Guide to Risk Assessment and Biosafety in Biotechnology, GRABB

An Initiative of the United Nations Environment Programme (UNEP)



Contained Use of Genetically Modified Organisms


Julian Kinderlerer


Contact: IRRO Secretariat



Are there differences in the way in which containment is handled in different countries?


What is protected when considering contained use?


Risk Assessment and Risk Management

How are GMO's handled?

Risk Assessment for the contained use of modified Organisms

Damage and expression are usually associated with the insert and the gene product

Summary of Laboratory Containment Requirements



The first uses to=15>

The first uses to which genetic modification were able to be put involved the use of micro-organisms in containment. Almost from the very beginning of the use of recombinant techniques it was realised that organisms could be designed which might prove to be 'dangerous' to those working with them, and to the environment. It was recognised that the technology provided a new means of forming organisms which were significantly different from those that had been known up to that point.

Because the first uses of modified micro-organisms were in the laboratory, it was primarily human health and safety that mattered. It is presumed that biological agents are hazardous, and may affect those handling them in predictable ways.

Containment must be used when micro-organisms are used whose function is known to be hazardous to humans, or where the presence or function of the organisms is unknown (as in clinical samples). Where an organism is not known to have pathogenic properties, it is assumties, it is assumed to be safe, presumably because had it been pathogenic (to immuno-competent individuals) it would have been observed to be so. Most human pathogens have been described and assigned by the WHO to 4 groups which relate to their likely effect on anyone coming into contact with them. Problems arise when considering new organisms created in the laboratory. How may these be assigned?. Where can a classification of risk to those in the laboratory or development environment be obtained?


 The presumption that the organism is a micro-organism results from the presumption that it is the health and safety of those who come into contact with the organism that need protection. Having identified the Group into which an organism falls, it is possible to identify the containment requirements that are needed to protect the handlers.

The initial concern for the health and safety of the handlers must now be modified to take into account the impact on the environment in the event of escape from containment or where release is intended. A plant or animal pathogen may havethogen may have no effect on humans, is likely to be placed in Group 1, and minimal containment requirements identified. If this increases the probability of escape into the environment, problems may well arise. If environmental risks are taken into account, then it is not only micro-organisms that fall within the terms of any containment requirements, for animals and plants may have implications as well.

A consideration of the safe use of genetically modified organisms, whether for use under contained conditions or for releases into the environment is hard. We really do not know where to start, particularly for release. We know that the introduction of novel species into a new environment can (and does) go wrong on occasion. Does the insertion of a gene into an organism that has been present in an environment for a very long period of time make a new novel organism? Where do we start assessing the risk associated with the insertion of the gene into a well-characterised organism, let alone those whichhose which might be novel in a particular environment? What happens when we agree that a particular organism is safe in Britain or in the Netherlands (for example), does that mean it is completely safe when used or grown in Spain or Greece? If designed for safe use in a temperate climate, is the organism safe for 'escape' into a tropical environment? If not, how do we assure that the permission to proceed to the use of the modified organism in one country (or region) does not extend to the whole world? This problem is exacerbated by the rules which have been put into place through the operation of the World Trade Organisation, which would appear to require an importing country to provide scientific evidence for the lack of safety of a particular import rather than require the exporting country to justify its safety assessment.

The risks posed by the newly manufactured organism are dependent on the uses to which they are put, but significantly often the risks may be considered in a narrow framework simmework simply because of the particular use, and perhaps an extension of use of the organism may not result in a 'proper' reconsideration of risk; in examining the safety of the organisms we have to try and determine what should be considered hazardous and it has not proved simple to identify the issues contributing to risk. Let me try to use an example to explain this problem. When a field trial of a new genetically modified oil-seed rape is proposed to the UK Government, the proposal will not usually consider the use of the plant as a food or feed, for the proposal is only concerned with the initial field trials. The ability to transfer the genes to wild relatives or to other oil rape plants adjacent to the trial field has been one of the main concerns, although whether this should be of concern is open to debate in the UK. Where seed is kept from year to year it could be a major problem, but where new seed is purchased in each year, and the seed merchant guarantees the quality of the seed, is there a probl a problem if a gene for say herbicide resistance is passed into wild relatives?- only where the wild relatives constitute weeds and need controlling within the agricultural environment itself, not if they only grow in areas that are not controlled by herbicide application. But there is a reason for trying this new construct, which must be its commercial exploitation. Should we not consider the general implications of the use of this new organism at an early stage, rather than waiting and considering the safe use of the organism within the narrow confines of the application itself.

