ENVIRONMENTAL RISK MANAGEMENT
AUTHORITY DECISION
Amended under s67A on 22 August 2007
10 November 2003
Application code
GMD03096
Application type
To develop in containment genetically modified organisms under
section 40(1)(b) of the Hazardous Substances and New Organisms
(HSNO) Act 1996.
Applicants
University of Auckland
Purpose
To develop in containment for use in biomedical research
recombinant adeno-associated viral vectors and genetically
modified rodents and mammalian cell lines expressing transgenes
that have roles or potential roles in regulating mammalian cell
growth.
Date received
9 September 2003
Consideration period 28 October 2003
Considered by
1
A Committee of the Genetically Modified Organisms Standing
Committee of the Environmental Risk Management Authority (the
Committee).
Summary of Decision
Application GMD03096 to develop in containment for use in biomedical research
recombinant adeno-associated viral vectors and genetically modified rodents and
mammalian cell lines expressing transgenes that have roles or potential roles in
regulating mammalian cell growth, an update of previous approval GMD01085, is
approved with controls, having been considered in accordance with the relevant
provisions of the Hazardous Substances and New Organisms (HSNO) Act 1996 and the
HSNO (Methodology) Order 1998.
Table 1: Organism description on ERMA New Zealand Register:
Host Organism
modified by the
vector and Donor
DNA on the right
Vector and Donor DNA
a. Homo sapiens
cell lines (C6,
human NTERA2, human A549,
human HEK293,
primary neuronal
Modified by chimeric, pseudotyped or serotype-specific rAAV
vectors with genetic material1 involved in cell survival, cell
proliferation, cell differentiation/maturation and plasticity including
those from the:
1. fibroblast growth factor family isolated from rat, mouse,
human;
1
sense cDNAs, sense constructs containing nucleotide substitution or deletions (to determine
functional domains), antisense and RNA interference sequences.
Host Organism
modified by the
vector and Donor
DNA on the right
Vector and Donor DNA
cultures and
other
immortalised cell
lines isolated
from humans)
(GMD03096)
b. Mus musculus
cell lines (murine
C17.2, murine
neuro2A, murine
P19, primary
neuronal cultures
and other
immortalised cell
lines isolated
from mouse)
(GMD03096)
2. sonic hedgehog and related family members isolated from rat,
human, mouse ;
3. members of the neurotrophin gene family isolated from
human, rat and mouse ;
4. cytokines and interleukins from rat, mouse, human;
5. Akt and other genes involved in the Akt signal transduction
pathway from rat, mouse, human;
6. anti-apoptotic genes isolated from human, rat and mouse
libraries;
7. transcription factor genes isolated from human, rat and mouse
libraries;
8. developmental genes isolated from rat, mouse and human
cDNA libraries;
9. growth factor genes isolated from rat, mouse and human
cDNA libraries;
10. genes encoding RNA binding proteins isolated from rat,
mouse and human cDNA or genomic libraries;
11. angiogenic and angiostatic genes isolated from rat, human,
mouse cDNA and genomic libraries;
12. genes encoding cell adhesion molecules and matrix proteins
isolated from rat, human and mouse cDNA and genomic
libraries;
13. genes encoding neurotransmitters and neuropeptides plus
related receptors isolated from mouse, rat and human cDNA
and genomic libraries;
14. other genes involved in regulating the proliferation,
differentiation and survival of the cells of the central nervous
system not fitting into categories as described above that may
have cDNA sequences to protein tags such as green
fluorescent protein (GFP), haemagglutin (HA), histidine
(His), FLAG, c-myc, glutathione S-transferase (GST), maltose
c. Rattus
norvegicus cell
lines ( rat PC12,
rat C6, primary
neuronal cultures
and other
immortalised cell
lines isolated
from rat)
(GMD03096)
Mus musculus
(Linnaeus 1758)
(GMD03096)
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Host Organism
modified by the
vector and Donor
DNA on the right
Vector and Donor DNA
Rattus norvegicus
(Berkenhout, 1796)
(GMD03096)
binding protein (MBP), calmodulin binding peptide (CBP)
fused to them to determine transgene localisation and/or
expression under the control of mammalian and viral DNA
elements involved in regulation of transcription and
translation such as those previously approved in a previous
application (GMD1085) and additional promoters and
regulatory elements including;
Promoters
15. CMV enhancer chicken B-actin;
16. human Glial Fibrillary Acidic [protein];
17. human elongation factor-1 (EF1);
18. human enkephalin;
19. rat neuron specific enolase (NSE);
20. rat neuron specific enolase 300 bp fragment (NSE300);
21. rat and chicken nicotinic-acetylcholine receptor (NachR);
22. rat insulin promoter (RIP);
23. rat, mouse and human T tubulin promoter;
24. rat, mouse and human myelin basic promoter;
25. rat, mouse and human GusB promoter;
26. rat, mouse and human U6 and H1 promoter;
Regulatory elements
27. cyclic AMP response element (CRE);
28. Woodchuck post-transcriptional regulatory element (WPRE);
29. Internal ribosome entry site (IRES);
30. Insulators;
31. SV40 late polyA;
32. Bovine growth hormone polyA;
33. Poly C domain;
34. Tetracycline, ecdysone and rapamycin regulatory elements;
35. CRE recombinase/ loxP system;
36. rat, mouse and human Nestin enhancer element;
37. human scaffold attachment region element;
38. rat hypoxic response element; and
39. other commercially available promoter or regulatory
elements.
