the safety and effectiveness of the new animal drug“ (i.e. the transgenic salmon).36 It was
followed by a public hearing where especially concerns regarding the assessment of potential
allergenicity had been raised (wild-type salmon is a known allergen).
In October 2010 VMAC finally confirmed that the company has fulfilled all requirements and that the
transgenic salmon is safe to eat and poses no threat to the environment. Simultaneously, several
„suggestions for further procedures that might be considered to clarify this issue“ have been phrased
by the Committee.37 As this votum by the VMAC is of non-binding character, it remains unclear if or
how these suggestions have been taken into account by FDA or have been further addressed by the
company.
The development took a surprising turn in June 2011.38 Some representatives of the Republican Party
34
ee/ucm201810.htm (1.12.2011)
35
U.S. FDA Briefing Packet 2010, p. 131f.
36
http://www.fda.gov/AdvisoryCommittees/Calendar/ucm223823.htm (2.12.2011)
37
available at
ee/ucm201810.htm (1.12.2011)
38
http://www.nytimes.com/gwire/2011/06/16/16greenwire-house-moves-to-ban-modified-salmon84165.html?scp=4&sq=salmon&st=cse (12.11.2011);
http://www.gentechnologie.ch/cms/index.php?option=com_content&view=article&id=275%3Ausamarkteinfuehrung-gentech-lachse-unterbunden&catid=14%3Ainvkat&Itemid=42 (12.11.2011)
Page 16 of 54
voted through an amendment to an agriculture spending bill to prevent the FDA from spending any
funds on genetically engineered salmon approvals.39 The objections were of an economic nature:
should the transgenic salmon be approved and grown profitably in inland tanks, the fish could
undermine traditional ocean-based farms, negatively impact the wild salmon fishing industry and
give Aquabounty a dominant position in the industry. The success of this action remains unclear, as
on the one side too few representatives were present.
At an international symposium of the Netherland´s Commission on Genetic Modification in October
2011, „GM animals, perspectives and perceptions“, a representative of Aquabounty explained: „The
firm is currently awaiting final action on the application.“40 In a publication from October
11, 2011, the US news agency Talking Points Memo released an article with the following message:
“The Food and Drug Administration has completed its highly-anticipated evaluation of the
environmental impact of the world’s first genetically-engineered (GE) fish for human consumption,
and written a document supportive of its commercialization on the U.S. market, according to a
person close to the review process. The evaluation is now under review at the White House’s Office
of Management and Budget.”41







Overfishing of oceans as well as growing consumer demand for healthy fish has led to an
increasing gap between demand and possible supply. This is one major driving force for the
industry to develop improved approaches towards breeding fish.
Fish are getting genetically modified with the following objectives: faster growth, improved feed
conversion ratio, increased weight, enhanced tolerance towards environmental conditions or
disease resistance. It should be noted that these breeding goals are not specific to genetic
engineering but simply may be achieved more easily through this technique.
The transgenic growth enhanced salmon developed by the Canadian company Aquabounty is
the best-known example of a genetically modified animal, which is intended for food purposes,
currently awaiting the US government´s decision on the approval.
Many further examples of fish species and potential traits are reported, e.g. the study
commissioned by EFSA lists on 58 pages appr. 50 species with over 400 fish/trait combinations.
Most of these will not result in commercially available food products.
It seems as if perhaps the long duration of the Aquabounty´s case has slowed down similar
efforts of other companies. At the same time, once the transgenic salmon is decided upon this
definitely will have a signal effect in either ways.
The most critical aspects related to transgenic fish are numerous potential adverse
environmental impacts, e.g. significant capacity to escape, potential to interbreeding with wild
species, displacement of native wild fish populations, influence on the predator-prey balance, to
name but a few.
Most results of scientific studies only cover one specific aspect or analyse just one single set of
(environmental etc.) conditions. As many species-trait-ecosystem combinations und thus
interactions may exist further independent research has to broaden the databases on which risk
assessment has to be based upon. Thus a case-by-case approach with potential applications
should be followed.
39
Juni 2011: F:\M12\YOUNAK\YOUNAK_063.XML: AMENDMENT TO H.R. 2112, as reported offered by Mr.
Young of Alaska and Ms. Woolsey of California.
40
Booklet of the symposium available at http://cogemsymposium.halito.nl/en/ (1.12.2011)
41
http://idealab.talkingpointsmemo.com/2011/10/fda-nears-decision-on-genetically-engineeredsalmon.php?ref=fpb (2.12.2011)
Page 17 of 54



As transgenic fish are intended to be used as food and within food products an in-depth
assessment of their composition, their nutritional quality as well as of potential toxicity or
allergenicity is required.
In this context, EFSA´s activities are of special importance, the „Draft Guidance on the risk
assessment of food and feed from genetically modified animals including animal health and
welfare“ expected to be ready for adoption at the end of 2011.
And the second guidance document on the environmental risk assessment of genetically
modified animals, taking a species-by-species approach focusing besides on genetically modified
fish also on genetically modified insects, and genetically modified birds and mammals. It remains
to be seen to what extent the outcomes and conclusions of the above mentioned three scientific
reports will be included into this guidance on environmental safety assessment. It is expected to
be published for a public consultation in spring 2012, being ready for adoption presumably in
summer 2012.
Page 18 of 54
1.3
Insects / Arthropods
Insects are genetically modified mainly out of two reasons: reduction of diseases such as Dengue
fever or Malaria through genetically modified mosquitos and reduction of crop losses using
genetically modified agricultural pests (e.g. pink bollworm, fruit flies), respectively. These insects
cause severe diseases in developing countries: the mosquito Aedes aegypti (also known as yellow
fever mosquito) is a threat to human health in numerous countries as a carrier of dengue fever and
yellow fever. Dengue fever can also be carried by the so-called Asian Tiger Mosquito, which is also
spreading in Europe.
The main concern with regard to genetically modified insects concerns a wide range of potential
environmental impacts in connection with the deliberate release of a great amount of such insects,
as they are highly mobile and not controllable. Concerns raised are all the more important if these
insects are vectors for human diseases.
With respect to genetically modified insects (or arthropods more generally) the study commissioned
by the European Food Safety Authority entitled “Defining Environmental Risk Assessment Criteria for
Genetically Modified Insects to be placed on the EU Market"42 provides a comprehensive and
relatively up-to-date overview of the current scientific status quo. It first sets out in detail current
work on different arthropods (which types, which genetic changes, which aims are being pursued),
though the focus is on agricultural pests and insects that carry disease. This is followed by an analysis
of potential adverse effects as well as a description of methods by means of which these effects can
be investigated. Details from this report concerning the environmental risk assessment are described
below (see below, Regulatory aspects/Risk assessment, European Union).
Products
Mosquito Aedes aegypti
The British company Oxitec Limited, a spin-off of Oxford University in Britain, developed a genetically
modified Aedes aegypti strain OX513A. It holds global patents on the technologies referred to as
RIDL, i.e. Release of Insects carrying a Dominant Lethal genetic system, also known as conditional
lethality. In addition to a fluorescence trait incorporated as a marker, the male mosquitoes of this
variety have an additional gene, the protein product of which is lethal to its own progeny. The
offspring deriving from such male mosquitoes mating with wild type females only survive into the
late larval stage or early pupation stage and then die - with the exemption of their survival in the
presence of Tetracycline, a widely used antibiotic in animal husbandry. The object of this genetic
modification is to decimate the existing population of Aedes aegypti, thus reducing the number of
potential disease carriers.
In 2009 and 2010 genetically modified Aedes aegypti strain OX513A were released in field trials on
the Cayman Islands43 between May and October.44 End of December 2010 such releases have taken
place at two different sites in Malaysia, „some 6,000 genetically modified mosquitoes were
deliberately introduced to an uninhabited forest in Malaysia”.45 Critical discussions arose not only
around the intransparent processes behind these release experiments under the responsibility of
42
Benedict et al., September 2010.
British Overseas Territory in the Caribbean.
44
GeneWatch UK Briefing, December 2010.
45
Nature Volume 470, 139, Editorial: Letting the bugs out of the bag, February 9, 2011
http://www.nature.com/nature/journal/v470/n7333/full/470139a.html (3.12.2011);
http://www.malaysiakini.com/news/154545 (3.12.2011)
43
Page 19 of 54
Oxitec, but focus on a lot of unsolved questions concerning mainly potential environmental impacts
(see discussion below, Regulatory aspects/Risk assessment, The Malaysian Mosquito case).
Further releases of this strain have taken place in Brazil (state of Bahia) in February 2011.46 The
company Oxitec states: „OX513A has regulatory approvals for import and contained testing in Brazil,
Cayman Islands, France, India, Malaysia, Singapore, Thailand, USA and Vietnam. Open field trials
have taken place in both Grand Cayman and Malaysia, and are currently also underway in Brazil.“47
The next release experiments are apparently intended to take place in Florida/USA end of 2011.48
Further examples
Another product developed by Oxitec is mentioned quite often in various publications, a genetically
modified pink bollworm containing a heritable fluorescent marker and sterilized by irradiation having
been released in the USA for the first time in 2006.
Besides the above-mentioned Aedes aegypti strain OX513A, Oxitec has developed another
genetically modified strain: Aedes aegypti OX3604C, a female-specific version with integrated
conditional lethality (RIDL). „Flightless females in the wild cannot seek hosts or mates, take a blood
meal or spread disease. They are likely to be rapidly eaten by predators so this trait is equivalent
functionally to a lethal condition.“49 OX3604C has been introgressed into a Mexican Genetically
Diverse Laboratory Strain background and has been evaluated in large-scale outdoor cages in Chiapas
in 2010.
Further strains are in the stage of „Product Optimization“ at Oxitec, e.g.:
 Aedes albopictus (Asian tiger mosquito) OX3688, another female-flightless RIDL strain, with a
focus in Asian genetic backgrounds, with the Rutger’s University in New Jersey doing contained
evaluation and testing50,
 Pink bollworm strain OX3402 containing conditional lethality (RIDL strain) available for testing in
the open field 51,
 Mediterranean fruit fly OX3647 containing conditional lethality (RIDL strain), ready for open field
trials52,
 Olive fruit fly OX3713A is a female-specific RIDL strain ready for open field trials53,
 Mexican fruit fly OX3713Q is a female specific RIDL strain54.
46
www.oxitec.com/our-products/lead-aedes-strain/; Nature Volume 470, 139, Editorial: Letting the bugs out of
the bag, February 9, 2011 http://www.nature.com/nature/journal/v470/n7333/full/470139a.html (3.12.2011);
Helen Wallace 2011, available at http://www.genewatch.org/sub-566989 (4.12.2011)
47
http://www.oxitec.com/our-products/lead-aedes-strain/ (3.12.2011)
48
Dengue re-emerged in Key West in 2009 with 27 cases, another 66 cases were confirmed last year. Oxitec is
suspected to have prepared such an experiment for quire some time: „Oxitec … more than a year, has been
quietly seeking permission to test in Key West.“ http://www.miamiherald.com/2011/11/11/vfullstory/2498023/key-west-mosquito-control-could.html (4.12.2011);
http://www.nytimes.com/2011/10/31/science/concerns-raised-about-genetically-engineeredmosquitoes.html?_r=1 (4.12.2011)
49
http://www.oxitec.com/our-products/femail-specific-aedes/ (3.12.2011)
50
http://www.oxitec.com/our-products/asian-tiger-mosquito-control/ (3.12.2011)
51
http://www.oxitec.com/our-products/pink-bollworm-ox3402/ (3.12.2011)
52
http://www.oxitec.com/our-products/fruit-flies/ (3.12.2011)
53
http://www.oxitec.com/our-products/olive-fly-ox3713/ (3.12.2011)
54
http://www.oxitec.com/our-products/mexfly-ox3713/ (3.12.2011)
Page 20 of 54
The following genetically modified arthropods may play a significant role in Europe according to the
authors of the study for EFSA above mentioned at the beginning of this chapter, although it is not
anticipated that they will be released within the next ten years: Aedes aegypti (yellow fever
mosquito), Aedes albopictus (Asian tiger mosquito), Bactrocera oleae (olive fruit fly), Ceratitis
capitata (Mediterranean fruit fly), Stomoxys calcitrans (stable fly), Cydia pomonella (codling moth)
and the Anopheles gambiae complex, Lucilia cuprina (Australian sheep blowfly) and Pectinophora
gossypiella (pink bollworm) - though the last three are only relevant in European overseas territories.
