Leaking From The Lab

4. THE REGULATORY FRAMEWORK

Being able to place a GMM in the appropriate risk group and containment class is fundamental to the success of the safety system

All users of GMMs have a legal responsibility to “limit contact with the general population and the environment”

The existence of risks associated both with the use of GMMs and their escape to the environment has long been recognised and has led to the evolution of a set of regulatory controls which are intended to prevent harm occurring (see Box 1). The UK regulations currently in place implement the European Union’s Contained Use Directive (90/219/EEC), but an amended version of this Directive has recently been agreed and UK regulations will be changed as a result, the consultation process beginning in May 1999. Both the Contained Use Directive and the revised Directive set baseline levels of protection and Member States are able to introduce more stringent regulations.

Although the Contained Use Directive only includes GMMs in its scope, the UK regulations also cover the contained use of GM plants (e.g. in greenhouses) and GM animals. However, this report only considers GMMs.
The way in which the regulations currently operate is shown in Box 2. Based upon a risk assessment process, the GMM is placed in either a low or higher risk category and, for the higher risk group, given an appropriate containment level. The actual assessment is undertaken by the person, institution or company wishing to undertake the work, with policing and granting of approvals the responsibility of the HSE. Being able to place a GMM in the appropriate risk group and containment class is fundamental to the success of the safety system.

4.1 Risk Assessment

The UK's approach to risk assessment is based upon a determination of whether the GMM poses a risk to human health or the environment, together with the scale of its use - large (usually industrial) or small (usually research). Depending on the risk category into which an organism is placed, the assessment may or may not be subjected to independent scrutiny.

4.1.1 The Approach to Risk
The definition of contained use in the Contained Use Directive does not mean that organisms which are regulated by it should be kept in absolute containment. All users of GMMs covered by the Directive have a legal responsibility to “limit contact with the general population and the environment”. This is undertaken through a combination of physical, biological and chemical containment measures. Physical containment includes measures such as air filtration systems, protective clothing, and the ability to fumigate and isolate premises as mechanisms to prevent a GMM physically escaping. Biological containment involves changes to the organism which mean that if it does escape it cannot survive, cause disease or other harm. These systems include disabling organisms so they cannot form spores, for example. Alternatively, they may be deficient in a replication factor which can only be supplied in the laboratory, or have plasmids which lack the ability to be mobilised. Chemical containment includes the use of disinfectants to clean work surfaces, fumigation of laboratories and chemical ‘kill tanks’ where chemicals are used to kill organisms which have been used in production systems.

Box 1: The History of the Regulation of the Laboratory Use of Genetically Modified Micro-organisms in the UK Error: Reference source not found^,38,39

1972 First successful transfer of DNA between different species.

1972 UK Government sets up working party under Lord Ashby which recommends strict safeguards be established.

1975 Asilomar conference in California – scientists agree to a voluntary moratorium on some recombinant DNA experiments until guidelines or regulations are in place.

1976 UK working party recommends establishment of a Genetic Manipulation Advisory Group (GMAG) to examine proposals for GMO work.

1978 Regulations introduced to make notification of laboratory use of GMOs to GMAG compulsory under Health and Safety at Work Act 1974.

1984 GMAG becomes the Health and Safety Commission’s Advisory Committee on Genetic Manipulation (ACGM).

1989 Regulations extended to include the release of GMOs to the environment.

1990 The term ‘manipulation’ in the ACGM’s title changed to ‘modification’.

1993 New regulations introduced under Health and Safety at Work Act 1974 to implement the 1990 European Directive on the Contained Use of GMOs – Genetically Modified Organisms (Contained Use) Regulations 1992 (as amended by the Genetically Modified Organisms (Contained Use) Regulations 1996). These cover the laboratory and greenhouse use of genetically modified micro-organisms, plants and animals.

1993 Separate regulations introduced to cover the release of GMOs to the environment.

1996 ACGM establishes new technical sub-committee (TSC) to advise on technical questions.

1998 Following industry pressure to relax regulatory control of the contained use of GMOs, a new European Directive (98/81/EC amending Directive 90/219/EEC on the contained use of genetically modified micro-organisms) is introduced.