At the other end of the scale, and one that has caused considerable problems to Europe over the last few months, and which will continue to provide real problems, is as follows. Suppose we approve an organism as completely safe for use within the European Union, whether it is anywhere in the geographical confines of Europe or restricted to 'cold' climate agriculture (for example). We have made this product and obviously waniously want to sell it as widely as possible -They have their own legislation relating to the use of such organisms, and may not be happy with our safety assessment; can they stop us marketing our 'product' because of safety concerns? What weight should our safety assessment play in their consideration of the safety issues? Our permission to market the product may be just as valid as their decision not to allow marketing of the product, perhaps because of indigenous organisms. How do we guard against protectionism cloaked within safety concerns? In the case of a developing country, where there might not be legislation that governs biosafety. Should we simply export to them without considering the risks that our organism might pose to them? If so, are we prepared to face the risk that a slightly 'more' modified organism returns to haunt us?

What about the opposite problem, where we receive biological products from other countries. We may know that it has been modified if it has come from the USA or CanUSA or Canada, but if it comes from countries which have no legislation in place to allow for the assessment of risk associated with modified organisms? How likely is it that their products will appear on our markets and pose problems for us in the future.

Within the European Union there are two directives that cover this part of Biosafety. Both directives were drafted in 1990, and required implementation within member states by 1993. 90/219 governs the contained use of genetically modified micro-organisms, whilst 90/220 governs both the release of the organisms into the environment and the marketing of any modified organism, whether for release of for contained use. The primary difference is that 90/219 assumes containment, and that the regulatory structure can be specific for the member state. 90/219 sets minimum standards for the making, use or keeping of the organisms, and member states are free to have legislation that extends both the range and scope of the directive. In the UK the legislation cislation covers all organisms, not only micro-organisms. Release is different, for even an experimental release has the potential for crossing the boundaries between states, and therefore, the harmonisation of community legislation is important. The marketing of modified organisms is also likely to be community-wide, even though geographical constraints may be applied. 90/219 is therefore global, and must be implemented 'as is' within the community, without allowing real discretion in member countries.

These directives have been criticised by many, for a multitude of reasons: perhaps the most important reason (not usually stated) is that they appear to be different from that which has been implemented in the USA. There are major problems with both directives.

It was always intended that the directives would change with time, in that the authors wrote into it that product specific legislation could exempt a particular substance from consideration as long as the risk assessment procedure in thedure in the specific legislation was at least as comprehensive as that identified in 90/220. It was also assumed that it was based on a presumption of a learning curve, that each case would be argued on its merits, but taking into account evidence and information obtained from previous releases of similarly modified organisms. Hence the legislation allowed for the institution of simplified procedures - or 'fast-track', where consent to release the modified organisms could be given much more quickly and easily than for a totally unknown construct. There are therefore, no major changes expected in this Directive, as most desirable changes (as far as industry is concerned) can be accomplished by product-specific legislation or through fast-track procedures. We remain different from the United States in many important respects.

Are there differences in the way in which containment is handled in different countries?

There are significant differences in the containment requirementsequirements in different countries. Although both the United States and the United Kingdom developed their regulatory systems following the Moratorium self-imposed by scientists in the 1970's, the regulatory systems moved apart significantly. In the United States it was decided not to impose new regulatory burdens on the biotechnology laboratory or industry. Guidelines for the safe use of modified organisms were introduced, in particular the NIH Guidelines, which imposed a set of safety precautions on those funded by the NIH for the safe use of modified organisms. Most industries, although not funded by NIH, followed these guidelines, at least in spirit.

In Europe, however, a statutory regulatory system is in force, which requires an assessment of the risks associated with the use of modified organisms in containment. The statutory system in Europe also depends on a Directive (90/679) which defines the conditions in which biological agents (whether genetically modiflly modified or not) may be used in the workplace. Most of this discussion relates to the system in place in Europe, as it is not dissimilar to that expected but not required by law in many countries.