Further developments are to be expected, although not in the near future. As an example the “i5k
initiative” should be mentioned which plans to sequence the genomes of 5.000 insects and related
arthropod species over the next 5 years.55 This project focuses mainly on insect species known to be
important to worldwide agriculture, food safety, medicine, and energy production and those used as
models in biology.
European Union
The European Commission in February 2007 has asked the European Food Safety Authority (EFSA) to
deliver risk assessment guidance on the food, feed and environmental safety assessment of
genetically modified animals. Such guidance documents define in detail requirements for an
application submitted under Regulation (EC) 1829/2003 on genetically modified food and feed, and /
or Directive 2001/18/EC on the deliberate release into the environment of genetically modified
organisms (see also more detailed discussion in chapter 1.1 Transgenic livestock, Regulatory
aspects/Risk assessment, European Union). As the requirements in Annex II of Directive 2001/18
have been developed with mainly genetically modified crops in mind, specification of this annex has
been undertaken already several times through such guidance documents.
Therefore, several related activities have been conducted in the context of transgenic animals: EFSA
commissioned three different so-called scientific/technical studies related to the environmental risk
assessment of various genetically modified animals.56 In addition, within the GMO Unit of EFSA
specific working groups have been set up, dealing with environmental risk assessment of genetically
modified fishes, of genetically modified insects and genetically modified mammals and birds
respectively.
One of the above mentioned scientific reports is dedicated to transgenic insects, „Defining
environmental risk assessment criteria for genetically modified insects to be placed on the EU
market“.57 This comprehensive report analyses over 300 hundred of scientific publications and
includes a description of various species, traits, potential risks, as well as methods to investigate
adverse effects.
The part of the study most important to the Federal Ministry of Health, as the Austrian authority with
primary responsibility, consists in a detailed description of those elements and endpoints which must
be part of any comprehensive, ecological risk assessment of genetically modified insects/arthropods
from a scientific point of view. The type of genetic modification, the respective species and the
ecological system affected by any release must be accorded especial consideration. Possible adverse
effects may consist of a disturbance of the respective ecosystem (for example, crowding-out effects),
unintended effects on target organisms, effects on non-target organisms and gene transfer to
naturally occurring types, or ultimately also impacts on human health. Due to the multitude of
55
http://arthropodgenomes.org/wiki/i5K (5.12.2011)
57
I. G. Cowx et al. 2010.
56
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different components as well as the complexity of the issue, the authors of the above-mentioned
study recommend a case-by-case approach in their conclusions, i.e. carrying out comprehensive risk
assessment for each individual case.
These activities undertaken by EFSA will result in two different guidelines with the one on risk
assessment of food and feed from genetically modified animals being of no relevance in the context
of genetically modified insects.58 The second guidance document will be developed by EFSA´s GMO
Panel and will address issues concerning the environmental risk assessment (ERA) of genetically
modified animals. „The guidance takes a species-by-species approach to ERA, focusing on GM fish,
GM insects, and GM birds and mammals. To help define the criteria for ERA of GM animals, EFSA
launched external calls for data for the three categories. The information received is being
considered by EFSA’s Working Group preparing the guidance document.“59 It remains to be seen to
what extent the outcomes and conclusions of the above mentioned three scientific reports will be
included into this guidance on environmental safety assessment. It is expected to be published for a
public consultation in spring 2012, being ready for adoption presumably in summer 2012.60
The Malaysian Mosquito case
The genetically modified mosquito Aedes aegypti strain OX513A, developed by the above-mentioned
company (see Products) Oxitec, has been tested in field releases on the Cayman Islands in 2009 and
2010.61 These trials were obviously not announced to the local public in advance62 and they became
public only in November 2010 when disclosed by Oxitec itself during a scientific conference. A press
release by Oxitec Limited together with the Mosquito Research & Control Unit of the Cayman Islands
Government titling "Open field trial demonstrates effectiveness of RIDL® system for suppressing a
target wild mosquito population" also concluded lapidary: "A significant reduction in the local
mosquito population was observed from August. All of the trial objectives were successfully met,
including the main goal of suppressing the local Aedes aegypti population."63 Due to the lack of
publicly available information it seems unclear whether a risk assessment was carried out prior to
these releases or whether evaluation or monitoring was carried out after the end of the field trials.
In Malaysia public discussion of planned field releases also with genetically modified mosquitoes of
the Aedes aegypti species began in about December 2010.
A new strain of transgenic mosquitoes developed by Oxitec was derived in Malaysia by the National
Institute for Medical Research (IMR): Aedes aegypti OX513A My1. The males of this type are
genetically modified so that that they have two new traits: fluorescence (as a marker) and the aforementioned "conditional lethality" (RIDL). In autumn 2010, the IMR applied to the National Biosafety
Board (NBB) to be allowed to conduct field releases with these genetically modified male insects. The
corresponding authorisation was granted in October 2010 for two localities: near the town of
Bentong (approx. 50km northeast of Kuala Lumpur) in the province of Pahang as well as for the
district of Alor Gajah in the province of Malakka (West-Malaysia). In both regions the release were to
take place first in uninhabited areas and afterwards in inhabited areas; in total 16,000 to 24,000
58
Detailed discussion of this draft in chapter 1.1, Regulatory aspects/Risk assessment, European Union.
60
The most comprehensive information sources in this and similar cases are provided by critical civil rights and
environmental organisations; e.g. www.biosafety-info.net/article.php?aid=757 (8.11.2011)
61
GeneWatch UK Briefing, December 2010.
62
The Cayman Islands are not a member of the Cartagena Protocol on Biosafety.
63
Oxitec´s presse release at:
http://www.gentechnologie.ch/cms/index.php?option=com_content&view=article&id=202%3Afreisetzungtransgener-insekten&catid=12%3Aschadkat&Itemid=1 (8.11.2011)
59
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mosquitoes were to be released.64 The aim of these field trials would be to compare the life
expectancy and survival rate as well as distribution of the transgenic mosquitoes with that of wild
type mosquito populations. Here too, the ultimate goal of this work was to decimate the diseasebearing mosquito population.65
At the end of December 2010 such releases actually have taken place at two different sites in
Malaysia, „some 6,000 genetically modified mosquitoes were deliberately introduced to an
uninhabited forest in Malaysia”.66 The public as well as NGOs thought that the trials had been
postponed. “There is no suggestion that any of the releases was unsafe, or contravened any law. In
line with Malaysia's biosafety rules and the Cayman Islands' draft rules, permits were issued after the
relevant national authorities performed risk assessments.“67
With the company being from the UK, also EU law is affected. Shipment of eggs of genetically
modified mosquitoes requires notification in advance to the relevant authority according to
Regulation (EC) No 1946/2003 on transboundary movements of genetically modified organisms
(GMO) which governs unintentional transboundary movements as well as exports of GMOs to third
countries.
Detailed information on risk assessment prior to the release, on measures of risk management
during and after it as well as on monitoring and evaluating the impact/success of such trials is not
easy to retrieve and is sometimes inconsistent.
Some information on the actual risk assessment conducted by the Ministry of Natural Resources and
Environment (MNRE) is available through the Biosafety Clearing House (BCH) mechanism under the
Cartagena Protocol on Biosafety.68 Approval with conditions of the import/use of the living modified
organisms has been issued on December 14, 2010. This decision seems to rest upon a risk
assessment report (obtainable at the BCH´s website) from the Genetic Modification Advisory
Committee (GMAC) based on the data submitted by the Institute of Medical Research in May 7, 2010
as well as on other information sources, such as e.g. meetings with scientists from NGOs, authorities
at the Cayman Islands (were the first releases of such transgenic mosquitos have taken place), and
the U.S. Environmental Impact Assessment related to transgenic fruit fly and pink bollworm.69
The specific scientific bases for the risk assessment of the use and release of genetically modified
Aedes aegypti remains somewhat unclear, as the report of the GMAC represents only a summary of
the considerations and findings of GMAC. E.g. the report mentions that a final list of 33 hazards was
identified, and that “Most of these hazards were rated as having an overall risk of 1 or effectively
zero”70, but no further details are provided in this context. Special attention was given to the
following points: manual sorting of pupae where it is recommended to strictly follow the Standard
64
http://www.biosafety-info.net/article.php?aid=750; www.biosafety-info.net/article.php?aid=752;
www.biosafety-info.net/article.php?aid=755 (8.11.2011)
65
Which ultimately could only be achieved by continual, possibly weekly, release of the genetically modified
mosquitos.
66
http://www.nature.com/nature/journal/v470/n7333/full/470139a.html (3.12.2011);
http://www.malaysiakini.com/news/154545 (3.12.2011)
67
http://www.nature.com/nature/journal/v470/n7333/full/470139a.html (3.12.2011)
68
http://bch.cbd.int/database/record-v4.shtml?documentid=101480 (22.11.2011)
69
Risk assessment report of the Genetic Modification Advisory Committee (GMAC) for an application to
conduct a limited Mark-Release-Recapture of Aedes aegypti (L.) wild type and OX513A strains, NBB REF NO:
NRE(S)609-2/1/3; http://bch.cbd.int/database/record-v4.shtml?documentid=101480 (22.11.2011)
70
ibd., p. 5.
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Operating Procedure submitted by the applicant (no details available); and the possibility of the
introduction of the transgene into wild population as appr. 3% of the progeny of OX513A(My1) will
survive. The overall risk of this event was rated to be low in the report, as the transgenic mosquito
should have no selective survival advantage. Extensive fogging is therefore required. As the „GMAC
has ... determined that the field trial does not endanger biological diversity or human, animal and
plant health“71 it approved the field trials with „terms and conditions“ concerning further
information to be submitted shortly before the trials and actions to be taken and reported during
and after the field trials (e.g. recapturing of insects, fogging and clean-up operations, monitoring for
one month after termination of the trials, reporting to the competent authority).
A lot of critical points concerning potential environmental impacts need to be assessed thoroughly,
inter alia:
 Male pupae are sorted manually according to size; this method involves uncertainties; each
female is a potential, additional disease vector.
 Genetically modified larvae only die if there is no tetracycline in the immediate environment
(an antibiotic used in animal breeding and veterinary medicine, also in Malaysia).
 3-4% of the progeny do not die (unexpected survival), i.e. transgenic animals or their genetic
material remains in the ecosystem.
 Potential impacts of a large number of dead and rotting larvae and pupae.
 Possibility that another, more virulent type take over the resulting ecological niche in
Malaysia, particularly Aedes albopictus (a vector both for dengue fever and chikungunya).72
 Unclear interaction between the two different species of mosquito as well as the four forms
of dengue virus and other similar diseases.73
 Horizontal gene transfer to non-target organisms.
 Effects of a drastic reduction of the mosquito population on the predator-prey balance (and
other factors) in the respective ecosystem.
 Probability of a so-called rebound effect.74
 Moreover, corresponding baseline data are necessary in order to evaluate these effects.
A Malaysian NGO issues a comprehensive assessment of the events as well as of environmental
concerns, “Memorandum on Malaysia’s GM Aedes mosquito planned release: ethical, legal and
human rights concerns by Consumers’ Association of Penang and Sahabat Alam Malaysia“.75
According to this paper the Malaysian Ministry of Natural Resources and Environment (MNRE)
conducted a "scientific analysis of risk assessment", taking as a basis for this the Environmental
Impact Statement (EIS), which has been used in the USA when assessing genetically modified insects
with "conditional lethality", e.g. pink bollworm or the fruit fly. However, as these concern agricultural
pests, the aspect of potential effects on human health so essential in relation to the GM mosquitoes
is naturally not brought to bear. Besides this U.S. EIS, only one further publication seems to have
provided the only scientific basis for the risk assessment by the MNRE. Moreover, this latter
publication is valued somewhat controversial, as it has been developed during a Workshop on the
“Risk Assessment of Transgenic Insects" (November 2008) under the lead of an expert from the
71
ibd., p. 10.
Interesting detail: Oxitec has taken this into consideration and is also developing a GM variant of this type;
www.biosafety.info.net/article.php?aid=752 (22.11.2010)
73
74
„A reduction in cases leads to a reduction in immunity. If the control measure becomes lesss effective, there
can be a rebound in cases.“ Helen Wallace 2011.
75
72
Page 24 of 54
company Oxitec.76 Genewatch77 levels clear criticism at this publication: it contended that certain
risks were more or less disregarded or described as irrelevant. As one of several examples it cites the
possible consequences of the genetic material remaining in the ecosystem (e.g. dead larvae), which
were apparently described in the report as additional fish-food and thus as an additional benefit.