This application is required to be considered by the Authority as it includes
developments that are considered “not low-risk” genetic modifications (clause 1(e) of
the Schedule of the HSNO (Low-Risk Genetic Modification) Regulations 2003)
involving “viral vectors whose host range includes human cells and that contain one or
more inserted nucleic acid sequence(s) coding for a product that can lead to
uncontrolled mammalian cellular proliferation or be toxic to mammalian cells, or both”.
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2
Legislative Criteria for Application
The application was lodged pursuant to section 40(1)(b) of the HSNO Act 1996. The
decision was determined in accordance with section 45, and matters relevant to the
purpose of the HSNO Act 1996, as specified under Part II of the HSNO Act 1996.
Unless otherwise stated, references to section numbers in this decision refer to sections
of the HSNO Act 1996.
Consideration of the application followed the relevant provisions of the HSNO
(Methodology) Order 1998 (the Methodology), with particular regard to clauses 12
(dealing with assessment of risks) and 13 (dealing with assessment of costs and
benefits). Unless otherwise stated, references to clause numbers in this decision refer to
clauses of the Methodology.
3
Application Process
3.1
Application Receipt
Application GMD03096 was formally received and verified on 9th September 2003 as
having adequate information for processing.
This application is essentially an update of GMD01085. The purpose of this application
is to add new adeno-associated viral (AAV) vectors including serotypes, pseudo-typed
and chimeric rAAV vectors, transgene inserts, promoters and regulatory elements to
enable better delivery and expression of genes to the central nervous system. The
proposed modifications to GMD01085 did not significantly alter the scope of the
original approval as they will potentially narrow the host range of the AAV vectors
originally approved and add transgenes that have a similar spectrum of functions to
those originally approved.
In accordance with section 58(c) of the HSNO Act 1996 and clause 5 of the
Methodology the Department of Conservation (DoC) and Ministry of Agriculture and
Forestry (MAF) were invited to comment on this application. The comments were
incorporated into the Evaluation and Review (E&R) report (pages 5-6).
3.2
Information Available for Consideration
The information available for the consideration was as follows:

The application prepared by the applicant.

ERMA New Zealand prepared an Evaluation and Review (E&R) report to assist
and support the Committee’s decision-making. The E&R report consolidated
and evaluated the relevant information in a format and sequence consistent with
the decision making requirements of the HSNO Act and Methodology.
Recognised techniques were used in identifying, assessing, and evaluating the
relevant information, as required under clause 24 of the Methodology. These
techniques are based on internal procedures as specified in the ERMA New
Zealand Technical Guides. The documents available for the preparation of the
E&R report were the application (including the containment manual) and
published references as cited in the application and comments provided by those
agencies notified of the application.
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3.3
Notification
It was considered there was unlikely to be significant public interest in this application.
Therefore, the application was not publicly notified, in accordance with ERMA New
Zealand policy.
3.4
Decision Making Committee
The application was considered by the Genetically Modified Organism Standing
Committee of the Authority, appointed in accordance with section 19(2)(b) of the
HSNO Act 1996. That Committee comprised the following members: Professor Colin
Mantell (Chair), Dr Max Suckling and Dr Marie Dziadek.