We turn to the use of genetically modified organisms in containment. Containment includes both the research stage, where modifications are made, development work whether in the laboratory, greenhouse or growth room, and in plant where modified micro-organisms are used as factories to produce new products. In this instance it is not intended that the modified organism is released into the environment, and if being used at a commercial or industrial level, they would only be being used as factories. The concerns are different. There is a peripheral problem with the environment, only if there is inadvertent escape, or if there are waste products that might contain viable organisms does the environment need considering. The true concern is with human heah human health and safety - protecting all those who might come into contact with the organisms during their production or use. The approach taken in the risk assessment is different to; here we devise confinement and containment that will minimise a risk. The risk might be substantial, like modifying HIV in order to unravel its 'secrets', or with polio virus to try and understand how it works, or why it only infects particular types of cell. The risk management procedures will minimise the risks and allow the work to proceed. How again, are we to determine the risk?

What is protected when considering contained use?

  • the health and safety of the human on which the procedure is applied (if any)
  • the health and safety of workers in the laboratory or industry in which the organisms are handled, used, made, kept, etc.
  • the health and safety of others who have access to the workplace, or near it (cleaners, secretaries, students, visitors)
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  • the health and safety of all other persons who might come into contact with the organism if it is incidentally or accidentally released into a wider environment.
  • the health and safety of animals within the laboratory environment if they are susceptible to the organism, whether they are used as 'guinea pigs' for testing of the modified organism, or if infection is unintended
  • the environment of the accidental or incidental release of the modified organism.


The original Directive which was produced for the European Union, 90/219 was clearly flawed. It worked on the basis type of work and of the hazard, rather than on the true risk.

The Directive defined two types of activity, Groups A and B. If the work was for research or development purposes, or non-commercial, or non-industrial, it was group A, otherwise B. The only purpose of these two groups was to identify the notification and consent requirements for the work. The the work. The separation is at least partially justified on the basis of the risk to workers - Group B work might involve less qualified or involved personnel who would not understand the risk, but takes little account of either risk or hazard.

Micro-organisms are then classified as type 1 or type 2. Type 1 organisms are those that pose no risk to human health or safety; type 2 organisms are all others. The classification is largely based on the host organism. I find it difficult to link the risk assessment with these classifications, which simply identify the needs of notification and consent once again. A risk assessment is still needed, but that which is closely defined is not the risk, but whether a consent is required.

Discussions concerning this Directive and possible modification have proceeded almost since it was first agreed in 1990. A change to a risk rather than hazard based system, with notification and consent based on risk rather than hazard or type of activity has beessessment - risk management system with the consent - notification system. That which I have to say here concerns the latest version that I have seen, somewhat later than that presented to the parliament, and dated November 1996. I have to state that I believe the draft Directive to be a massive improvement on that which we have now, and workable in that it directly relates the results of the risk assessment to the containment that would be required to minimise the risk.

The main provision is withinwithin article 5 of the draft, which states

  1. That the reason for the directive is primarily to require Member States to ensure "that appropriate measures are taken to avoid adverse effects on human health and the environment that might arise from the contained use of genetically modified organisms"
  2. The user shall carry out an assessment of the contained uses as regards to the risks to human health and the environment that they may incur.
  3. The assessment shall result in a classification of the contained uses in four classes applying the procedures set out in Annex III of the directive, which will result in an assignment of containment
    1. Class 1: Activities of no or negligible risk that is activities for which level 1 containment is appropriate to protect human health as well as the environment.
    2. Class 2: activities of low risk that is activities for which level 2 containment is appropriate to protect human health as well as the environment.
    3. Class 3: activities of moderate risk that is activities for which level 3 containment is appropriate to protect human health as well as the environment.
    4. Class 4: activities of high risk that is activities for which level 4 containment is appropriate to protect human health as well as the environment.

The directive continues to define the requirements for notification or permission for each of the 4 classes defined above.