The GMAC seems to be aware of the existing shortfalls: the above mentioned risk assessment report
contains a short section with “Identification of issues to be addressed for future releases”78, which
would be “important during the assessment of an application for a larger scale or commercial release
of OX513A(My1)”. There, some of the environmental concerns are being addressed, e.g. the risk that
these genetically modified mosquitos may cause other pests to become more serious should be
considered more thoroughly; the behaviour (e.g. mating, biting) in the field has to be assessed in
comparison to its behaviour in containment or information on the stability of the transgenes through
multiple generations in the field.
The National Biosafety Board has in October 2010 issued (rather general) measures concerning risk
management and monitoring related to the approval.79 It states that the transgenic mosquito „...
does not endanger biological diversity or human, animal and plant health when proper risk
management strategies are followed as stipulated through the terms and conditions imposed with
the approval.“ And further: „Risks identified for this field experiment were quite low in the context of
a limited Mark-Release-Recapture field trial … the released male mosquitos will be recaptured using
standard procedures ...“. This measure is yet dependent on a functioning fluorescence marking of the
genetically modified mosquitos. As additional measure fogging is recommended.
After the releases having obviously taken place end of December 2010 it remains unclear if and how
monitoring measures have been actually conducted or how any potential success of these trials has
been evaluated.
USA
In 2007 the U.S. Department of Agriculture (USDA), which oversees most bio-control releases,
approved trials of the first genetically altered insect, a pink bollworm80 developed by Oxitec.
In October 2008 the U.S Department of Agriculture (USDA) together with the Animal and Plant
Health Inspection Service (APHIS) published an extensively document on the risk assessment of
genetically modified insects, „Use of Genetically Engineered Fruit Fly and Pink Bollworm in APHIS
Plant Pest Control Programs, Final Environmental Impact Statement“. Such an Environmental Impact
Statement (EIS) may be necessary according to the National Environmental Policy Act (NEPA) and
requires e.g. the following elements: Statement of purpose and need; alternatives, including the No
Action & Proposed Alternative; description of the affected environment; environmental effects,
impacts, consequences of each alternative; risk assessment criteria and analysis; analysis of impacts
on endangered and threatened species in the program control areas.
76
Experts of Oxitec hold ambivalent positions in the whole process: they develop genetically modified insects
with a commercial interest while at the same time providing political consulting, assisst in developing
regulatory guidelines (e.g. with WHO´s Collaborating Centre for Vectors), train staff of authorities in countries
(under the frame of UNEP-GEF projects) where they want to conduct releases etc. Such incidents show the
importance of ensuring independent expertise as well as conducting and supporting independent risk research.
77
Genewatch UK Briefing 2010.
78
GMAC 2010, p. 9.
79
80
A crop pest affecting cotton.
Page 25 of 54
The plant pests selected for inclusion in the EIS were the pink bollworm (Lepidoptera: Gelechiidae)
and three species of tephritid fruit flies (Mediterranean, Mexican, and oriental). Within this EIS three
alternatives in pest fighting have been compared: (1) no action, (2) expansion of existing programs,
and (3) integration of genetically engineered insects into programs (the preferred alternative).81 The
conclusions are that the environmental consequences of the preferred alternative were found to
have no more adverse environmental impact than the continuation or expansion of present sterile
insect technique fruit fly and pink bollworm control programs, which use radiation to sterilize insects
and include other control and monitoring measures. The considerations within this EIS focus on the
comparison of these alternatives and to a lesser extent on potential impacts of these transgenic
insects.
Currently, it seems to be unclear which authority in the U.S. would be responsible for an application
for the release of transgenic mosquitoes Aedes aegypti (see above, Products). The U.S. Federal Drug
Administration is responsible for genetically modified animals, but nor for insects. The Environmental
Protection Agency deals with bio-/pesticides, but does equally not cover insects even if these are
modified for plant pest control programs. The above-mentioned USDA APHIS is responsible for plant
pests, which does not cover mosquitos.
An article from November 11, 2011 within the newspaper Miami Herald stated: „But late last month,
the agency issued a letter concluding that the mosquito was outside its jurisdiction because it poses
no threat to animal health. The USDA suggested Oxitec contact other federal agencies - the Fish and
Wildlife Service, Centers for Disease Control and Food and Drug Administration. State agriculture
officials, Ivey said, are consulting with attorneys and other agencies to decide who should review the
plan.“82 This may be related to the USDA´s announcement to improve internal procedures and
strategies, „The U.S. Department of Agriculture’s (USDA) Animal and Plant Health Inspection Service
(APHIS) today announced plans to dramatically streamline and improve several programmatic
processes, including the Agency’s processes for conducting risk assessments and rulemaking.“83
Already in 2009, in a footnote to the Guidance for Industry on genetically engineered animals the
FDA stated: „In addition, FDA is discussing with other agencies the best approach for oversight of GE
insects.“84
WHO, Cartagena Protocol on Biodiversity
In 2009 the World Health Organization (WHO) stated that there are currently no guidelines regarding
trials, or regulation, of genetically modified mosquitoes, and it identified an urgent need to
standardize principles for safety and efficacy testing.85 A series of technical meetings was planned on
„Progress and prospects for the use of genetically modified mosquitos to inhibit disease
transmission“, with the first one in Geneva in May 2009. This effort should finally result in a guidance
framework for the evaluation of genetically modified mosquitos for malaria and dengue control
including e.g. description of standard procedures for safety testing, addressing ethical, legal and
social issues, and recommend processes for independent testing. A first report has been published in
April 2010, “Progress and prospects for the use of genetically modified mosquitoes to inhibit disease
transmission. Report on planning meeting 1: Technical consultation on current status and planning
for future development of genetically modified mosquitoes for malaria and dengue control“. The
current progress of this remains unclear.
81
USDA 2008, p. 29.
http://www.miamiherald.com/2011/11/11/v-fullstory/2498023/key-west-mosquito-controlcould.html#ixzz1ffnq0Jck (4.12.2011)
83
http://www.aphis.usda.gov/newsroom/2011/11/risk_assessment_process.shtml (4.12.2011)
84
U.S. FDA, Guidance for Industry 187, footnote 1, p. 6.
85
http://apps.who.int/tdr/svc/news-events/news/gm-mosquito-review (6.12.2011)
82
Page 26 of 54
In August 2010 the final report of the Ad Hoc Technical Expert Group on risk assessment and risk
management has been delivered and adopted at the Meeting of the Parties to the Cartagena
Protocol on Biosafety in October 2010. The objective of this specific report was to give additional
guidance on the risk assessment of genetically modified mosquitoes in accordance.
While it is important to be aware of on-going activities and stay updated on international
developments, it should be bared in mind that the activities and documents mentioned above focus
mainly on approaches relevant in particular for developing countries. They cover issues such as e.g.
capacity building and training, development and implementation of respective state procedures,
definition of competencies between national authorities, etc.







A range of genetically modified insects has already been developed, mainly mosquitoes and crop
pests focusing on reduction of diseases such as Dengue fever or Malaria and reduction of crop
losses.
Field releases have taken place at least in the USA, Cayman Islands, Malaysia and Brazil. The next
trial is presumably to be expected for Florida/USA.
The scientific study commissioned by the European Food Safety Authority entitled “Defining
Environmental Risk Assessment Criteria for Genetically Modified Insects to be placed on the EU
Market" provides a comprehensive overview of the current scientific status quo and identifies
genetically modified arthropods that may play a significant role in Europe, although it is not
anticipated that releases will take place within the next ten years.
The main concern with regard to genetically modified insects relates to a wide range of potential
environmental impacts in connection with the deliberate release of a great amount of such
insects, as they are highly mobile and not controllable. Concerns raised are all the more
important if these insects are vectors for human diseases.
Therefore, the guidance document to be developed by EFSA´s GMO Panel defining criteria
concerning the environmental risk assessment (ERA) of genetically modified animals, including
insects, is very important as it will set the standard for environmental protection in Europe. It
remains to be seen to what extent the outcomes and conclusions of the respective scientific
reports will be included into this guidance.
Experiences like that in Malaysia additionally underline the importance of having comprehensive
respective standards and requirements available.
Last not least, also in the context of genetically modified insects the necessity and importance of
independent risk research has to be stressed. “We are concerned that the novelty of this
application of GM technology has made regulators in several countries too dependent on advice
provided by the company.“86
86
GeneWatch UK comments on Risk Assessment report of the Malaysian Genetic Modification Advisory
Committee (GMAC) for an application to conduct a limited Mark-Release-Recapture of Aedes aegypti (L.) wild
type and OX513A strains; January 2001, available at http://www.genewatch.org/sub-566989 (2.12.2011)
Page 27 of 54
2
GENE PHARMING
Gene pharming, i.e. the production of pharmaceuticals in the milk, blood or urine of genetically
modified animals, is one of the most advanced applications in the field of transgenic animals. The
expression of these proteins from the milk gland takes centre stage due to the amounts obtainable
and the tried-and-tested methods available in this respect for both extraction and cleansing. A
further approach is the cultivation of vaccines in chicken eggs.
The potential advantages of obtaining these substances from transgenic animals instead of
transgenic plants (or in some cases also instead of conventional production systems) are manifold:
 Higher concentration of recombinant proteins e.g. in the milk of transgenic animals as
compared with bacteria cultures or similar systems, which also has economic connotations as
well as the better availability in quantitative terms.87
 Production of complex proteins or such that do not function well in the production systems
up till now.
 Greater compatibility of the protein produced, in particular due to post-translational
modifications.
 Development of new pharmaceuticals.
Critical debate on the development and use of transgenic animals for the production of
pharmaceutically relevant proteins focuses above all on questions of animal welfare, animal health
and species-appropriate husbandry thus being related to the question of how to adequate handle
laboratory animals in general. Due to the genetic modification, the organism of the respective animal
is confronted with large amounts of biologically active proteins foreign to the species, which may
impair the animal's health. However, the development of a healthy animal or a healthy herd is very
much in the interest of the respective company, as effective pharmaceuticals can only be obtained
from such animals. Overall, the aspects concerning animal welfare are not looked at in any more
detail in this opinion.
Environmental risks in connection with individual, escaped transgenic animals are most unlikely in
this context (in contrast to the production of such pharmaceuticals in genetically modified plants)
and are not dealt with in depth in the relevant literature. Generally, no field releases are carried out
in respect of these animals.
The assessment of the possible risks of pharmaceuticals from transgenic animals to human health is
the main aspect. This risk assessment is dealt with comprehensively in the authorisation rules for
pharmaceuticals, which form an entirely separate legal area. In general, the type of production, i.e.
whether a particular protein was obtained from microbes or from a transgenic animal, does not play
any significant role. The focus of medicine authorisations is on the purity of the product and in
particular the individual steps of the clinical studies testing and analysing effectiveness as well as
possible adverse effects to human health. One aspect that is criticized here - and generally in the
field of genetically modified organisms - is the fact that authorities and/or risk assessors are usually
dependent on the information and documentation provided by the company applying for the
authorisation. Hence, the call for supporting independent risk research is also formulated sometimes
in respect of gene pharming.88
It may be observed here (as in other technical fields) that everything that affects human health in the
medical sense is almost unreservedly accepted. This means that in the context of using transgenic
animals for the production of pharmaceuticals (apart from the questions of animal welfare), debate
87
Especially treatments with antibodies may require repeated usage of large doses.
For example, Rehbinder et al. 2009, p. 295.
88
Page 28 of 54
is always more or less uncontroversial. Apart from purely scientific articles that concern detailed
research questions, there are hardly any reports, statements or other publications on gene
pharming.
Products
In July 2006 the first medicine harvested from a transgenic animal, the anti-coagulant
Antithrombin III89 obtained from the milk of a transgenic goat (company GTC Biotherapeutics), was
approved by the European Medicines Agency (EMA). In the USA the corresponding authorisation was
granted by the U.S. Food and Drug Administration in February 2009.90
Since then only one further authorisation has been issued: a recombinant human C1 esterase
inhibitor (called Ruconest), used to treat hereditary angioedema91, which is obtained from the milk of
transgenic rabbits. The market authorisation for the entire EU was issued by EMA on 28 October
2010 to the Netherlands Pharming Group.92
Several other pharmaceuticals that contain recombinant proteins are at various stages of pre-clinical
and clinical research. A somewhat complete overview over recent on-going pharmaceutical research
as well as related papers and publications is not feasible due to the sheer quantity as well as to the
rapid developments in this field. Another possibility to gain an overview over potential emerging
products would lie in screening pending and already granted patents. Both approaches are not
manageable to conduct within the time constraints of this report. Nevertheless, efforts have been
undertaken to e.g. screen the website of at least some of the pharmaceutical companies mentioned
at EMA´s Website.