1999 Consultations on the revision of UK regulations in the light of the new European Directive.

2000 5^th June implementation deadline for revised regulations.

The actual containment level is decided upon by comparing the properties of the GMM with those of the parental strain and with other organisms that have been classified already. This method of risk assessment relies upon being able to predict the properties of the GMM by assuming the risk will be equal to the sum of the GMM’s constituent parts (the parental strain, the inserted gene sequence and the vector).

Risk assessments are undertaken by the GMM user in consultation with a local GM safety committee – there is no formal scrutiny of the categorisation by the HSE

GMMs are assigned to one of four categories depending on the risk group of the organism (I or II) and the scale of production (Type A or B). The four categories are:

IA	low risk, small scale (usually research) - e.g. the use of E.coli K12 in a university laboratory.
IB	low risk, large scale (usually for industrial production) - e.g. the use of E.coli K12 in a fermenter (over 10 litres in capacity) to produce the drug bovine somatotrophin (BST).
IIA	higher risk, small scale - e.g. the use of a potential pathogen such as influenza virus in a university or company laboratory.
IIB	higher risk, large scale - e.g. the use of a potential pathogen to produce a drug (N.B. there are none of these in the UK at present).

In the case of Group I GMMs, there is only a legal requirement to follow ‘good microbiological practice’. However, where Group II status has been allocated, it is also necessary to determine a specific containment level for the GMM. There are four containment levels with 1 being the most lax and 4 being the most stringent, and categorisation is based on an assessment of their potential to cause harmful effects to human health or the environment. These containment levels are defined in Annex IV of the Contained Use Directive. It is only at containment levels 3 and 4 that the requirement to prevent rather than limit release exists. The main features of increasing containment are more physical barriers to escape since the classification of a GMM in the higher risk category acknowledges that it would cause harm if it escaped.

Before using GMMs, the person or company intending to do so must register the centre where the work is to be carried out with the HSE. The HSE evaluates the proposal and the centre's suitability and decides whether or not to grant its approval. If the centre is approved for ‘low risk’ Group I organisms (either Type A or B), different GMMs may be produced subsequently without further approval as long as they fall within the Group I category. For centres approved for Group II use, each new use must be notified to and, in the case of Group IIB organisms, approved by the HSE. The risk assessments are undertaken by the GMM user in consultation with a local GM safety committee – there is no formal scrutiny of this categorisation by the HSE.
The UK guidelines outline how organisms should be categorised and recommend safety measures to mitigate against some risks such as gene transfer by stating that “plasmid vectors should be immobilised” (Schedule 2 Paragraph 5) and this is more strictly interpreted for large scale operations. Thus, for Type A operations, organisms should be Tra^-, Mob⁺ (not transmissible but mobilisable) and for Type B operations, GMMs should be Tra^- Mob^- (neither transmissible nor mobilisable).

4.1.2 Assessing the Human Health Risks

Introduced genes may alter or exacerbate existing pathogenic traits unpredictably

Risk assessment for human health is usually based upon the ‘Brenner Scheme’. This works by applying numerical values to the following characteristics of the GMM:

Access – the likelihood that the organism could enter and survive in a human.

Expression – a measure of the level of expression of the cloned protein.

Damage – the potential for the organism or the expressed protein to cause harm.

These values are combined to give an indication of the appropriate containment level. However, as the HSE acknowledges, the Brenner Scheme may not always give a reliable indication of risk. This is because there are circumstances where there may be effects which cannot be predicted from experience with other (non-GM) organisms which is the basis of the Brenner Scheme. For example:

introduced genes (e.g. pathogenicity determinants or antibiotic resistance genes) may alter or exacerbate existing pathogenic traits unpredictably;

when there is uncertainty over the level of attenuation (the weakening of an organism to make it less able to cause disease or survive) of the host strains;

when completely new types of constructs (e.g. deletion mutations) are formed from a plasmid vector and an inserted coding sequence.