4
Consideration
4.1
Purpose of the Application
The University of Auckland seeks to update their original application GMD01085,
notified by ERMA New Zealand on the 25 July 2001. The purpose of this application is
to add new adeno-associated viral (AAV) vectors including serotypes, pseudo-typed and
chimeric rAAV vectors. In addition, new transgene inserts, promoters and regulatory
elements are included to enable better delivery and expression of genes to the central
nervous system. This continues the development of recombinant adeno-associated viral
(rAAV) vectors for in vitro use in rat, mouse and human cell lines, and in vivo use in rat
and mice in order to study neurological diseases, and the undertaking of functional
genomic studies.
In accordance with section 45(1)(a)(i) of the HSNO Act 1996, the Committee
determined that the purpose was appropriate under 39(1)(a) of the HSNO Act 1996: The
development of any genetically modified organism.
4.2
The Sequence of Steps in the Consideration
In accordance with clause 24 of the Methodology, the approach to the consideration
adopted by the Committee was to first examine the scope of the application, and the
range of organisms applied for, then to look sequentially at identification, assessment
and evaluation of risks, costs and benefits. Qualitative scales used by the Committee to
measure likelihood and magnitude of risks, costs and benefits are provided in Appendix
2 of this decision.
In assessing risks and costs, issues affecting the adequacy of the containment regime
and potential for population establishment and population eradication were considered
(as required by section 37 and 44 of the HSNO Act and clause 10(e) of the
Methodology). The containment regime was considered in the context of a risk
management regime for controlling the identified risks and costs (clauses 12(d) and 24).
In doing so, the Committee set controls to satisfactorily provide for the matters in the
Third Schedule (Part I) of the HSNO Act. It was then considered whether or not there
were any residual risks that required further consideration.
Benefits associated with this application were considered in accordance with
Methodology clauses 9, 10, 13 and 14 and section 6(e) of the HSNO Act.
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4.3
Scope of Application and Organism description
The scope of the organisms subject to the approval is limited to that described in Table
1 above.
The Committee noted that the organism description proposed the addition of “other
genes” involved in regulating the proliferation, differentiation and survival of the cells
of the central nervous system not fitting into categories as described above and “other
commercially available promoter or regulatory elements”. The Committee concurred
with the project team that the wide range of gene families from which the transgenes
may be sourced is appropriate to the purpose of this application. The Committee noted
that though multiple gene families are specified as sources of donor DNA, their putative
functions are very similar and therefore, their risk profiles will be very similar.
5
Identification of risks, costs and benefits
The Committee identified risks and costs related to the application in accordance with
clauses 9 and 10 of the Methodology, which incorporate sections 5, 6, 8 and 43 of the
HSNO Act.
The Committee considered Section 3 of the E&R report when carrying out the
identification of potential adverse and beneficial effects (risks, costs and benefits).
Adverse effects and beneficial effects were identified in relation to potential impacts on
the:





Environment;
Māori culture;
Economy;
Human health and safety;
Society and the Community.
The Committee concurred with the E & R report for the identification of the risks, costs
and benefits as follows:
5.1
Potential adverse effects to the environment
The Committee records that risks to the environment were considered, in accordance
with clauses 9(a)-9(c) and 10 of the Methodology. The Committee accepts the
conclusions reached in the application and E&R Report that the development and use of
the animals, cell lines and viruses in containment is very unlikely to pose significant
risks related to these areas of effect. Therefore no further consideration of these aspects
was warranted.
5.2
Potential adverse effects to Māori culture
The Committee considered the potential adverse Māori cultural effects and noted
sections 3.4 and 6.5 of the E & R report. The Committee considered the potential
cultural effects in accordance with clauses 9(b) and 9(c)(iv) of the Methodology and
sections 5(b), 6(d) and 8 of the HSNO Act. The Committee noted that the applicant had
undertaken consultation with the Hauraki Trust Board, including Ngati Whatua, which
had been inadvertently overlooked in the E & R report. The Committee concurred with
the E & R report (section 6.5.3) and considered that the nature and level of the
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consultation process was adequate. The Committee also acknowledged the advice given
to the applicant by Dr Mere Roberts, representative of Ngā Kaihautū Tikanga Taiao
(NKTT).
The Committee noted that the applicant have assured iwi in acknowledging the
concerns about the whakapapa and mixing genes, they will aim to keep the mixing of
genes to a minimum out of respect of tikanga Māori.