Since the EMA does not put a special label on medicines containing substances obtained from
transgenic animals, it was only possible to analyse by spot checks using key words and following up
indications found in other sources. For example, the key word search on the EMA website delivers
1,760 different, sometimes overlapping, results for the word "recombinant", e.g. the „Work plan for
the Safety Working Party 2012“ within which the preparation of a „Guideline on similar biological
product containing recombinant interferon beta“ or the draft of „Guideline on similar biological
medicinal products containing recombinant follicle stimulation hormone“ are mentioned.93 Since
2009 the EMA itself notes in the introductory remarks94 regarding the revision of the guideline "Use
of transgenic animals in the manufacture of biological medicinal products for human use" (see
below, Regulatory aspects / Risk assessment) that in the meantime numerous pharmaceutically
relevant recombinant proteins have been developed, for example C1 inhibitor, monoclonal
89
With a gene coding for the human antithrombin combined with a regulating sequence responsible for
lactation.
90
http://www.fda.gov/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/LicensedProductsBLAs/Fr
actionatedPlasmaProducts/ucm134050.htm (22.11.2011)
91
Rare hereditary disease, which can manifest in life-threatening swellings of the skin, mucous membrane or
internal organs.
92
http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/001223/human_med_00
1382.jsp&murl=menus/medicines/medicines.jsp&mid=WC0b01ac058001d125 (22.11.2011)
93
http://www.ema.europa.eu/ema/index.jsp?curl=search.jsp&site=pfoi_collection&entsp=0&client=pfoi_fronten
d&curl=search.jsp&btnG=Search&entqr=0&oe=UTF-8&proxyreload=1&q=recombinant&ie=UTF8&ud=1&mid=&output=xml_no_dtd&proxystylesheet=pfoi_frontend&filter=0&ip=172.16.100.1&access=p&sor
t=date%3AD%3AS%3Ad1 (2.12.2011)
94
European Medicines Agency 2009, p. 2.
Page 29 of 54
antibodies or fibrinogen, all of which are at different stages of pre-clinical or clinical research. The
animal species used to this end are mice, goats, sheep, rabbits and cows.
Examples of on-going works / product developments
In July 2011 the newly established Christian Doppler Labor für Innovative Immunotherapie under
the direction of Prof. Gottfried Brem at the University of Veterinary Medicine Vienna has been
opened. The focus of the research work will lie upon establishing new approaches for fighting a
special form of skin cancer (malignant melanoma) as well as a specific cerebral tumour (glioblastoma)
through the development of transgenic cows. From their blood or milk a specific recombinant
antibody should be extracted which would support the human immune system in destroying tumour
cells. The company Volkspharma acts as private sponsor.
GTC Biotherapeutics, the company which has gained approval for the first pharmaceutical from a
transgenic animal (mentioned above), is currently working on the development of several
recombinant plasma proteins and monoclonal antibodies from transgenic animals, e.g. human
Antithrombin, human alpha-1 Antitrypsin, Albumin, CD137 Antibody, as well as coagulation factors
VIIa, VIII and IX respectively.95 Focus is laid upon the extraction from milk of genetically modified
goats, to a lesser content from mice. These proteins are at different stages of research, development
and/or testing: „Factors VIII and IX were recently in-licensed from ProGenetics, LLC for development
in North America, Europe, and Japan. Factors VIIa, IX and VIII are all in the development phase at
GTC.“96 In May 2011 GTC has been granted a patent (extending to 2021) by the United States Patent
and Trademark Office covering DNA constructs for the production of any therapeutic protein in the
milk of any transgenic animal. Another US patent covers methods for the production of any
therapeutic protein in the milk of non-human transgenic mammals.
Like GTC Biotherapeutics, the Dutch Pharming Group NV, which has received the approval for
Ruconest, the second ever granted pharmaceutical from a genetically modified animal (described
above), is also further pursuing the development of recombinant therapeutic proteins. The main
production system are the mammary glands of transgenic rabbits or cattle. Besides being used in the
treatment of the hereditary angioedema the above mentioned recombinant human C1 inhibitor
(Ruconest) is investigated in other indications such as antibody-mediated rejection and delayed graft
function after organ transplantation (currently in Phase II clinical trials). The company is also working
on recombinant products used in case of fibrinogen deficiency (pre-clinic) or in tissue repair (also
pre-clinical stage).97 Another focus is the development of human lactoferrin (research &
development stage) for use in nutritional products or in pharmaceutical applications (e.g. against
systemic infections). Furthermore, Pharming holds patents (until 2020) covering the recombinant
human proteins fibrinogen, lactoferrin, collagen, and the field of DNA repair as well as e.g. for the
generation and use of transgenic cattle, milk specific expression in transgenic animals, animals
carrying large transgenes (>50kb), structure and design of transgenes for high level production or
transgenic antibody production.98
Synageva Ltd. (UK) is focusing on pharmaceuticals for the treatment of rare diseases (so called
orphan diseases). Pharmaceutical proteins of interest are expressed in hen oviduct cells, i.e. the
secretion and packaging of the therapeutic protein into egg white.99 The protein matrix of egg white
allows bulk storage of unpurified egg white for prolonged periods. One of the main products is
recombinant human liposomal acid lipase for the treatment of the respective lipase deficiency
95
http://www.gtc-bio.com/products.html (22.11.2011)
http://www.gtc-bio.com/products.html (23.11.2011)
97
http://www.pharming.com/index.php?act=prod (12.11.2011)
98
http://www.pharming.com/index.php?act=tech (12.11.2011)
99
http://www.synageva.com/science-and-technology-synageva-expression-platform.htm (23.11.2011)
96
Page 30 of 54
(inherited genetic conditions). Currently clinical trials are underway. Additionally, several other
therapeutic protein targeting at rare diseases are in various stages of preclinical development
including therapeutic enzymes, cytokines, monoclonal antibodies and fusion proteins.100
The U.S. company Hematech has - at least until 2010 - been developing genetically modified cattle
(TC Bovine™) for the production of human polyclonal antibodies which are expected to be used in
the „treatments of viral or bacterial infections, autoimmune disorders and other medical conditions
occurring in humans“.101 The current state of these efforts remains a bit unclear as the company’s
website itself offers no extensive information on this and no further details seem to be available. As
the development of transgenic cattle takes a long time, is rather expensive as well as needs a longer
waiting period up to the beginning of the lactation period it may be justified to assume that once
such cattle has been successfully developed the next promising step would lie in cloning these
transgenic animals.
Taiwan-based Abnova has set up collaboration with the Japanese National Institute for
Environmental Studies to conduct a joint research in chicken primordial germ cell for protein and
monoclonal antibody production. The focus lies upon the development of transgenic chicken for the
production of pharmaceutical relevant proteins.102
Regulatory Aspects / Risk assessment
European Union
Medicine from genetically modified animals is relevant both to EU and national legislation. An
authorisation by the European Medicines Agency (EMA) is necessary. In general, pharmaceuticals are
one of the most comprehensively regulated legal matters. Safety issues may refer to purity, efficacy
and potential adverse effects (side effects) related to human health, but these are to be answered
independent of the production process of the pharmaceutical, i.e. they are not specifically connected
to genetically modified animals.
A specific EMA Guideline, in force since July 1995, entitled "Use of transgenic animals in the
manufacture of biological medicinal products for human use (3AB7A)", is relatively short and very
general. It more or less roughly summarises necessary descriptions, for example for the
characterisation of specific gene sequences, control elements or the methods used to create the
transgenic animal, which should be explained in the respective application.
In knowledge of the numerous shortfalls in this guideline and taking into account the research
developments in the meantime, the "Committee for medicinal products for human use" began work
on revising the guideline in 2009; this revision is intended to integrate the following aspects among
others: breeding strategy, pathogen safety, quality standards for generations of transgenic lines,
product characterization, control of active substances, consideration of the variability of the
respective recombinant proteins in animals due to sexual reproduction. It was announced that the
revised version of this guideline would be issued in 2010. However, in November 2011 as yet no
more recent information is available in this respect.
Besides this general guideline EMA has laid out several protein-specific requirements, e.g. „Guideline
on the clinical investigation of recombinant and human plasma-derived factor VIII products“ or
100
http://www.synageva.com/programs-pipeline.htm (23.11.2011)
www.hematech.com (23.11.2011)
102
http://www.biospectrumasia.com/content/041011OTH17213.asp (1.12.2011);
http://www.abnova.com/aboutus/news_detail.asp?CTID={BB1D843D-A62A-49BF-81CB-172A816A0741}
(1.12.2011)
101
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„Guideline on clinical investigation of recombinant and human plasma-derived factor IX products“
(both turn into effect February 1st 2012) dealing inter alia with safety questions with regard to viral
contamination of these specific products.
USA
In the USA a guidance document concerning pharmaceutical proteins (for diagnostic, preventative or
therapeutic purposes) from transgenic animals has been released by the U.S. Food and Drug
Administration (FDA) and the Committee for Proprietary Medical Procedures already in 1995, „Points
to consider in the manufacture and testing of therapeutic products for human use derived from
transgenic animals“. The issues in that guidance cover inter alia aspects related to the creation and
characterization of transgenic founders, establishing and maintaining production herds, questions
concerning housing facilities or disposal of these animals, the purification process, as well as
questions around the pre-clinical safety evaluation.
Previous to the approval of Antithrombin III from transgenic goats, the FDA´s Center for Veterinary
Medicine (CVM) has conducted an „Environmental Assessment for the Bc6 rDNA Construct in GTC
155-92 Goats Expressing Recombinant Human Antithrombin III (rhAT or ATRYN)“103 as required under
the New Animal Drug Act. Detailed requirements also laid out in the FDA´s “Guidance for Industry
#187, Regulation of Genetically Engineered Animals Containing Heritable rDNA Constructs“
(discussed in chapter 1.1. of this opinion. This legal action was conducted to assess the rDNA
construct in the transgenic animal (e.g. construct safety, animal health, potential environmental
impacts).
The document on the environmental assessment for the Bc6 rDNA construct explains the approach:
„As described in Guidance 187, CVM has proposed a risk-based hierarchical review strategy that can
fulfil sponsor’s requirements for demonstrating safety and effectiveness ... This approach begins with
a product definition, and continues through a series of steps that characterize potential hazards in
the rDNA construct and resulting lineage of GE animals. Once those hazards have been identified, the
agency can determine whether any significant risks to animal health, humans or other animals via
food/feed consumption (if appropriate), and the environmental can occur. ... Rather than
reproducing the entire hazard/risk reviews for each step of the process in this document, we will
concentrate here on those components relevant to the environmental assessment.“104 And further
on: „In order to conduct the environmental assessment, the results of the previous four evaluations
are combined with an analysis of the husbandry and containment of the GE goats, including a review
of the animal production facilities and practices; the conditions under which the animals are housed;
containment and biosecurity, including animal identification; disposition of animal carcasses, and
disposal of animal wastes.”105
FDA’s CVM approved the rDNA construct based on its safety and ability to consistently produce the
human Antithrombin over seven generations of the genetically modified goats, whereas the Center
for Biologics Evaluation and Research approved the human anticoagulant based on its safety and
effectiveness in humans.106
103
Available at
http://www.fda.gov/AnimalVeterinary/DevelopmentApprovalProcess/GeneticEngineering/GeneticallyEngineer
edAnimals/default.htm (24.11.2011)
104
U.S. FDA, January 29, 2009, p. 5.
105
idbd., p. 8.
106
http://www.fda.gov/AnimalVeterinary/NewsEvents/FDAVeterinarianNewsletter/ucm190728.htm
(24.11.2011)
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It may be observed here that everything that affects human health in the medical sense is
almost unreservedly accepted. This means that in the context of using transgenic animals for the
production of pharmaceuticals (apart from the questions of animal welfare), debate is always
more or less uncontroversial.
Critical debate on the development and use of transgenic animals for the production of
pharmaceutically relevant proteins focuses above all on questions of animal welfare, animal
health and species-appropriate husbandry.
Environmental risks in connection with individual, escaped transgenic animals are most unlikely
in this context (in contrast to the production of such pharmaceuticals in genetically modified
plants) and are not dealt with in depth in the relevant literature. Generally, no deliberate
releases are carried out in respect of these animals.
The assessment of the potential risks of pharmaceuticals (side effects) from transgenic animals
to human health is the core challenge. These risk assessment questions, which are not
specifically connected to genetically modified animals, are dealt with comprehensively in the
authorisation rules for pharmaceuticals (which are one of the most comprehensively regulated
legal matters).
It could be critically remarked that authorities and/or risk assessors are usually dependent on
the information and documentation provided by the company applying for the authorisation.
Hence, efforts to strengthen independent risk research could be useful.