The shortcomings of simply comparing GMMs to non-GM organisms is seen in the case of GM baculoviruses. Baculoviruses may be used in genetic modification as vectors to transfer genes into other micro-organisms. It had been assumed that baculoviruses were not capable of infecting human or plant cells and so were not hazardous to workers. However, recent studies have shown that baculoviruses can infect mammalian cells and, when combined with mammalian promoters, can result in the expression of foreign genes in those cells⁴⁰. If baculovirus vectors were to infect the cells of workers, they could be exposed to the products (such as drugs), which could prove harmful, and this has necessitated a reassessment of the risk assessment procedure for baculoviruses⁴¹.

4.1.3 Assessing the Environmental Risks
Environmental harm is not precisely defined in the regulations but is related to effects on overall populations and ecosystems rather than harm to an individual, as may be the case in dealing with endangered wild animals. In contrast to the health risk assessment, there is no attempt to quantify the environmental risks.
The procedure for assessing environmental risk is:

hazard identification;

assessment of the likelihood of any identified hazards being manifested;

assessment of the consequence of the identified hazards being manifested;

determination of risk of ‘harm’ (likelihood multiplied by consequence);

management (control) of risk.

Although there is a requirement for those using GMMs to carry out an environmental risk assessment, these are extremely poorly conducted in practice

“The assessment of risk was in several instances based upon assertion rather than evidence.”

Although there is a requirement for those using GMMs to carry out an environmental risk assessment, these are extremely poorly conducted in practice. The criticisms one of the HSE’s advisory committees, the ACGM Technical Sub-Committee, has made about certain environmental risk assessments include:

“A number of statements were made, e.g. that the overall risk to the environment was effectively zero, without any supporting evidence. The assessment of risk was in several instances based upon assertion rather than evidence.” ⁴²

“… the notifications generally dealt very poorly with these [environmental] aspects. There was, in particular, an absence of justification for statements that the work posed no risk to the environment.” ⁴³

“Dr Bowden commented that a lot of centres did not appear to be aware of what was required in an environmental risk assessment.” ⁴⁴

4.1.4 Uncertainty in Risk Assessments
Genetic modification allows organisms to be altered in very dramatic ways. Many of the functions of micro-organisms - such as why they do or do not cause disease - are complex and poorly understood. In both the human and environmental risk assessments there are clearly considerable areas of uncertainty and ignorance.
This risk assessment procedure relies fundamentally on the parental strain having been correctly assigned a containment level. As more and more vectors are constructed and GMMs are themselves further modified, any mistakes which are made may become compounded.
As well as this uncertainty surrounding the classification of risk, other issues are neglected. Neither when assessing risk to human health nor the environment is the effect of naked DNA taken into account. Each organism is considered in isolation and other operations taking place at the site are not considered. If the same centre is used for several different GMMs, unexpected recombinations may arise leading to previously innocuous organisms becoming harmful.

4.2 Advisory Committees

The HSE has two main advisory committees involved in GMMs – the Advisory Committee on Genetic Modification (ACGM) and its Technical Sub-Committee (TSC). The ACGM deals with matters of policy and the TSC advises on scientific and technical matters.

The current members of the ACGM and the TSC are listed in Appendix 1. The HSE does not hold any information about the financial or other interests of members which might influence their opinions about the risks of GMMs. The committees are made up largely of academics and CBI and TUC nominees who may also be academics. One industry employee is on the ACGM and chairs the TSC. The HSE say they are to add a second CBI nominee and an independent ‘public interest’ representative to the ACGM ‘soon’⁴⁵. There is no public interest representative on the TSC although there is a CBI and a TUC nominee.


The HSE does not hold any information about the financial or other interests of advisory committee members which might influence their opinions about the risks of GMMs

There is no requirement in the Regulations for the HSE to undertake routine, independent monitoring and the HSE has not undertaken any

Neither the ACGM or its TSC prepare an annual report, making it difficult to gain an overall picture about the committees, how they operate and make their decisions. However, one area where the TSC excels in relation to other committees working in the area of GMOs - such as the Advisory Committee on Releases to the Environment (ACRE) and Advisory Committee on Novel Foods and Processes (ACNFP) - is in the publication of detailed minutes (since early 1998) of their meetings which have comments attributed to individual members. This provides useful insights into the recent deliberations behind decisions and often demonstrates that there is considerable questioning of some proposals. It also provides the public with an opportunity to question further from a basis of knowledge. However, the removal of some sections on grounds of confidentiality makes some issues frustratingly difficult to understand.