5.3
Potential adverse effects to the economy
The Committee records that adverse effects to the economy were considered, in
accordance with clauses 9(a)-9(c) and 10 of the Methodology. The Committee accepts
the conclusions reached in the application and no further consideration of these aspects
was given.
5.4
Potential adverse effects to human health and safety.
The Committee identified that adverse health effects on human health and safety due to
occupational exposure was a potentially significant adverse effect in accordance with
clauses 9 and 10 of the Methodology and is further discussed in section 7.1 of this
decision document.
6
Containment
In assessing risks and costs, the Committee considered issues affecting the adequacy of
the containment regime (in accordance with section 45(1)(a) of the HSNO Act); the
potential for population establishment and population eradication (sections 37 and 44 of
the HSNO Act and clauses 10(e) and 10(f) of the Methodology); and other matters in
order to give effect to the purpose of the HSNO Act (section 45(2)(b)). Risk
management techniques were used in relation to the identified risks and costs (clauses
12(d) and 24 of the Methodology). As such, the assessment of risks and costs (refer to
section 7 of this decision) was taken into account in setting the containment
requirements that are discussed in this section.
6.1
Ability to Escape from Containment
The controls imposed by this approval (as specified in Appendix 1) address the matters
detailed in the Third Schedule Part I of the HSNO Act: Matters to be addressed by
containment controls for importing, developing or field testing of genetically modified
organisms under the Act, plus other controls to give effect to the purpose of the Act.
These controls incorporate requirements for the management of risks and costs (under
clauses 12(d) and 24 of the Methodology) posed by the genetically modified rodents,
viral vectors and cell lines subject to this approval. The controls have been imposed to
ensure that exposure of laboratory workers and other persons, and the outside
environment, to risks and costs posed by the organisms is negligible.
6.2
Ability of Organism to establish a self-sustaining population and the
ease of eradication
In accordance with section 44 and 37 of the HSNO Act the Committee considered the
ability of the organism to establish undesirable self-sustaining populations, should it
escape from containment, and the ease with which such populations could be eradicated.
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The Committee considers that with the containment controls it has imposed (refer to
Appendix 1 of this decision); it is very unlikely for cell lines, rodents or the rAAV
vector to escape or be removed inadvertently from containment and establish selfsustaining populations.
7
Assessment of Risks and Costs and Benefits
In section 5 above, the Committee identified a significant potentially adverse effect. The
infection of laboratory workers with rAAV vectors via accidental injection to have an
adverse effect on human health and safety.
7.1
Assessment of risks - Infection of laboratory workers
Adverse health effects on human health and safety due to occupational exposure was
identified as potentially significant adverse effect and the Committee considered it in
accordance with clauses 12, 13 and 14 of the Methodology. The degree of uncertainty
attached to evidence is taken into account, as required under clauses 25(1), 29, 30, 32
and 33 of the Methodology.
The Committee considered the probability and the magnitude of an adverse effect
occurring in the event that a researcher did inadvertently inject themselves with a rAAV
vector.
The Committee concurred with conclusion reached in the E & R report (section 6.6.25)
that the accidental infection of laboratory workers with rAAV is highly improbable (in
accordance with clauses 12 and 13) due to the experience of the applicant in handling
vector material and the characteristics of the vector material itself (relatively instable at
room temperate and small quantities are available at any one time compared to the large
amount that would be needed to infect cells in humans and cause any discernible effect).
The Committee also noted that the rAAV vectors are totally replication incompetent.
In the event that a person did become infected with rAAV it is likely to be localised to
the exposed cells within the affected individual and have no discernible effect. It is
highly improbable that rAAV vector will spread to other cells within the individual or
from the individual to other people.
The Committee also noted, in accordance with clause 33, that an element of the risk
posed by the injection of rAAV vector is voluntary (as outlined in section 6.6.20 of the
E & R report), in the sense that people choose to undertake this type of research, either
as a scientist or a technician. In accordance with clause 33(c), the Committee that the
risk is not subject to uncontrollable spread as the rAAV viral vector would infect
somatic cells only once and therefore, infection would be limited to the tissues exposed
within the worker and not transmittable to other people. It is noted that the potential
adverse effects are irreversible (i.e. once infected it is not reversible), do not expose the
general public and are well understood by the researchers whom work with the rAAV
vectors.
The Committee noted the degree of scientific uncertainty (clauses 25(1), 29, 30,32 and
33) relating to the adverse effects adverse effect in the event of a researcher
inadvertently injecting themselves with rAAV vector, as this has not been tested. The
Committee concurred with the E & R report it was improbable to have any discernable
effect because of the large quantities of rAAV vector that would have to be injected
Uncertainty also arises as it would depend on what transgene was being inserted, the
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site of insertion and as discussed in section 6.6.16, and the complete host range of
rAAV virus has not been elucidated.
The Committee noted that additional controls had already been proposed in GMD01085
to mitigate the probability of occurrence of accidental injection. Additional control 8.1
ensures that a biological safety cabinet of class II should be used for all experiments
where the handling of adeno-associated viruses may result in the production of aerosols,
in order to reduce the possibility that a researcher could inadvertently infect themselves.
Additional control 8.2 ensures that recombinant AAV vector stocks shall be clearly
identified and kept in kept in secured storage when not in use. Access to the stocks shall
be restricted to authorized researchers. Finally, as specified by additional control 8.3, to
minimise the risk of accidental colonisation of workers with infected cell lines,
laboratory workers should not infect cultures of their own cells, nor, as a general rule,
those of their immediate family or other members of the laboratory.
The Committee noted that controls imposed in this decision were the same as those
imposed in GMD01085 and noted no recorded instances of a researcher being
accidentally or deliberately injected with rAAV vector over the course of the research
for GMD01085. The Committee therefore, felt assured that no additional measures were
necessary above those proposed for GMD01085.
In summary, the Committee agreed that the development of adeno-associated virus
vectors, as described in this application, poses a low risk to the researchers, and the
containment regime and the applicant’s experience in working with these viral vectors
means that it is highly improbable that those working with the vectors will become
infected if handling and containment procedures are followed (Clause 12(c)). While
there is some uncertainty about the nature of the effects of any particular infection
incident (because of the range of genes potentially involved), the experimental and
laboratory procedures to be used are well established and the Committee is confident
that the risks can be adequately managed (Clause 12(e)).
7.2
Assessment of Benefits
The Committee agreed with the E&R report and identified the following benefits
associated with the application, in accordance with the Methodology clauses 9, 10, 13,
and 14 and section 6(e) of the HSNO Act:
The Committee concurred with section 6.3.3 of the E & R report and noted that
potentially the research could have monetary benefits if it produced rAAV vectors that
led to the development of new and novel therapy strategies and the applicant were able
to commercialise the technology. The magnitude of the expected monetary benefit is
difficult to gauge, but could potentially be large if the research was successful (i.e.
proceeded to clinical trials and the market). However, there is a large degree of
uncertainty surrounding and expected monetary benefits, as it depends on how
successful the research is and a number of other factors. It was also difficult to gauge
the distributional effects of the benefits over time as there are too many uncertainties.
The Committee concurred with section 6.3.4 of the E & R report and considered that
potentially the research could have significant non-monetary benefits for human health
if the applicant were able to develop new and novel gene therapy strategies for
treatment of neurological diseases. The diseases the researchers are attempting to
develop gene therapy strategies for (i.e. Parkinson’s Disease, epilepsy, stroke,
Environmental Risk Management Authority Decision: Application GMD03096
Page 9 of 17
Alzheimer’s Disease, Huntington’s Disease) are serious diseases and any scientific
breakthrough that contributed to some type of therapy to alleviate these conditions
would be of massive benefit to the community. However, there is a large degree of
uncertainty surrounding expected non-monetary benefits, as it depends on how
successful the research is and on a number of other factors.
The Committee concurred with section 6.3.6 of the E & R report and considered that
benefits to scientific knowledge are very likely to eventuate based on the applicant track
record in attracting funding for this work from the New Zealand Health Research
Council, Marsden Fund, NZ Neurological Foundation and the New Economy Research
Fund; and their publication record in top-tier scientific journals such as Science and
Nature Medicine.
8
Other matters
The Committee considered that no other matters were relevant in setting controls
outside the Third Schedule, in order to give effect to the purpose of the HSNO Act (in
accordance with section 45(2)(b)).
9
International and Related Matters
The Committee considered international obligations relevant to this approval in
accordance with clause 9(c)(vi) of Methodology and section 6(f) of the HSNO Act.
10 Overall Evaluation and weighing up of Adverse and
Benefits and the overall adequacy of containment
In reaching its decision on this application, the Committee records that the following
criteria in the HSNO Act and Methodology have been particularly relied on (in
accordance with clauses 21 and 36(2)(b) of the Methodology):
The application has been considered in the context of the purpose and principles of the
HSNO Act (sections 4-8 inclusive).
Pursuant to section 45(1)(a)(i) of the HSNO Act, the Committee is satisfied that the
purpose of the application falls under section 39(1)(h): Such other purposes as the
Authority thinks fit, that purpose being import of a GMO into containment for the
purpose of scientific research.
In accordance with section 45 of the HSNO Act, and clauses 9, 10 and 12 of the
Methodology, the Committee concluded that each of the risks and costs was negligible.
Thus, the Committee considered the application under clause 26 of the Methodology.
As indicated in the foregoing text, a number of potentially significant risks are
considered to be negligible, after taking account of the organism description and the
impact of containment and other controls set out in Appendix 1.
As assessed in section 7.2 of the decision the benefits are largely scientific. While these
benefits are very likely to exist, their magnitude may range from minimal to moderate
depending on the success of the research and the scientific value of the research results.
The Committee then considered whether, given the organism description and the
containment and controls proposed, the benefits outweigh the non-negligible risks and
costs. The Committee’s view is that the benefits do outweigh the costs and risks.
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The Committee is satisfied that the cell lines and rodents transduced with rAAV vectors
can be adequately contained (sections 45(1)(a)(iii) and 44(b) of the HSNO Act), by the
controls required in this decision (refer to Appendix 1).
In accordance with clause 36(2)(b) of the Methodology, the Committee records that in
reaching this conclusion, it has applied the balancing tests in section 45 of the Act.
11 Decision
The application to develop in containment genetically modified cell lines and rodents
(as described in Table 1 of this decision) is approved in accordance with section
45(1)(a) of the HSNO Act. As required under section 45(2) the approval is subject to
controls (as listed in Appendix 1 of this decision).
Professor Colin Mantell
Date 10-11-03
Chair, GMO New Organisms Standing Committee of the Authority
Approval codes: GMD002815-9
Amendment: November 2006
Changes to controls:
 Addition of footnotes to the containment facility references and the
Australian/New Zealand containment facility references to “future proof” the
decision
 Standardise the wording of the breach of containment control
 Removal of the control regarding inspection of facilities by the Authority, its
agent or enforcement officers
____________________________
Dr Kieran Elborough
Chair, GMO Standing Committee
Date: 22 August 2007
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Appendix 1: Controls required by this approval
In order to satisfactorily address the matters detailed in the Third Schedule Part I:
Containment controls for importing, developing or field testing of genetically modified
organisms2 of the HSNO Act, and other matters in order to give effect to the purpose of
the HSNO Act (section 45(2)), the Authority’s approval of this application is subject to
the following controls:
1 To limit the likelihood of any accidental release of any organism or any
viable genetic material3:
1.1
The person responsible for a particular research area and/or the person
responsible for the operation of the containment facilities (‘the facility’) shall
inform all personnel involved in the handling of the organisms of the
Authority’s controls.
1.2
The microorganism containment facilities shall be approved by Ministry of
Agriculture and Forestry (MAF), in accordance with the MAF Biosecurity
Authority/ERMA New Zealand Standard 154.03.024: Containment Facilities
for Microorganisms at PC2 and the controls of the Authority.
1.3
The operation and management of the vertebrate containment facilities shall be
in accordance with the:
(a)
Ministry of Agriculture and Forestry (MAF) Regulatory
Authority/ERMA New Zealand Standard 154.03.034: Containment
Facilities for Vertebrate Laboratory Animals
(b)
Australian New Zealand Standard AS/NZS 2243.3:19954 Safety in
Laboratories: Part 3: (Microbiology), at Animal House Physical
Containment Level 2 (PC2)
1.4
All pipettes, glassware, plasticware and other used equipment shall be
decontaminated by submersion in a suitable disinfectant or by placing in
polyethylene bags that should subsequently be sealed and autoclaved or
incineration. Sharps (e.g. needles and scalpel blades) shall be disposed of in
puncture-resistant containers (refer AS 40315) and incinerated.
1.5
The maximum number of genetically modified rats and mice in the
containment facilities shall not exceed the capacity of the facilities, and/or any
requirements of the relevant Animal Ethics Committee.
2
Bold headings refer to Matters to be Addressed by Containment Controls for Development and
Field Testing of Genetically Modified Organisms, specified in the Third Schedule of the HSNO
Act 1996.