The major requirements of the Directive apply to the risk assessment and to the definition of techniques that are included within the definitions. These both appear in annexes, and there is still discussion as to which of these annexes should be adaptable to technical progress (modifiable without having to modify the directive) and which not. The discussion that follows closely follows the text of the draft directive, for obvious reasons. The discussion between competent authorities and the commission to try to achieve an agrachieve an agreed text to this directive often becomes bogged down in detail, which results in extremely careful choice of words. As the directives are translated into each of the Community languages, and the meaning of words in each of these languages may well differ, this seems pointless, but problems between member States may often be resolved by judicious choice of words.

In Annex III we see the Principles which would be followed for the assessment of risk, which include

  1. A definition of harmful effects (including allergenicity and toxigenicity, disease, establishment or dissemination in the environment, gene transfer)
  2. Identification of potential harmful effects, particularly those associated with the recipient or host organism, the donated material, the vector, donor if used during the operation rather than just its sequence, and the resulting modified organisms.
  3. the characteristics of the activity
  4. The severity of the potentially harmful effects (haul effects (hazard?)
  5. The likelihood of these potentially harmful effects being realised.

The procedure used to perform this risk assessment involves first identifying the harmful properties of the host organism, and then the properties of the donor organism, vector and finally the modified organism, making sure that only organisms for which

  • Both donor and recipient are unlikely to harm humans, animals or plants (where appropriate)
  • the vector and the insert are such as not to provide a phenotype likely to cause disease to humans, animals or plants in the facility in which the organisms are used, or to cause adverse effects in the environment;
  • The modified organism is unlikely to cause human, animal or plant disease or to harm the environment.

are classified as class 1.

The user should take account of the various tables classifying pathogens for animals, plants and humans (90/679 and 93/88) in assigning organisms to classorganisms to classes.

Selection of containment and control measures should then be made on the basis of the level of risk associated with the modified organisms together with information on the likely environment into which the organism could escape; characteristics of the use (e.g. scale) and any non-standard operations. This should lead to assignment to one of the classes defined previously.

A variety of tables appear in the draft directive to define the conditions of containment that are needed for each of the four classes of risk.


Risk Assessment and Risk Management.

      1. The legal process which regulates the use of genetically modified organisms is concerned with the health and safety of those in the workplace and with the possible harm that may be caused to the environment by the modified organism. A formal risk assessment is risk assessment is required to identify any likely risks and management procedures must be designed to minimise them
      2. Risk Assessment depends on an assessment of the hazard associated with the modified organisms or the procedures used in handling the organism, and on the likelihood of the hazard occurring.
      3. For CONTAINED USE, where it is presumed there are both physical and biological barriers which limit the likely impact on the environment, it is almost solely the health and safety of those who are likely to enter the laboratory or factory that causes concern. The assessment of risk considers the likely effects of the modified organism on the humans using it, including those who enter the facility but are not aware of the sort of work being done (cleaners, secretaries...). It must also take into account both the incidental release of the organisms into a wider environment (waste streams, rubbish) and accidental release - what are the likely efflikely effects if the organism escapes from its physical containment, not only on human health and safety outside the containment facility but also on the environment?

This is crucially important where the 'micro-organism' being used is a plant or animal pathogen, or even a plant or animal cell. The initial test, for risk to humans, indicates lack of problem and hence safe usage in relatively light containment, but the impact on the environment may be severe should they escape, and hence the need for greater containment (both physical and biological) is indicated.

      1. Where the organism in containment is an animal or plant, the risk to the environment on escape is the most crucial, although risk to humans remains a consideration. If 'animals' are mentioned, it is often assumed that large farm or domestic animals - cats, dogs, sheep, pigs or cows are involved. It is these animals where the risk is probably least, and to some extent, biologicallyent, biologically contained (There is little risk of genes inserted into a cow 'escaping' into the environment, but there is risk associated with the escape of such genes from a tom-cat). Modified animals which might pose a real threat to humans might be mites or insects and a consideration of the likely effects of escape or infestation becomes more important as the biological containment is less effective.
      2. Where the organism constitutes a risk to public health, special considerations apply. A report recently published by the Advisory Committee on Dangerous Pathogens in the UK on Microbiological Risk Assessment tabulates a risk assessment procedure as follows for risk assessment, not specifically for genetically modified organisms, but in general (summarised): A United States Presidential and Congressional Commission has recently reported in similar terms: