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Risk Assessment of Genetic Engineering Research Projects, etc.

These guidelines describe the risk assessment that must be prepared for all genetic engineering projects, testing and production.

The Danish Working Environment Authority’s guidelines describe the risk assessment that must be prepared for all genetic engineering projects, testing and production. The guidelines only deal with risk assessment of genetically modified micro-organisms, but a large number of the points also apply to genetically modified animals and plants. The guidelines provide more detailed guidelines for which aspects of the biological system should be included in the risk assessment as a minimum. The guidelines can be viewed as an elaboration of Annex 3a: "Assessment pursuant to Section 6 of the Biological Systems" and 3b: "Guidelines for Risk Assessment" in the Executive Order on Genetic Engineering and the Working Environment.

The Executive Order describes the individual points that must be included as a minimum in order for the risk assessment to be adequate. It is an overall assessment of the possible hazards of biological systems for human safety and health as well as for the external environment. Based on the risk assessment, it must be assessed in which class the activities are to be carried out.

The risk assessment must be in writing, and a copy must be attached to the notification of the activities. The safety organisation must contribute to or be involved in the preparation of the risk assessment.

The activities involving genetically modified organisms (GMOs) cover all handling of these organisms. This includes testing, analyses, storage, production etc. of GMOs. There is no lower dilution or volume limit for the definition of GMOs.

The risk assessment must be structured pursuant to the guidelines set out in the Executive Order. This makes it easier for the company, the safety representative, and the Danish Working Environment Authority's supervisor to investigate whether all points have been reviewed. In addition, changing and updating the risk assessment is much faster if it is structured pursuant to the applicable guidelines.

The Danish Working Environment Authority’s guidelines only describe the general principles for risk assessment, as the combination possibilities for host, donor and transferred genetic material (genes, inserts and vectors) are endless. The guidelines show by example how it is possible to draw analogous conclusions about classifying the activities into the different classes.

The Danish Working Environment Authority’s guidelines are divided into two main sections:

  1. General information on risk assessment, which describes the biological aspects to be included in an assessment of potential risks and provides general guidelines for class selection.
  2. Risk assessment in practice, which provides examples of combinations of biological systems, analyses of these and the resulting classification.

1. General Information about Risk Assessment

According to the Executive Order, the following factors must be included in the assessment of potential risks to human safety and health as well as to the external environment associated with the activities:

A. Disease to humans, animals or plants caused by the micro-organisms used.

B. Deleterious effects due to the transfer of genetic material, including allergenic or toxic effects.

C. Potential health hazards when carrying out activities involving whole animals and plants as well as cell cultures, including viruses and virus fragments used.

D. Deleterious effects due to the impossibility of treating a disease or providing an effective prophylaxis.

E. Other possible health hazards associated with all parts of the biological systems used.

F. Deleterious effects due to establishment or dissemination in the environment, e.g. due to the transfer of inserted genetic material to other organisms.

G. The likelihood of the potentially harmful effects being realised.

H. Characteristic properties of the environment which are likely to be exposed in case of unintended release.

It is important to assess whether the genetic modification may affect the host organism’s ability to harm human health and the environment. The severity of any harm must be assessed regardless of the probability of the damage actually occurring.

1.1. Procedure for risk assessment

The first stage in the assessment process should be to identify any harmful properties of the biological system (donor, host, vector, and genes) and to classify the GMO into a provisional class, Classes 1-4.

In order for the GMO to be considered for inclusion in Class 1, the following must be met:

  • None of the organisms used is likely to cause disease to humans, animals, or plants.
  • The transferred genetic material cannot give the host organism a phenotype so that it becomes pathogenic.
  • The final GMO must not be likely to cause disease to humans, animals, or plants or to have deleterious effects on the environment.

The second stage of the assessment process should be an assessment of the likelihood of adverse effects occurring. The assessment includes both employees and the external environment. The nature and extent of the activities must be considered, as well as the containment measures associated with the provisional classification of the GMO, first stage.

The third stage is the final classification of the activities and the determination of the necessary containment measures that the activities require. Here, it is especially important to consider whether the activities require special safety regulations in relation to those associated with the classification of the laboratory.

The level of human and environmental exposure should then be reassessed, i.e. a review of the risk assessment. Only then is the risk assessment process completed.

The Danish Working Environment Authority should be contacted if there is uncertainty regarding final classification into a class, i.e. the final classification 13; and the necessary containment measures.

1.2. Classification of micro-organisms into risk classes

Any pathogenic properties of the micro-organisms or inserts to be used in the activities must be included in the risk assessment.

To make it easier, a large number of micro-organisms are classified into risk classes.

The current list of Group 2-4 micro-organisms that are infectious to humans can be found in the Executive Order on Biological Agents and the Workplace.

The four classes of risk define the increasing degree of risk of human disease:

  • A micro-organism highly unlikely to cause disease to humans.
  • A micro-organism that can cause disease to humans and endanger employees. There is little risk of spreading into the environment and there is usually effective prevention or treatment available.
  • A micro-organism that can cause serious disease to humans and can pose a serious danger to employees. There may be a risk of spreading to the environment, but there is usually effective prevention or treatment available.
  • A micro-organism that can cause serious disease to humans and that poses a serious danger to employees. There may be a high risk of spreading into the environment and there is usually no effective prevention or treatment available.

Risk Class 3 is subdivided into two groups: The actual Risk Class 3 organisms, and those marked with an asterisk (*). The asterisk means that, in some cases, the micro-organism poses only a limited risk of infection to employees, as it is not normally transmitted through the air.

In the case of genetic engineering activities with micro-organisms that is not mentioned in the Executive Order on Biological Agents and the Workplace, it is the responsibility of the research director to make a proper classification of the micro-organism. The following factors must as a minimum be considered in the classification:

1. The pathogenicity of the micro-organism to humans, animals or plants, including:

  • Disease and pathogenicity mechanism caused, including invasiveness, virulence, route, and site of infection.
  • Communicability, transmission capability.
  • Infectious dose.
  • Antibiotic resistance.
  • Toxin-forming properties.

2. The allergenic properties of the micro-organism.

3. The colonisation ability of the micro-organism.

4. The availability of effective prophylaxis and treatment. If a micro-organism not mentioned in the Executive Order on Biological Agents and the Workplace cannot be classified with certainty into a class of risk, it must be provisionally classified into the highest risk class among the classes that may be involved.

1.3. Transferred genetic material

It appears from Annex 3 to the Executive Order that the potentially harmful properties of the transferred material and the substances from which it is formed must be included in the risk assessment.

The transferred genetic material covers both inserts and vectors to be used in the activities.

The transferred genetic material, i.e. the recombinant DNA, most often contains two different types of information: The transferred genetic material may encode a product, usually of a protein nature, and the genetic material may have a regulatory function. Both types of information are often present in the same vector. In addition, most vectors contain various selection markers, usually genes for antibiotic resistance.

Products

In the risk assessment, special emphasis must be placed on whether the transferred genetic material will result in the formation of:

Toxins

In everyday speech, the word toxin is often used as a synonym for poison. Poisons are substances that, in small amounts, can be lethal – especially to mammals. In a more precise sense, a poison is a substance that, in a given dose, can trigger a detrimental effect on a biological mechanism, so that the function of the biological mechanism is inhibited, destroyed or, more rarely, accelerated.

Toxins are natural poisons, i.e. substances produced by animals, plants, bacteria, or other organisms. The word is not usually used about synthetic products.

In microbiology, a distinction is made between endotoxins and exotoxins.

Endotoxins are substances that are either part of the structure of the organism/cell or are intracellular. Examples of endotoxins are lipopolysaccharides (LPS), which are associated with the outer membrane of gram-negative bacteria, and ß-1,3-glucans in certain moulds. Both types of substance can cause severe irritant lung effects after inhalation of high doses. LPS is also pyrogenic and affects the thermoregulatory centre of the brain in the event of blood poisoning.

Exotoxins are substances that the organism (bacterium or cell) secretes into the environment. Microbial exotoxins are proteins. Many have an enzymatic effect that destroys the tissue. For example, Clostridium tetani releases two toxins, one of which, tetanospasmin, causes spastic paralysis of nerves to striated muscles, and the other, tetanolysin, is an enzyme that acts hemolytically.

Exotoxins that are produced by intestinal pathogens and released into the intestine affecting the intestinal wall are called enterotoxins. These toxins cause nausea, diarrhoea and vomiting. The toxins cause severe stomach symptoms in diseases such as cholera and dysentery but are also found in milder infections with Salmonella or virulent coli bacteria.

The toxicity of many exotoxins is determined by their LD50 value assessed by their toxicity to vertebrates, especially mice, rats, and rabbits. Information on the LD50 value of a toxin must be included in the assessment of parental or recipient organisms known to be able to produce toxins.

Highly biologically active substances

This refers to substances that have a signal function in the human organism, e.g. hormones, lymphokines, growth factors and proteins from certain oncogenes.

It is crucial to assess the risk of biological effects that cause discomfort, which may be associated with a highly biologically active substance being produced and affecting the wrong place, at the wrong time, or in increased concentration, including with the possibility of cellular transformation.