So far, two pharmaceuticals harvested from a transgenic animal are approved by the European
Medicines Agency:
- Anti-coagulant antithrombin III obtained from the milk of a transgenic goat in July 2006,
which was also granted approval in the USA in February 2009
- Recombinant human C1 esterase inhibitor (28 October 2010)
Several other pharmaceuticals that contain recombinant proteins are at various stages of preclinical and clinical research being developed by various pharmaceutical/chemical companies.
Product development takes place in transgenic cows, rabbits, goats and chicken.
After having successfully received approval in the European Union as well as in the USA,
reinforced research efforts can be expected which definitely will lead to further applications for
pharmaceuticals from transgenic animals.
Page 33 of 54
3
CLONING OF ANIMALS
It is noted that in the strict scientific sense cloning technologies are not categorized per se as genetic
modifications. Cloning concerns the production of a genetically more or less (depending on the
technology used) identical animal and does not involve interference in the genome in order to carry
out a modification. The cloned animal itself is not used for the production of food products; instead it
is used to spread certain features identified as being beneficial. Against that, the progeny of a cloned
animal are the result of conventional sexual reproduction. It is only this generation that is then used
for e.g. processing of food. This report is focused on cloned livestock - the cloning of family pets,
sporting animals, etc. will not be discussed here.
When animals are cloned, especially if they are cattle, miscarriages are numerous. Besides this, less
than half of the surviving animals develop into healthy juveniles. The main critical arguments thus
concern questions of animal health and welfare. In its 2008 opinion the EFSA defined in particular
defective epigenetic regulation as the cause of death or miscarriages or adverse effects in cloned
animals. These aspects lie outside of the ambit of this paper and will not be further discussed.
There are hardly any concerns in connection with environmental issues in this area, since cloned
animals are generally not released in field trials. It is sometimes cautioned that the cloning of only
certain animals (or features) could lead to a reduced genetic pool for particular breeds. However, this
would only apply if cloning were carried out to a larger extent.
The main aspect to be taken into consideration is thus the risk assessment of the products resulting
from the healthy progeny of cloned animals (as discussed below, Regulatory aspects/Risk
assessment). It must also be ensured that cloned animals do not unintentionally end up in feed
production or in the human food chain.
In connection with this topic, reference is made to the dossier entitled "Technische Information zum
Klonen von Nutztieren" (in English: Technical Information on the cloning of agricultural animals) put
together by Dr. Dietmar Vybiral (Federal Ministry of Health, Dept. Abt. II/B/15) in spring 2011. This
dossier looks at different cloning methods, at potential applications associated therewith for
agricultural animals (whether transgenic or not) and points to cattle or pigs as the most advanced
developments. It is also noted that "extensive studies have not found any differences between meat
and milk composition in cattle in relation to same-age control specimens." Similar findings are
reported in respect of pigs.
Products
Allegations that cloned animals and/or their products (or products of their progeny) are already on
the market in Europe are regularly found in various publications. These allegations are rarely
accompanied by corresponding hard facts or evidence. In this respect the following may be
established: It may be assumed that reproductive material from cloned animals (especially sperm)
has been imported into the European Union. Therefore, it is highly probable that products derived
from the progeny of such animals have been placed on the market. This is also assumed on the part
of the European Commission as recorded in a non-public, so-called non-paper entitled “Cloning non-paper on WTO compatibility, trade and agricultural production impacts”.107
107
http://www.testbiotech.org/node/456 (26.11.2011)
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In 2010 the European Commission108 further reported that Great Britain had imported three cattle
embryos that were offspring of cloned animals. In Germany, cloned donor bulls were developed and
their sperm exported to third countries. At the French INRA several cloned cattle were developed
solely for research purposes. The Canadian NGO Organic Consumers reported in this connection of
over 100 cattle in Great Britain that were already the offspring of cloned animals and whose products
(with the knowledge and/or approval of the British Food Standards Agency) are sold.109
As already stated in chapter 1.1 concerning transgenic farm animals, also in the context of cloned
animals is has to be noted that especially concerning future developments a thorough screening of
on going activities has to focus on South American and Asian countries, which are economically and
geopolitically of increasing importance. E.g. in September 2011, the first international workshop on
the food and environmental safety assessment of genetically modified animals - organized inter alia
by the Argentinian Ministry for Agriculture, the International Centre for Genetic Engineering and
Biotechnology and the United Nation´s Programme for Biotechnology in Latin America and the
Caribbean - took place in Buenos Aires City.110 The focus of interest lay upon transgenic agricultural
animals for food purposes as well as cloned animals, including also questions of food and
environmental safety.
Besides Argentina (June 2011, National Institute of Agricultural Technology, Buenos Aires)111 also
China (China Agricultural University, Beijing)112 is reported to have cloned transgenic cattle that
produce milk (insertion of genes coding for two human milk proteins) very similar to human breast
milk.113 The objective behind these efforts to enrich cow´s milk with antibacterial proteins such as
Lysozyme or Lactoferrin. This milk is intended to be processed into milk powder that is then used as
baby foods.
European Union
Cloned animals themselves or the products of their offspring are not subject to any specific legal
rules directed at the fact of cloning. Food products deriving directly from cloned animals would be
subject to an authorisation proceeding under the Novel Foods Regulation, i.e. Regulation (EC) No.
258/97 of the European Parliament and Council of 27 January 1997 on novel food and novel food
ingredients. Should such animals also have been genetically modified, they fall within the scope of
the relevant gene technology legislation. Products from the offspring of cloned animals are at
present not subject to any statutory regulations going beyond the rules on food. All animals that are
used to produce food are subject in the European Union to rules on traceability. In this context, no
reference to the possible use of cloning techniques is currently foreseen.
In response to the report by the U.S. Food and Drug Administration on the safety of food from cloned
animals (see below, USA), the European Commission requested the European Food Safety Authority
(EFSA) to provide an opinion on “Food Safety, Animal Health and Welfare and Environmental Impact
of Animals derived from Cloning by Somatic Cell Nucleus Transfer (SCNT) and their Offspring and
Products Obtained from those Animals” and such was ultimately published in July 2008.114
108
European Commission 2010.
http://www.organicconsumers.org/articles/article 22184.cfm (24.11.2011)
110
111
112
113
114
European Food Safety Authority 2008.
109
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The EFSA expressed the following findings in this opinion, among others:
Due to the few available studies and the small sample sizes uncertainties arise in relation to
risk assessment.
Due to the available data a risk assessment could only be carried out in end effect for cattle
and pigs and their progeny.
Both cow and pig surrogate mothers have a higher rate of miscarriage.
In cattle the offspring are significantly heavier at birth.
The health and welfare of a significant proportion of clones, mainly within the juvenile period
for bovines and perinatal period for pigs, have been found to be adversely affected, often
severely and with a fatal outcome.
Most clones that survive the perinatal period are normal and healthy (physiological
measurements, behavioural studies, clinical investigations).
In the case of sexually fertile offspring of cattle and pig clones, there are no signs of
undesired effects. However, no investigations have been carried out over the entire natural
lifespan of such animals and their progeny.
At present there is no indication that clones or their progeny represent any new or additional
risk to the environment as compared with conventionally bred animals.
Finally, cow milk as well as meat from cattle and pig clones and from their progeny were subjected to
a safety evaluation as potential food products, and in this respect the following parameters were
analysed: composition, nutritional value, probability of novel constituents being present, health
status of the respective animal and available data on toxicity and allergenicity. In its opinion the EFSA
ultimately reaches the conclusion that as regards food safety there are no indications for any
difference between food products deriving from healthy cattle and pig clones and their progeny and
such deriving from conventionally bred animals.
In June 2009 the EFSA issued a further publication on this topic: Further Advice on the Implications of
Animal Cloning.115 This statement focussed on the health and welfare of clones during their lifetime
as well as an investigation of the causes of pathologies and mortality during the gestational and postnatal periods. Furthermore, it examined whether and how the present findings on the cloning of
cattle and pigs can also be applied to sheep, goats and chickens - in this respect, however, too little
data was available. Hence, apart from cattle and pigs, it was still scarcely possible to make any
tenable findings in this respect. Ultimately, the EFSA confirmed its own conclusions and
recommendations of 2008.
A new examination of the current research results on the cloning of animals was carried out by the
EFSA in September 2010.116 Once again the EFSA confirmed its previous findings and noted that no
new scientific information was available that required reconsideration of the conclusions and
recommendations of the Authority’s previous work in the area.
Besides these activities by the EFSA, the possibility of an amendment to the Regulation on Novel
Foods117 was discussed, specifically to target food from cloned animals and their progeny. In this
respect no consensus could as yet be attained between the European Commission, the European
Parliament and the Member States. Negotiations collapsed on several points: the question of
labelling the products of cloned animals and their progeny, an import ban on such products, a
complete ban on such products, a principle requirement that the cloning of livestock as such be
subject to approval. An interim moratorium, i.e. a temporary suspension of cloning or the marketing
of the corresponding food products, was also discussed. New consultations and negotiations in this
field are to be expected, probably not before 2013.
115
117
Regulation (EC) No. 258/97.
116
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USA
Cloning is considered to fall on the continuum of assisted reproductive technologies, i.e. regulations
related to genetically modified animals are not applied.
A voluntary moratorium on the placing on the market of food products from cloned animals, issued
by the U.S. Food and Drug Administration (FDA), has been in effect in the USA since 2001. Products
from their offspring are not affected. Neither are sperm or embryos from cloned animals covered.
Food from the sexually reproduced offspring of clones has been entering the food supply freely.118 It
may be assumed that these are also imported into the European Union (see discussion above,
European Union).
In its report on the situation in the USA, the European Commission noted in 2008 that:119 “In the USA
three major companies sell clones to farmers. Two of the companies put in place a voluntary tracking
system, giving every clone a unique identification (ID). The system does not however extend to
tracking the offspring of clones. The programme works through the use of a national registry, based
on written statements of truth and incentives. … Regarding the number of clones, the companies
have not provided … precise figures but have often mentioned "hundreds of pigs" and "thousands of
cattle". Therefore products of offspring of clones have entered the food chain, not only in the US but
also in other parts of the world (not least in Brazil where there are five companies involved in
cloning). Regarding traceability, clones are tracked through a registry, plus there is an economic
incentive for farmers not to introduce clones into the food chain. However, this tracking is not
mandatory, so it cannot be guaranteed that milk from clones does not enter the food chain (even if it
is unlikely that such milk would be used for food purposes). Offspring from clones are not tracked.”
Then also specifies in its study drawing on a source from 2008 that three companies are known to
market cloned animals for food production in the USA, namely ViaGen (pigs), TransOva (cattle) and
Cyagara (cattle).120
In January 2008 the FDA published a report of about 900 pages on cloned animals and their products
entitled “Animal Cloning. A Risk Assessment”.121 It deals in detail with the principles of risk
assessment and possible endpoints (developing risk assessment methodology), facts and problems in
the context of epigenetics of cloned animals and their offspring (epigenetic reprogramming:
implications for clones and their progeny), possible risks in terms of animal health, possible food
consumption risks and numerous statistics and detailed investigations (of cattle, pigs, sheep and
goats) in several annexes. The most extensive data material appears to relate to cattle. Likewise this
report looks at how to deal with uncertainties in evaluating data.
In the field of food, the report focuses on the milk and meat of cloned animals and their progeny.
Finally, the FDA comes to the conclusion that the meat and milk of cloned cattle and pigs are just as
safe for consumption as food from conventionally bred animals. Neither was any risk found in
relation to products from cloned goats; as regards sheep the FDA does not make any finding due to
the lack of information available. In this context it must be emphasised that these conclusions are
presented in a differentiated manner in the detailed chapter on cattle. The various growth stages are
distinguished and it is noted that a risk may exist in relation to food from cattle in the perinatal stage
(nonetheless it must be emphasised that in reality no food products are obtained from cattle at this
stage of development).122 This is connected with the problems specific to clones directly after the
118
U.S. FDA, September 20, 2010, p. 7.
European Commission 2010, p. 8.
120
Then 2010, p. 25.
121
U.S. FDA 2008.
122
ibd., “Edible products from perinatal bovine clones may pose some very limited human food consumption
risk.”, p. 312.
119
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birth, which were observed up until now especially in connection with cattle and sheep but not with
pigs and goats. Furthermore, the conclusions note that each cloned animal must be looked at
individually in terms of possible risk: “Because each clone arises from an independent event,
identification and characterization of potential subtle hazards (e.g. alterations in gene expression,
immune function, or hormone levels) is best accomplished by the evaluation of individual animals, at
as fine a level of resolution as possible.”123
In the opinion of the FDA no additional or new risk derives from healthy juveniles, or from the
progeny of cloned animals.
In 2008 the FDA consequently issued a Guidance for Industry: “Use of Animal Clones and Clone
Progeny for Human Food and Animal Feed”.124 These non-binding recommendations relate to the
voluntary moratorium in effect since 2001 as regards the marketing of milk or meat from cloned
animals or their offspring as well as to FDA´s report discussed above.
FDA notes that:
 No specific measures are necessary in relation to the use of cloned animals in the field of
animal feed.
 Meat and milk from cloned cattle, pigs and goats do not require any additional controls.
 Edible products from animals other than those cited here should not at present be allowed
to enter the human food supply.
 Products from the progeny of cloned animals (of whichever species) are safe for
consumption and therefore may also be used for producing feed and food without any
additional measures.
The U.S. Center for Food Safety, an NGO, which examines the approach taken within US food policy
and the authorities critically, finds faults with the conclusions in the above-mentioned FDA report as
well as does the report by the German NGO Testbiotech. Mainly, the criticism is directed at the fact
that the (positive) recommendations are based on insufficient data, that hardly any weight is
accorded to unanswered scientific questions, that necessary research questions are not defined and
that ethical issues and problems concerned with animal protection are not integrated in the
recommendations.125
The U.S. Department of Agriculture (USDA) in January 2008 released a statement on FDA´s risk
assessment of cloned animals:126 "USDA fully supports and agrees with FDA's final assessment that
meat and milk from cattle, swine and goat clones pose no safety concerns, and these products are no
different than food from traditionally bred animals. Now that FDA has evaluated the scientific data
and public comments and issued its final risk assessment, USDA will join with technology providers,
producers, processors, retailers and domestic and international customers to facilitate the marketing
of meat and milk from clones.“ Cloning is appraised as just another method of an assisted
reproductive technology helping to transmit superior characteristics. USDA further expressed the
intention to „ensure a smooth and seamless transition into the marketplace for these products. …
At the same time, we understand there are currently only about 600 animal clones in the U.S., and
most of them are breeding animals, so few clones will ever arrive in the marketplace. Further, USDA
has encouraged technology providers to maintain their voluntary moratorium on sending milk and
meat from animal clones into the food supply during this transition time."
123
ibd., p. 329.
U.S. FDA, Center for Veterinary Medicine 2008.
125
http://www.centerforfoodsafety.org/campaign/cloned-animals/ (24.11.2011);
http://www.testbiotech.org/node/521 (24.11.2011)
126
http://www.usda.gov/wps/portal/usda/usdahome?contentid=2008/01/0012.xml&contentidonly=true
(25.11.2011)
124
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Canada
On the basis of a scientific as well as public consultation on “Health Canada’s Guidelines for the
Safety Assessment of Novel Foods, Part III Foods derived from cloned animals” in 2003, the health
authority (Health Canada, Food Directorate) set out a so-called interim policy on foods from cloned
animals with the following rationale:
“Until more is known about the products of this technology, Health Canada will consider foods
produced from livestock developed using SCNT and the progeny of such livestock to be captured
under the definition of “novel food” in the Food and Drug Regulations in that they have been
obtained by a reproductive technology which has not previously been applied to generate animals
that would be used to manufacture foods (meat, eggs, milk, etc.) and which may result in a major
change in these foods. They are therefore subject to the regulations in Division 28, Part B, of the
Food and Drug Regulations (Novel Foods). Developers producing cloned animals through SCNT must,
therefore, not sell the products or by-products of any cloned animals or their progeny in the human
food supply in Canada unless they have been subjected to the pre-market safety assessment
required of novel foods.”127
And further: „SCNT animal clones, their progeny and their products and by-products are also
considered "new substances" under the Canadian Environmental Protection Act, 1999 and,
therefore, require notification under the New Substances Notification Regulations. Prior to import or
manufacture in Canada, manufacturers and importers of such substances are required to supply to
the Minister of the Environment the information prescribed in these regulations that will allow this
Minister and the Minister of Health to perform a risk assessment to determine if the new substance
poses a risk to the health of Canadians and to their environment.“128 Import of and work with cloned
animals (this also applies to transgenic animals) thus require an approval either by the environmental
authority or the health authority: “Cloned or transgenic animals of any species from any country are
legislated under the Canadian Environmental Protection Act and any activity or request for import
involving these animals requires the prior approval of Environment Canada or Health Canada.” Food
products deriving from clones require in individual cases a safety examination or approval before
being placed on the market. Likewise potential feed products from cloned animals or their progeny
are classified as “Novel Feed”: “Therefore, notification and assessment is required before any derived
products from these animals are released in the feed chain.”129
In 2008 reference is made again to this interim policy established in 2003: “However, as there is
currently insufficient data to guide the pre-market safety assessment of these products, developers
who wish to use SCNT technology for producing livestock, are requested to withhold novel food
notifications until requirements are determined and guidance is available.”130
Apparently revision of this policy in terms of food safety and animal protection was begun in 2010 in
Canada.131 However, as of November 2011 it was not possible to find any references to any updating
of the legislative situation or status of the discussion either at the Canadian Food Inspection Agency,
the Canadian Environmental Assessment Agency or Health Canada. The interim policy on foods from
cloned animals with the risk assessment as novel foods is still in force.
127
http://www.hc-sc.gc.ca/fn-an/legislation/pol/pol-cloned animal clones animaux-eng.php (25.11.2011)
http://www.hc-sc.gc.ca/fn-an/gmf-agm/anim_clon_lett-eng.php (25.11.2011)
129
http://www.inspection.gc.ca/english/anima/feebet/bio/bfeebete.shtml (25.11.2011)
130
http://www.hc-sc.gc.ca/fn-an/gmf-agm/anim clon lett-eng.php (25.11.2011)
131
European Commision 2010, p. 8.
128
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








The cloned animal itself is not used for the production of food products; instead it is used to
spread certain features identified as being beneficial.
The main critical arguments around cloning of animals concern almost exclusively questions of
animal health and welfare. In its 2010 report even the European Commission sees the risks for
animal welfare as a sufficient reason to initiate a legislative proceeding by the Commission.132
Ethical concerns are occasionally expressed to the effect that the cloning of animals might turn
out to be a sort of “slippery slope” towards the cloning of humans.
Environmental protection issues are of clearly secondary significance in relation to cloned
animals.
Current information, which however is partly based on scanty data, indicates that there are only
few concerns regarding products from the progeny of healthy cloned animals as far as food
safety is concerned. However, somewhat reliable data is only available for cattle and pigs.
Thus, one important aspect will be to require and support independent safety research to carry
out risk assessment of the products of healthy progeny of cloned animals on a reliable scientific
basis.
It must also be ensured that cloned animals do not unintentionally end up in feed production or
in the human food chain.
It seems justified to assume that if the legal situation remains unchanged, products from the
progeny of cloned animals will continue to enter the European market, as particularly in the USA
intensive work is continuing on cloned animals (especially since the positive assessment by the
U.S. FDA).133
Besides Argentina also China is reported to have cloned a transgenic cattle that produces milk
very similar to human breast milk. The objective behind these efforts to enrich cow´s milk with
antibacterial proteins such as Lysozyme or Lactoferrin. This milk is intended to be processed into
milk powder that is then used as baby foods.
132
European Commission 2010, p. 7.
„It's important to remember, however, that at this time there are only a few hundred cattle clones, most of
which are not dairy cows, so again, it's highly unlikely that there will be much milk from dairy cow clones in the
food supply.” http://www.fda.gov/AnimalVeterinary/SafetyHealth/AnimalCloning/ucm055516.htm
(24.11.2011)
133
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4
SUMMARY
Transgenic animals are being developed for various reasons, e.g. to serve as model organism in basic
medical research, as faster growing farm animals, for being disease resistant, with altered
compositions for food products or within the production of pharmaceutically relevant proteins.
Cloning of animals is mainly used for spreading certain features identified as being beneficial in
breeding with the progeny of such animals (derived through sexual reproduction) being potentially
intended for food uses. The successful development of a genetically modified animal is a lengthy
process. Despite the already long-running and extensive research work done, transgenic animals
have up till now attained rather little readiness for the market.
Within the present expert opinion the most recent developments (pipeline, products, applications) in
this field have been investigated and evaluated in order to provide a rough overview over the status
quo with specific regard to the following topics:
 Transgenic animals as food resources (i.e. farm animals, fish).
 Transgenic animals used for the production of pharmaceutically interesting proteins.
 Genetically modified insects used for vector control concerning the transmission of human
diseases.
 Cloning of farm animals.
The relevant protection objectives are food safety and questions of environmental protection.
Products
Despite the already long-running and extensive research going on, transgenic animals have up till
now attained rather little readiness for the market. There are several reasons for this, primarily the
limited fundamental knowledge about the relevant biological/genetic processes and structures, the
causes of which are especially constituted in the considerably complex biological backgrounds.
The most advanced example of a genetically modified farm animal intended to be used as food /
product is the transgenic pig developed by the University of Guelph/Ontario. The so-called Enviropig
produce the enzyme phytase in the salivary glands which makes it capable of breaking down the
normally indigestible phytic acid to readily metabolised phosphate This distinctly reduces the content
of phosphor in the manure which normally causes adverse environmental impacts especially in
freshwater. Regulatory submissions have been made to both the Food and Drug Administration in
the United States and to the Canadian Regulatory Authorities in 2007 and 2009 respectively.
The Roslin Institute at the University of Edinburgh developed genetically modified chickens to
prohibit the transmission of avian influenza (bird flu), a common problem in poultry production and
subsequently to human health. For the time being, “these particular chickens are for research
purposes only and are not intended for consumption.“134 This purpose is yet not excluded for the
future.
As mentioned also below (“Prospect”), there are on-going activities especially in Latin America as
well as in some Asian countries that awaits further screening. Besides Argentina (June 2011, National
Institute of Agricultural Technology, Buenos Aires)135 also China (China Agricultural University,
Beijing)136 is reported to have cloned a transgenic cattle that produces milk (insertion of genes coding
for two human milk proteins) very similar to human breast milk.137 The objective behind these efforts
134
http://www.roslin.ed.ac.uk/news/2011/01/13/gm-chickens-that-don%27t-transmit-bird-flu-developed/
(8.12.2011)
135
136
137
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to enrich cow´s milk with antibacterial proteins such as Lysozyme or Lactoferrin. This milk is intended
to be processed into milk powder that is then used as baby foods.
The transgenic growth enhanced salmon developed by the Canadian company Aquabounty is the
best-known example of a genetically modified animal, which is intended for food purposes, currently
awaiting the US government´s decision on the approval. Many further examples of fish species and
potential traits are reported, e.g. the study commissioned by EFSA lists on 58 pages appr. 50 species
with over 400 fish/trait combinations. Most of these will not result in commercially available food
products.
A range of genetically modified insects has already been developed, mainly mosquitoes and crop
pests focusing on reduction of diseases such as Dengue fever or Malaria and reduction of crop losses.
Field releases with genetically modified pink bollworm and Aedes aegypti strains respectively have
taken place at least in the USA, Cayman Islands, Malaysia and Brazil. The next trial is presumably to
be expected for Florida/USA.
So far, two pharmaceuticals harvested from a transgenic animal are approved by the European
Medicines Agency: Anti-coagulant antithrombin III obtained from the milk of a transgenic goat in July
2006, which was also granted approval in the USA in February 2009 and recombinant human C1
esterase inhibitor from the milk of transgenic rabbits (28 October 2010).
Concerning cloned animals it seems justified to assume that if the legal situation remains unchanged,
products from the progeny of cloned animals will continue to enter the European market, as
particularly in the USA intensive work is continuing on cloned animals (especially since the positive
assessment by the U.S. FDA). Further investigations may clarify the status quo especially in South
America or some Asian countries.
Risk assessment
The focus and extent of risk assessment of genetically modified animals and/or their products and of
cloned animals respectively depends on the intended use as well as the extent of subsequent
processing. For example, genetically modified fish intended as food product requires different
scientific and regulatory treatment than a pharmaceutical protein derived from a transgenic animal,
a highly processed product, which is subject to comprehensive purifying provisions.
Food safety and thus human health is particularly important concerning foods from transgenic
livestock and fish as well as from progeny of cloned animals. Preliminary findings suggest that for
foods from healthy progeny of cloned animals there are only few concerns, with data being available
only for cattle and pig. So far, risk assessment in the USA of a transgenic salmon is the first one being
conducted for a product intended for food use.
A wide range of potential environmental impacts relate especially to highly mobile animals such as
fish and insects. Concerns raised are all the more important if transgenic insects that are vectors for
human diseases are released.
Generally, no releases are carried out with transgenic animals in gene pharming and with cloned
animals.
It may be observed here that everything that affects human health in the medical sense is almost
unreservedly accepted. This means that in the context of using transgenic animals for the production
of pharmaceuticals (apart from the questions of animal welfare), debate is always more or less
uncontroversial. The assessment of the potential risks of pharmaceuticals (side effects) from
transgenic animals to human health is the core challenge.
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European Food Safety Authority
The European regulatory framework for genetically modified organisms has initially been developed
with mainly genetically modified crops in mind. As various applications of genetic engineering such as
gene pharming through animals or the development of transgenic insects emerged it appeared that
the existing regulations could not provide satisfying guidance in this field, neither for an applicant nor
for the competent authorities. So far, no applications for an approval of a genetically modified animal
have been made in the European Union.
In February 2007 the European Commission has asked the European Food Safety Authority (EFSA) to
develop a comprehensive risk assessment guidance on the food, feed and environmental safety
assessment of genetically modified animals, taking also into account animal health and welfare.
Therefore, several related activities have been conducted: EFSA commissioned three different socalled scientific/technical studies related to the environmental risk assessment of various genetically
modified animals - i.e. for mammals and birds; insects; and fish respectively - which have been
delivered in 2010. In addition, specific working groups have been set up, dealing with various aspects
of food and environmental safety and human health issues with regard to genetically modified
animals.
These activities undertaken by EFSA will result in two different guidelines. First, a „Guidance on the
risk assessment of food and feed from genetically modified animals including animal health and
welfare“ has been developed by EFSA’s Panel on Genetically Modified Organisms (GMO) and the
Panel on Animal Health and Welfare which was open for public consultation until September 30th
2011. The final guidance is expected to be ready for adoption at the end of 2011.
The second guidance document will be developed by EFSA´s GMO Panel and should address issues
concerning the environmental risk assessment of genetically modified animals used for food and feed
purposes. It remains to be seen to what extent the outcomes and conclusions of the above
mentioned three scientific reports will be included into this guidance on environmental safety
assessment. It is expected to be released for a public consultation in spring 2012, being ready for
adoption presumably in summer 2012.
Prospect
going activities has to focus on South American and Asian countries, which are economically and
geopolitically of increasing importance. Quite some scientific research and development of
transgenic animals is going on e.g. in China, India, Argentina, Brazil, or Singapore.
In September 2011, the first international workshop on the food and environmental safety
assessment of genetically modified animals - organized inter alia by the Argentinian Ministry for
Agriculture, the International Centre for Genetic Engineering and Biotechnology and the United
Nation´s Programme for Biotechnology in Latin America and the Caribbean - took place in Buenos
Aires City.138 The focus of interest lay upon transgenic agricultural animals for food purposes as well
as cloned animals, including also questions of food and environmental safety.
A report of the FAO139 focusing on livestock biotechnologies in developing countries states that China
produced the first transgenic buffalo in 2004, India followed in 2009. A main topic especially in Asian
countries may be transgenic or cloned pets, e.g. the now famous ornamental fish „GloFish“ has
originally been developed by the National University of Singapore as a model system in research.
138
139
FAO March 2010.
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Sources in English language such as e.g. Bio Spectrum Asia Edition could also provide useful
overviews over current activities and issues. An article of October 2011 mentions a focus on medical
research as well as on drug development from transgenic animals.140
Further conclusions
Livestock
 So far, no genetically modified livestock intended as use for food has been commercialized
worldwide.
 The study “Defining environmental risk assessment criteria for genetically modified (GM)
mammals and birds to be placed on the EU market” commissioned by EFSA compiled a list some
15 species being genetically modified but these also include mice (which are almost exclusively
used as model animals in research), animals used for gene pharming or pets.
 To get the whole picture especially concerning future developments a thorough screening of on
going activities has to focus on economically and geopolitically emerging countries.
Fish
 It seems as if perhaps the long duration of the Aquabounty´s case concerning the transgenic
salmon has slowed down similar efforts of other companies. At the same time, once the
transgenic salmon is decided upon this definitely will have a signal effect in either ways.
 Most results of scientific studies only cover one specific aspect or analyse just one single set of
(environmental etc.) conditions. As many species-trait-ecosystem combinations und thus
interactions may exist further independent research has to broaden the databases on which risk
assessment has to be based upon. Thus a case-by-case approach with potential applications
should be followed.
 As transgenic fish are intended to be used as food and within food products an in-depth
assessment of their composition, their nutritional quality as well as of potential toxicity or
allergenicity is required.
Insects
 Experiences like that in Malaysia additionally underline the importance of having comprehensive
respective standards and requirements available.
 Therefore, the guidance document to be developed by EFSA´s GMO Panel defining criteria
concerning the environmental risk assessment (ERA) of genetically modified animals, including
insects, is very important as it will set the standard for environmental protection in Europe.
 Last not least, also in the context of genetically modified insects the necessity and importance of
independent risk research has to be stressed.
Gene Pharming
 It could be critically remarked that authorities and/or risk assessors are usually dependent on
the information and documentation provided by the company applying for the authorisation.
Hence, efforts to strengthen independent risk research could be useful.
 Several further pharmaceuticals that contain recombinant proteins are at various stages of preclinical and clinical research being developed by various pharmaceutical/chemical companies.
Product development takes place in transgenic cows, rabbits, goats and chicken.
140
Page 44 of 54

After having successfully received approval in the European Union as well as in the USA,
reinforced research efforts can be expected which definitely will lead to further development
and applications for pharmaceuticals from transgenic animals.
Cloning of animals
 As reliable data seems to be only available for cattle and pigs, one important aspect will be to
require and support independent safety research to carry out risk assessment of the products of
healthy progeny of cloned animals on a reliable scientific basis.
 It must also be ensured that cloned animals do not unintentionally end up in feed production or
in the human food chain.
 As already analysed in the study "Transgenic animals. Status-quo in relation to Risk assessment
and the state of research" in 2007, reproductive cloning of livestock that has already been
successfully genetically modified is seen as a prospective economically relevant approach.
 Besides Argentina also China is reported to have cloned a transgenic cattle that produces milk
(insertion of genes coding for two human milk proteins) very similar to human breast milk. The
objective behind these efforts to enrich cow´s milk with antibacterial proteins such as Lysozyme
or Lactoferrin. This milk is intended to be processed into milk powder that is then used as baby
foods.
Page 45 of 54
ZUSAMMENFASSUNG
Transgene Tiere werden mit den unterschiedlichsten Zielen entwickelt, beispielsweise als Modelltiere
in der Grundlagenforschung, als schneller wachsende landwirtschaftliche oder krankheitsresistente
Nutztiere, mit veränderter Zusammensetzung bezüglich Lebensmittelprodukten (z.B. veränderter
Fettsäureanteil im Schweinefleisch) oder zur Herstellung pharmazeutisch relevanter Proteine. Klonen
von Tieren findet insbesondere zur Verbreitung von in der landwirtschaftlichen Züchtung als wertvoll
angesehenen Merkmalen statt.141 Die Nachkommen von geklonten Tieren entstehen durch
herkömmliche sexuelle Reproduktion, erst diese Tiere würden in der Lebensmittelerzeugung
Verwendung finden.
Im Rahmen des vorliegenden Expertengutachtens wurden die aktuellsten Entwicklungen (Pipeline
bzw. konkrete Produkte) recherchiert und evaluiert, um einen Überblick über den Status-quo
bezüglich der folgenden Themen zu erarbeiten:
 Transgene Tiere zur Verwendung als Lebensmittel (Nutztiere, Fisch)
 Transgene Tiere zur Produktion von Pharmazeutika
 Gentechnisch veränderte Insekten zur Verminderung der Übertragung von Krankheiten (z.B.
Gelbfieber, Malaria)
 Geklonte Nutztiere
Die in diesem Zusammenhang relevanten Schutzziele sind menschliche Gesundheit,
Lebensmittelsicherheit und Umweltschutz.
Produkte
Die erfolgreiche Entwicklung eines transgenen oder eines geklonten Tieres ist ein zeitaufwendiger
Prozess. Trotz der bereits sehr lange erfolgenden Forschungs- und Entwicklungsarbeiten in diesem
Bereich sind gentechnisch veränderte Tiere noch kaum zur Marktreife gelangt. Dies hat mehrere
Gründe, beispielsweise das eingeschränkte Grundlagenwissen über die entsprechenden
biologischen/genetischen Prozesse und Strukturen, dessen Ursachen insbesondere in den im
Vergleich zu Pflanzen deutlich komplexeren biologischen Grundlagen liegen.
Zu den am weitesten fortgeschrittenen Entwicklungen bei Nutztieren zählt das gentechnisch
veränderte Schwein der Universität Guelph in Toronto, das sogenannte Enviropig. Schweinen fehlt
das Enzym Phytase, das Phosphorverbindungen abbaut, weswegen dem Futter üblicherweise dieses
Enzym oder mineralischer Phosphor beigemischt wird. Das transgene Schwein produziert Phytase in
seiner Speicheldrüse, was zu einer deutlichen Reduktion der Umweltbelastung durch Phosphat aus
der Gülle führt. Sowohl bei den zuständigen Behörden in den USA (2007) als auch in Kanada (2009)
wurden Dossiers in Vorbereitung eines eventuellen Antrags auf Zulassung als Lebensmittelprodukt
eingereicht.
Am Roslin Institut der Universität of Edinburgh entwickelte transgene Hühner, die Vogelgrippe nicht
mehr übertragen können. Eine spätere Verwendung im Lebensmittelbereich ist nicht ausgeschlossen.
Neben Argentinien (Juni 2011, National Institute of Agricultural Technology, Buenos Aires)142 hat
auch China (China Agricultural University, Beijing)143 transgene Rinder geklont, deren Milch eine
ähnliche Zusammensetzung wie Muttermilch aufweist und antibakteriell wirkende Proteine wie
141
Klonen von beispielsweise Haustieren oder wertvollen Sporttieren wird im Rahmen des vorliegenden
Expertengutachtens nicht diskutiert.
142
143
Page 46 of 54
Lysozym bzw. Laktoferrin enthält. Geplant ist in Folge eine Verarbeitung zu Milchpulver sowie die
Verwendung als Säuglingsnahrung.
Das bekannteste Beispiel im Bereich Fische ist der vom kanadischen Unternehmen Aquabounty
entwickelte schneller wachsende transgene Lachs, der als Lebensmittel/-produkt verwendet werden
soll. Derzeit wird eine finale Entscheidung bezüglich der Zulassung seitens der US Regierung
erwartet. Forschungsarbeit findet und zahlreichen weiteren Arten statt, jedoch scheint derzeit kein
weiteres Produkt in absehbarer Zeit Marktreife zu erlangen. Die weiteren Entwicklungen werden
auch von der Entscheidung über die Zulassung in den USA abhängen.
Im Bereich der Insekten wurden insbesondere Moskitos bzw. Pflanzenschädlinge gentechnisch
verändert. Die Ziele sind dabei eine Reduktion der krankheitsübertragenden Insekten, die
beispielsweise Gelbfieber oder Malaria verursachen bzw. eine Reduktion des Ernteverlustes.
Freisetzungen haben in den USA mit einer transgenen Baumwollkapselraupe (pink bollworm) sowie
mit transgenen Stechmücken (Aedes aegypti) auf den Kayman Inseln (britisches Überseeterritorium),
in Malaysia und in Brasilien stattgefunden. Weitere Freisetzungsversuche mit Aedes aegypti werden
in Florida/USA erwartet.
Bisher wurden seitens der Europäischen Arzneimittelagentur (EMA) zwei pharmazeutische Produkte
aus gentechnisch veränderten Tieren zugelassen: Antithrombin III aus der Milch einer transgenen
Ziege im Juli 2006, das in den USA im Februar 2009 ebenfalls eine Zulassung erhielt. Und ein humaner
C1 Esterase Inhibitor aus der Milch transgener Kaninchen (Oktober 2010).
Bezüglich geklonter Tiere scheint es gerechtfertigt anzunehmen, dass bei unveränderter
Gesetzeslage weiterhin Produkte aus den Nachkommen geklonter Tiere auf den europäischen Markt
gelangen werden, da insbesondere in den USA (vor allem seit dem positiven Gutachten der Behörde
zu Produkten aus geklonten Tieren) und in einigen südamerikanischen Ländern wie Argentinien und
Brasilien intensive Forschungs- und Entwicklungsarbeiten dazu erfolgen.
Risikoabschätzung
Die konkreten Fragestellungen sowie das erforderliche Ausmaß einer Risikoabschätzung von
gentechnisch veränderten oder geklonten Tieren bzw. von deren Produkten hängt vom
Verwendungszweck sowie von eventuell erfolgenden Verarbeitungsprozessen ab. Beispielsweise
erfordert ein gentechnisch veränderter Fisch, der als Lebensmittel verwendet werden soll, eine
gänzlich andere Risikoabschätzung als ein pharmazeutisches Produkt aus einem transgenen Tier, das
zahlreichen Aufbereitungs- und Reinigungsschritten unterworfen wird.
Die Risikoabschätzung bezüglich der Lebensmittelsicherheit und damit der möglichen Auswirkungen
auf die menschliche Gesundheit stehen bei transgenen Nutztieren und Fischen sowie bei Produkten
aus geklonten Tieren bzw. deren Nachkommen im Mittelpunkt. Die diesbezügliche
Risikoabschätzung, die derzeit in den USA in Zusammenhang mit einem transgenen Lachs stattfindet,
ist die erste, die sich auf ein mögliches Lebensmittelprodukt aus einem gentechnisch veränderten
Tier bezieht. Bei geklonten Tieren sind derzeit wissenschaftliche Daten zur Evaluierung nur bei Rind
und Schwein verfügbar.
Fragen des Umweltschutzes sind insbesondere bei sehr mobilen Tieren wie Fischen und Insekten
relevant, die zusätzlich eventuell in größeren Mengen freigesetzt werden. Hier ist eine Vielzahl an
möglichen Auswirkungen auf die Umwelt bzw. das jeweilige Ökosystem möglich. Mit transgenen
Tieren, die zur Erzeugung von pharmazeutisch relevanten Proteinen entwickelt werden, finden im
Allgemeinen keine Freisetzungen statt. Bei Labortieren, aber auch bei einzelnen landwirtschaftlichen
Nutztieren muss darüber hinaus die Möglichkeit des unbeabsichtigten Entkommens einzelner Tiere
in Betracht gezogen werden.
Page 47 of 54
Zu beobachten ist hier (wie auch in anderen technischen Feldern), dass alles, was die menschliche
Gesundheit im medizinischen Bereich betrifft, beinahe uneingeschränkt akzeptiert wird. Bezüglich
der Verwendung transgener Tiere zur Produktion von Pharmazeutika (abgesehen von den Fragen
zum Tierschutz) finden daher kaum kontroversielle Diskussionen statt. Die Abschätzung der
Wirksamkeit eines Arzneimittels sowie der möglichen Nebenwirkungen steht hier im Mittelpunkt des
gesetzlichen Regelwerks.
Europäische Behörde für Lebensmittelsicherheit (EFSA)
Bisher wurden in der Europäischen Union noch keine Anträge auf Zulassung eines gentechnisch
veränderten Tieres bzw. eines Produktes daraus gestellt. Um die existierenden Regelungen mit Bezug
auf die aktuellen Entwicklungen zu ergänzen, ersuchte die Europäische Kommission im Februar
2007die EFSA, Leitliniendokumente für die Risikobewertung von gentechnisch veränderten Tieren zu
erstellen, die folgende Bereiche abdecken: die Sicherheit von Lebens- und Futtermitteln aus diesen
Tieren sowie damit zusammenhängende Aspekte der Tiergesundheit und des Tierschutzes; die
Sicherheit der Freisetzung von transgenen Tieren, die zu Lebens- und Futtermittelzwecken gezüchtet
wurden, in die Umwelt. Parallel zu den Arbeiten in den entsprechenden Gremien der EFSA wurden
drei externe wissenschaftliche Studien in Auftrag gegeben, die Methoden und mögliche Endpunkte
einer Risikoabschätzung von gentechnisch veränderten Fischen, Insekten bzw. Säugetieren und
Vögeln im Umweltbereich definieren sollten.
Das Leitliniendokument „Guidance on the risk assessment of food and feed from genetically modified
animals including animal health and welfare“ wurde seitens des GMO Panels sowie des Panels on
Animal Health and Welfare der EFSA entwickelt und wurde bereits einer öffentlichen Konsultation
unterzogen (endete mit 30. September 2011). Die endgültige Version dieses Dokuments soll Ende
2011 zur Annahme gelangen.
Das zweite Guidance Document des GMO Panels wird die Risikoabschätzung im Umweltbereich von
gentechnisch veränderten Tieren für Futter- bzw. Lebensmittelzwecke behandeln. Es bleibt
abzuwarten, in welchem Ausmaß die Erkenntnisse der erwähnten wissenschaftlichen Reports
integriert werden. Der Entwurf soll im Frühjahr 2012 für eine öffentliche Konsultation zur Verfügung
stehen.
Ausblick
Um künftig einen umfassenden Überblick insbesondere bezüglich zu erwartender Entwicklungen zu
erlangen, wäre jedenfalls eine Analyse der in wirtschaftlich und geopolitisch zunehmend
bedeutenden südamerikanischen bzw. asiatischen Ländern erfolgenden Aktivitäten vorzunehmen.
Forschung und Entwicklung von transgenen Tieren, teilweise auch von geklonten Tieren, findet
mittlerweile verstärkt beispielsweise in Argentinien, China, Indien, Brasilien oder Singapur statt.
Im September 2011 fand in Buenos Aires /Argentinien der „First international Workshop on the food
and environmental safety assessment of genetically modified animals” statt, der unter anderem vom
argentinischen Ministerium für Landwirtschaft, dem International Centre for Genetic Engineering and
Biotechnology (ICGB) sowie dem United Nation´s Programme for Biotechnology in Latin America and
the Caribbean organisiert wurde.144 Im Mittelpunkt des Interesses standen transgene
landwirtschaftliche Nutztiere und geklonte Tiere sowie Fragen der Lebensmittel- und der
Umweltsicherheit.
144
Page 48 of 54
Ein entsprechender Report der FAO145 über Biotechnologie im Nutztierbereich in
Entwicklungsländern erwähnt beispielsweise, dass China im Jahr 2004 mit der Entwicklung eines
transgenen Büffels begonnen hat, Indien folgte im Jahr 2009. Ein in asiatischen Ländern populäres
Thema sind gentechnisch veränderte oder geklonte Zierfische bzw. Haustiere; der mittlerweile
bekannte sogenannte “GloFish” (Zierfisch) wurde ursprünglich von der Nationalen Universität
Singapur als Modelltier entwickelt. Quellenmaterial in englischer Sprache wie beispielsweise “Bio
Spectrum Asia Edition” kann ebenfalls einen Überblick über aktuelle Themen in diesen Ländern
bieten. In einem Artikel vom Oktober 2011 wird ein Fokus in der Verwendung transgener Tiere auf
Medizinforschung sowie zur Entwicklung von Pharmazeutika angeführt.146
Weitere Schlussfolgerungen
Nutztiere
 Bisher gibt es weltweit keine einzige Zulassung für ein gentechnisch verändertes Nutztier für
Lebensmittelzwecke.
 Um auch künftig einen vollständigen Überblick über aktuelle Entwicklungen bzw. zu erwartende
Produkte zu erlangen, ist zunehmend eine Analyse der entsprechenden Aktivitäten in
lateinamerikanischen bzw. asiatischen Ländern erforderlich.
 Neben Argentinien hat auch China transgene Rinder geklont, deren Milch eine ähnliche
Zusammensetzung wie Muttermilch aufweist und antibakteriell wirkende Proteine wie Lysozym
bzw. Laktoferrin enthält.
Fisch
 Die sehr lange Dauer des Genehmigungsverfahrens rund um den transgenen Lachs in den USA
scheint ähnliche Arbeiten bzw. Bemühungen anderer Unternehmen zumindest vorläufig
verlangsamt zu haben. Die finale Entscheidung in diesem Fall wird jedenfalls ein deutliches
Signal setzen und Auswirkungen auf vergleichbare Projekte haben.
 Die meisten wissenschaftlichen Studien fokussieren lediglich auf einen spezifischen Aspekt (eine
Umweltwirkung, ein Teil eines spezifischen Ökosystems etc.). Da jedoch zahlreiche
unterschiedliche sogenannte species-trait-ecosystem Kombinationen sowie daher eine Vielzahl
an Wechselwirkungen möglich sind, ist eine breitere Datenbasis zur Durchführung haltbarer
Risikoabschätzungen erforderlich.
 Da transgene Fische als Lebensmittel/-produkt verwendet werden sollen, ist im Rahmen einer
Risikoabschätzung eine umfassende Analyse beispielsweise der Zusammensetzung, der
Nährstoffe, einer möglichen Toxizität bzw. Allergenität erforderlich.
Insekten
 Erfahrungen wie jene mit dem Genehmigungsverfahren zur Freisetzung gentechnisch
veränderter Moskitos (Stamm Aedes aegypti) zeigen die Notwendigkeit von umfassenden
wissenschaftlichen und gesetzlichen Anforderungen im Vorfeld.
 Daher sind insbesondere die diesbezüglichen Aktivitäten der Europäischen Behörde für
Lebensmittelsicherheit (EFSA) zur Entwicklung eines einschlägigen Guidance Dokuments
bezüglich Risikoabschätzung in Umweltfragen von besonderer Bedeutung, da dieses eine
notwendige Ergänzung der bestehenden, teilweise zu wenig spezifischen Gesetzgebung
darstellt.
 Unabhängige Risikoforschung mit Bezug auf die Vielzahl an möglichen Umweltwirkungen scheint
unablässig.
145
146
FAO März 2010.
Page 49 of 54
Gene Pharming
 In diesem Zusammenhang ist kritisch anzumerken, dass Behörden im Bereich der
Risikoabschätzung oftmals von den seitens der entwickelnden Unternehmen zur Verfügung
gestellten wissenschaftlichen Daten und Informationen abhängig sind. Unabhängige
Risikoforschung könnte auch in diesem Bereich eine notwendige Unterstützung bzw. Ergänzung
der vorhandenen Datenbasis sein.
 Etliche weitere Pharmazeutika, die rekombinante Proteine beinhalten, sind in verschiedenen
Stadien der prä-klinischen und klinischen Studien. Eingesetzt werden dabei transgene Rinder,
Kaninchen, Ziegen bzw. Hühner.
 Nach den erfolgreichen Zulassungen für zwei pharmazeutische Produkte aus transgenen Tieren
(siehe oben, Produkte) kann mit weiteren, verstärkten Aktivitäten zur Entwicklung und
Kommerzialisierung derartiger Produkte gerechnet werden.
Geklonte Nutztiere
 Ausreichende haltbare wissenschaftliche Daten zur Lebensmittelsicherheit scheinen lediglich
bezüglich Rind bzw. Schwein verfügbar zu sein. Die Forderung nach bzw. die Unterstützung einer
unabhängigen Sicherheitsforschung zur wissenschaftlichen Risikoabschätzung eventueller
Produkte von gesunden Nachkommen geklonter Tiere ist ein wesentlicher Aspekt.
 Es wäre zu gewährleisten, dass geklonte Tiere bzw. Teile davon nicht unbeabsichtigt in die
Futtermittelerzeugung bzw. in die menschliche Nahrungskette gelangen.
 Neben Argentinien hat auch China transgene Rinder geklont, deren Milch eine ähnliche
Zusammensetzung wie Muttermilch aufweist und antibakteriell wirkende Proteine wie Lysozym
bzw. Laktoferrin enthält. Geplant ist in Folge eine Verarbeitung zu Milchpulver sowie die
Verwendung als Säuglingsnahrung.
Page 50 of 54
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Page 54 of 54
www.bmg.gv.at
Das Ziel des Expertengutachtens ist die Recherche und Analyse
von neuesten Entwicklungen bei transgenen Tieren seit 2007
inklusive einer Risikoabschätzung und Status-quo bezüglich
geklonter Tiere.
Die Inhalte umfassen transgene Nutztiere inklusive Fische sowie
deren Anwendung im Lebensmittel-Futtermittel-Bereich einschließlich gentechnisch veränderten Insekten zur Kontrolle der
Ausbreitung von menschlichen Krankheiten wie Malaria und der
Bereich Gene Pharming; weiters wurde das Klonen von landwirtschaftlichen Nutztieren analysiert.
The objective of the expert opinion is investigation and analysis
of recent developments regarding transgenic animals since 2007
including risk assessment and status-quo in respect of cloned
animals.
The contents cover transgenic farm animals including fish as
well as its application in food-feed-sector including genetically
modified insects used for vector control concerning the transmission of human diseases such as Malaria and the section of
Gene Pharming; furthermore cloning of farm animals was analyzed.

Überschrift 1 - Bundesministerium für Gesundheit und Frauen

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