4.3 Regulatory Monitoring Requirements

The EU Contained Use Directive refers to monitoring of GMM facilities to determine if organisms have escaped “when necessary”. This is implemented in the UK regulations as Article 12 (1) (d) of the Genetically Modified Organisms (Contained Use) Regulations 1992 which requires users of GMMs:

“(d) to test, when necessary, for the presence of viable organisms outside the primary physical containment”.

The HSE’s Guidelines to the Regulations give an indication of when they consider monitoring necessary. There is none specified for small scale work at any containment level. For large scale low risk GMMs, the HSE’s advice is that:

“Monitoring is unlikely to be required for many activities at Level B1. However, where there is a risk to human health or environmental safety from process organisms outside the closed system, monitoring for viable process organisms should be carried out.”

For higher risk, large scale use, the HSE advises:

“Where there is risk to human health or environmental safety from process organisms outside the closed system monitoring for process organisms should be carried out.”

There is no requirement in the Regulations for the HSE to undertake routine, independent monitoring and the HSE has not undertaken any. The information that is available suggests that monitoring varies from being limited to non-existent (see Section 6.2 below).

4.4 Enforcement

One of the roles of the HSE is to inspect premises where GMMs are used. For the approximately 500 sites registered as using GMMs, 1,665 person hours (225 days) are allocated annually for inspections of GMM facilities⁴⁶. This is equivalent to one person working full time.

Following inspections, the HSE has the power to issue either improvement or prohibition notices to centres or to prosecute them if they do not comply with the regulations. Improvement notices instruct the user to take specified actions such as rectifying shortcomings in risk assessments, and prohibition notices prevent further work on a GMM project until specified safety measures have been introduced and this has been verified by the HSE. Since 1992, five improvement notices have been served, one prohibition notice served (University of Birmingham), and there has been one prosecution (University of Edinburgh) (see Table 2).

Date	GM Centre	Breach of legislation	Enforcement action
Nov 1993	National Institute of Medical Research	Failure to undertake a written assessment for a containment level 3 project	Improvement notices
Dec 1993	Birmingham University	Inadequate risk assessment and the use of containment facilities that failed to meet the requirements of containment level 2	Prohibition notice
July 1994	Kings College School of Medicine and Dentistry	Shortcomings in work procedures and facilities used for work at containment level 3	Voluntary cessation of work. 3 improvement notices
June 1995	School of Hygiene and Tropical Medicine, London	Inadequate risk assessments, failure to notify Group II work and shortcomings in work procedures and facilities used for work at containment level 3	Voluntary cessation of work. Improvement notice
Dec 1996	Institute for Animal Health, Pirbright	Inadequate risk assessments, failure to notify a number of Group II projects	Improvement notice. Voluntary agreement that proposed work should not be undertaken until a full notification had been made
July 1998	University of Edinburgh	Failure to undertake risk assessments or hold GM safety committee meetings	Improvement notice
July 1998	University College, London	Failure to notify a containment level 3 project concerning HIV virus	Improvement notice
February 1999	University of Edinburgh	Failure to respond to improvement notice and carry out risk assessments	Prosecuted and fined £3,500

Table 2: Enforcement action taken by HSE on centres not complying with the Contained Use regulations

The improvement and prohibition notices suggest that research workers take a particularly cavalier approach to the risks associated with the use of GMMs. Risk assessments have not been undertaken, containment has not been adequate and the HSE has not been notified about projects. These were not trivial failings. For example, University College, London did not notify the HSE about its work with genetically modified human immunodeficiency virus (HIV). The University of Edinburgh did not appear to consider the risks sufficient to heed an improvement notice served on them and were successfully prosecuted, although the £3,500 fine is hardly punitive for such a large institution.



Improvement and prohibition notices suggest that research workers take a particularly cavalier approach to the risks associated with the use of GMMs

Given the tiny commitment which the HSE makes to inspection, it is likely that the breaches they identify are the tip of the iceberg. Coupled with a lack of monitoring, those institutions failing to comply with regulations are unlikely to be detected.