3
Viable genetic material is biological material that can be resuscitated to grow into tissues or
organisms. It can be defined to mean biological material capable of growth even though
resuscitation procedures may be required, e.g. when organisms or parts thereof are sub lethally
damaged by being frozen, dried, heated or affected by chemical.
4
Any reference to this standard in these controls refers to any subsequent version approved or
endorsed by ERMA New Zealand
5
AS 4031 Non-reusable containers for the collection of sharp medical items in health care
areas
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2 To exclude unauthorised people from the facility:
2.1
The identification of entrances, numbers of and access to entrances, and
security requirements for the entrances and the facility shall be in compliance
with the standards listed in control 1.2 and 1.3.
3 To exclude other organisms from the facility and to control undesirable
and unwanted organisms within the facility:
3.1
The exclusion of other organisms from the facility and the control of
undesirable and unwanted organisms within the facility shall be in compliance
with the standards listed in control 1.2 and 1.3.
4 To prevent unintended release of the organism by experimenters
working with the organism:
4.1
The prevention of unintended release of the organisms by experimenters
working with the organisms shall be in compliance with the standards listed in
control 1.2 and 1.3.
5 To control the effects of any accidental release or escape of an
organism:
5.1
Control of the effects of any accidental release or escape of the organisms shall
be in compliance with the standards listed in control 1.2 and 1.3.
5.2
In the event of any breach of containment the contingency plan for the
attempted retrieval or destruction of any viable material of the organisms that
have escaped shall be implemented immediately. The contingency plan shall be
included in the containment manual in accordance with the Standards
(154.03.024 and 154.03.034).
5.3
If a breach of containment occurs, the facility operator must ensure that the
MAF Inspector responsible for supervision of the facility has received
notification of the breach within 24 hours.
5.4
The applicant shall comply with the requirements of the standards listed in
controls 1.2 and 1.3 relating to the maintenance of records demonstrating
compliance with the Standard (054.03.024 and 154.03.034), as required by the
quality assurance programme, and documented in the containment manual.
6 Inspection and monitoring requirements for containment facilities:
6.1
The inspection and monitoring requirements for containment facilities shall be
in compliance with the standards listed in control 1.2 and 1.3.
6.2
The containment manuals shall be updated, as necessary, to address the
implementation of the controls imposed by this approval, in accordance with
the MAF/ERMA New Zealand Standards 154.03.024 and 154.03.034.
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7 Qualifications required of the persons responsible for implementing
those controls:
7.1
The training of personnel working in the facility shall be in compliance with
the standards listed in control 1.2 and 1.3.
7.2
The facility operator shall ensure that only suitably trained individuals will
handle human-infectious rAAV vectors covered under this approval.
7.3
The facility Operator shall record the qualifications and training undertaken of
all personnel working with organisms under this approval, and make these
records available for examination by the Inspector.
8 Additional controls
8.1
A biological safety cabinet of class II shall be used for all experiments
requiring PC2 containment where the handling of adeno-associated viruses
may result in the production of aerosols.
8.2
Recombinant AAV vector stocks shall be clearly identifiable and be kept in
secured storage when not in use. Access to the stocks shall be restricted to
authorised researchers.
8.3
Under no circumstances should investigators be infecting cultures of their own
cells, or of their immediate relatives, or those of other staff of the laboratory.
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Appendix 2: Qualitative scales for describing effects
Qualitative scales for describing effects
Table 1 provides an example of a set of generic likelihood descriptors for adverse and
beneficial effect. Note that when estimating these likelihoods, the impact of default controls
should be taken into account.
In most circumstances the likelihoods for adverse effects will fall into categories 1 through
4, while beneficial effects will be in categories 4 through 7. The table is not symmetrical.
This is to allow for classification of very low probability adverse effects.
Table 1: Likelihood (adverse effect)
Descriptor
Description
1
Highly improbable
Almost certainly not occurring but cannot be
totally ruled out
2
Improbable (remote)
Only occurring in very exceptional
circumstances.
3
Improbable
4
Unlikely (occasional)
5
Likely
6
Very likely
Considered only to occur in very unusual
circumstances
Could occur, but is not expected to occur under
normal operating conditions.
A good chance that it may occur under normal
operating conditions.