4.5 Public Information

The regulations allow for certain information to be made available about the use of GMMs in a public register held by the HSE. Additional information about centres can be requested by application to the HSE and this includes annual returns which users are expected to complete and details of risk assessments carried out. However, information may be withheld on the grounds of commercial confidentiality.

4.5.1 The Public Register
Under the Contained Use Directive there is provision for the supply of public information. In the UK, this takes the form of a public register, held and administered by the HSE, but this only began in 1992 after the introduction of the Contained Use Directive. For information about GMMs registered before that time, application has to be made to the HSE under the freedom of information provisions. However, this approach depends on knowing what information exists and what questions to ask.
The centre or person intending to use GMMs (the notifier) is asked to give the following information:

name and address of organisation (and department if applicable);

the purpose of the genetic modification;

a description of the genetically modified organism(s) involved or intended to be involved;

the methods for monitoring the genetically modified organisms and for emergency responses (if any);

an evaluation of foreseeable effects and, in particular, any pathogenic and ecologically disruptive effects created by the genetically modified organisms involved.

In reality, the public register consists mainly of undated, single sheets of paper which outline the work being proposed when each centre first gave notification and is a cursory summary of the assessment required by the HSE. The quality of the information on these sheets varies enormously. Some give one sentence answers while others include attached sheets which go into much more detail. Because the register was first set up in 1992 and many laboratories and industrial facilities had already registered as Group I, A or B users, they are not included in the register.

4.5.2 Commercial Confidentiality




Information about the inactivation of waste referred to in Zeneca BioProducts’ notification of the large scale use of GMMs to produce human lactoferrin was denied on the grounds of commercial confidentiality

Companies can withhold information on the grounds of commercial confidentiality although they must justify their reasons for doing so. However, they also exploit loopholes in the regulations to withhold information. GeneWatch requested more information about the large scale commercial activities (Group IB) and commercial research use of Group II organisms registered with the HSE. However, Delta Biotechnology, SmithKline Beecham and Zeneca all withdrew some or all of their notifications. They are allowed to do this if they no longer undertake or never started the work originally notified. This means there could be no publicly available historical information on past (now completed) uses of GMMs and possible releases to the environment. GeneWatch had to obtain this information under the Freedom of Environmental Information Regulations.

Some information about waste treatments is also withheld because of commercial confidentiality. For instance, GeneWatch requested more details about the inactivation of waste referred to in Zeneca BioProducts’ notification of the large scale use of GMMs to produce human lactoferrin at Billingham in Cleveland, but this was denied on the grounds of commercial confidentiality. The information requested was data referred to in the application showing the degree to which the GMM was killed by heat treatment before discharge into waste. It is difficult to understand why this is of commercial significance and seems to be a misuse of the exemption to deny the public access to information of environmental importance which would reveal the extent of discharges of GMMs.

4.5.3 Annual Returns
Notified centres are expected to supply an annual return to the HSE about their activities. GeneWatch has examined several of these and found that they provide very little useful information. Only the number of risk assessments undertaken are given, not what they involve. Gathering such data would assist inspectors in detecting when GMMs may be wrongly classified as low risk.

4.5.4 Accidents and Emergencies
Notified centres are also expected to inform the HSE of any accidental releases or accidents that arise in the use of GMMs. Rather implausibly, in the seven years since the regulations were first introduced, it seems there has never been a single accident⁴⁷. This is probably because an accident only has to be reported under UK regulations if its release would be considered harmful. Since users of Group I GMMs normally claim that their organisms would be harmless if released to the environment, they escape recording. By contrast, in Denmark, Novo Nordisk reported accidental releases of GMMs from one of their enzyme factories in 1997 and they have occurred at other times⁴⁸.

4.5.5 Shortcomings in Public Information


The public register, and information which can be unearthed from it, is hugely inadequate and has been given low priority

It is clear that the public register and information which can be unearthed from it is hugely inadequate and has been given low priority. For example, there is not even a date on the summary sheets included in the public register. As described below, the inadequacies of the public register (particularly the lack of information before 1992; lack of recording of the risk assessments undertaken by notified centres; and lack of information about when activities started and ended) means that it is impossible to gain an accurate picture of the use of GMMs in the UK.