Expected to occur if all conditions met
7
Extremely likely
Almost certain
In practical terms, where the exposure pathway is complex, it may be conceptually difficult
to condense all the information into a single likelihood. For any risk where the likelihood is
other than ‘highly improbable’ or ‘improbable’, then an analysis of the pathway should
include identifying the ‘critical points’, i.e. (a) the aspects that are the most vulnerable, and
(b) the elements where controls might be used to ‘cut’ the pathway.
Development of scales for magnitude of effect
The magnitude of effect is described in terms of the element that might be affected. The
qualitative descriptors for magnitude of effect are surrogate measures that should be used to
gauge the end effect or the ‘what if’ element.
Tables 2 and 3 contain generic descriptors for magnitude of adverse and beneficial effect.
These descriptors are examples only, and their generic nature means that it may be difficult
to use them in some particular circumstances. They are included here simply to illustrate
how qualitative tables may be used to represent levels of risk. The tables to be developed
for Appendix C will be more specific and tailored towards the particular groups of
application to be considered.
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Table 2: Magnitude of adverse effect (risks and costs)
Descriptor
Minimal
Examples of descriptions
Mild reversible short term adverse health effects to individuals in highly
localised area
Highly localised and contained environmental impact, affecting a few (less
than ten) individuals members of communities of flora or fauna, no discernible
ecosystem impact
Low dollar cost of containment/cleanup/repair (<$5,000)
No social disruption6
Minor
Mild reversible short term adverse health effects to identified and isolated
groups7 Localised and contained reversible environmental impact, some local
plant or animal communities temporarily damaged, no discernible ecosystem
impact or species damage
Dollar cost of containment/cleanup/repair in order of $5,000-$50,000
Potential social disruption (community placed on alert)
Moderate
Minor irreversible health effects to individuals and/or reversible medium term
adverse health effects to larger (but surrounding) community (requiring
hospitalisation)
Measurable long term damage to local plant and animal communities, but no
obvious spread beyond defined boundaries, medium term individual ecosystem
damage, no species damage
Dollar cost of containment/cleanup/repair in order of $50,000-$500,000,
Some social disruption (e.g. people delayed)
Major
Significant irreversible adverse health effects affecting individuals and
requiring hospitalisation and/or reversible adverse health effects reaching
beyond the immediate community
Long term/irreversible damage to localised ecosystem but no species loss
Dollar cost of containment/cleanup/repair in order of $500,000-$5,000,000
Social disruption to surrounding community, including some evacuations
Massive
Significant irreversible adverse health effects reaching beyond the immediate
community and/or deaths
Extensive irreversible ecosystem damage, including species loss
Dollar cost of containment/cleanup/repair greater than $5,000,000
Major social disruption with entire surrounding area evacuated and impacts on
wider community
The economic effects category has been given a surrogate magnitude. This is for
demonstration as a means of illustrating the type of magnitudes that might be encountered.
6
The concept of social disruption includes both physical disruption, and perceptions
leading to psychological disruption. For example, some chemicals may have nuisance effects
(through odour) that result in communities feeling threatened.
7
Note that the reference to ‘groups’ and ‘communities’ in the context of human health
effects includes the notion of groups defined by health status.
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Table 3: Magnitude of beneficial effect (benefits)
Descriptor
Minimal
Examples of descriptions
Mild short term positive health effects to individuals in highly localised area
Highly localised and contained environmental impact, affecting a few (less
than ten) individuals members of communities of flora or fauna, no discernible
ecosystem impact
Low dollar benefit (<$5,000)
No social effect
Minor
Mild short term beneficial health effects to identified and isolated groups
Localised and contained beneficial environmental impact, no discernible
ecosystem impact or species damage
Dollar benefit in order of $5,000-$50,000
Minor localised community benefit
Moderate
Minor health benefits to individuals and/or medium term health impacts on
larger (but surrounding) community and health status groups
Measurable benefit to localised plant and animal communities expected to
pertain to medium term.
Dollar benefit in order of $50,000-$500,000,
Local community and some individuals beyond immediate community receive
social benefit.
Major
Significant beneficial health effects to localised community and specific
groups in wider community
Long term benefit to localised ecosystem(s)
Dollar benefit in order of $500,000-$5,000,000
Substantial social benefit to surrounding community, and individuals in wider
community.
Massive
Significant long term beneficial health effects to the wider community
Long term, wide spread benefits to species and/or ecosystems
Dollar benefit greater than $5,000,000
Major social benefit affecting wider community
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