One example of the assessment is the formation of highly biologically active substances in a microbial host. In this case, the colonisation ability of the organism, the ability to transfer genetic material to other organisms and the biological effect of the substance must be considered, as any colonisation of the host organism in the intestinal tract or airways could cause a sustained local dose of the substance. It may also be relevant to include the normal physiological concentration of the substance in the assessment.

Another example is activities involving cell cultures with proto-oncogenes and the oncogenes that arise from them. They contribute to the growth and differentiation pattern of cells as well as transformation. The main risks include whether the vector (virus) has a human specificity, whether a helper virus is present, and, if so, whether it has the same host specificity as the vector.

In addition, the effect of the highly biologically active substance as well as the expression strength of the corresponding gene must be assessed.

In the assessment of expression strength, specific regulatory sequences, including strong promoters, play a role.

Finally, one must be aware that genes for highly biologically active substances may be conserved through evolution. Thereby, the substances from other organisms can be active in humans, e.g. porcine insulin, and c-Ras from yeast.

Antibiotic resistance

Here, antibiotic resistance is considered along with other products. Vector-borne resistance is exerted through enzymatic degradation of the antibiotic, e.g. beta-lactamase against penicillin and cephalosporin, acetyl transferase against chloramphenicol and a wide range of other enzymes that adenylate, acetylate, or phosphorylate substances.

Projects that involve the transfer of antibiotic resistance must be preapproved by the Danish Working Environment Authority if the transfer can endanger the use of this antibiotic for the treatment of diseases.

It is important to determine whether the use of antibiotic resistance can have adverse consequences in the fight against infectious diseases. It must therefore be assessed whether the transmitted antibiotic resistance is directed at one of the preparations that are primarily used to control the particular organism into which the resistance is introduced. For example, it would be unfortunate to introduce resistance into penicillin in Bacillus anthracis because penicillin is one of the first-line drugs to combat anthrax.

When selection markers are used, it may be possible to develop and use vectors with markers other than antibiotic resistance, e.g. the ability to overcome specific growth requirements for the host organism.

Other

Products with any potential rejuvenating effects causing discomfort other than those mentioned above, e.g. proteins that may have allergenic effects or microbial virulence factors, must also be included in the assessment.

Vectors

Vectors are used to introduce genetic material into a host organism. Many complex vector systems have been developed that contain both plasmid and viral elements. It is important for the assessment of the vector used that one knows the origin of each vector element, i.e. which plasmid and viral elements are included in the vector.

The assessment must, as a minimum, include the following aspects:

  • Transferability: Whether the vector system is conjugable or non-conjugable. That is, whether the genetic material can be transferred to organisms other than the host organism.
  • Host specificity: Which organisms can the vector be transferred to and expressed in?
  • Helper virus: Is there a helper virus in the host cell that allows the genetic material to spread?

As the vector plays a role in the transfer from one organism/cell to another, it must be assessed whether the recombinant genetic material can be introduced or integrated into the natural organisms’ genome, e.g. by recombination, conjugation, or helper function.

The risk of importation or integration of the recombinant genetic material must be included in the overall risk assessment.

1.4. Health aspects of the final genetically modified organism

The risk assessment must include the donor and recipient organism, insert and vector, as well as the properties of the final GMO. Significant features of the GMO, including substances that are formed or may be formed as a result of the genetic modification, have already been described. An assessment of the final GMO must include both human health and environmental considerations as well as a description of methods for monitoring.

In addition to the mentioned conditions regarding host organisms (see Page 6), assessment of health aspects of the final GMO must include the following aspects:

  • Expected toxic or allergenic effects of the GMO and its metabolic products.
  • Product risks, including the formation of toxins or highly biologically active substances.
  • A comparison between the GMO and the recipient organism, or parental organisms, in terms of pathogenicity.
  • Known and expected habitats.

If the organism is pathogenic:

  • Same points as under the recipient organism; as well as
  • Possible change in route of infection or tissue specificity due to the genetic modification.
  • Possibility of survival outside of a mammalian host.
  • Presence of vectors or other modes of propagation.
  • Biological stability.

1.5. Environmental considerations

  • Ecosystems, into which the organism might escape from the laboratory or facility – the contained use.
  • The GMO's expected survival, reproduction and spreading in the identified ecosystems.
  • Expected outcome of the interaction between the GMO and the organisms that may be exposed in case of unintended release into the environment.
  • Known or anticipated effects on plants and animals, such as pathogenicity, toxicity, allergenicity, healthy pathogen carrier, altered antibiotic resistance patterns, altered tropism or host specificity and colonisation ability.
  • Known or anticipated participation in biogeochemical processes.

1.6. Monitoring techniques

  • Techniques for detecting, identifying, and monitoring the GMO.
  • Techniques for detecting the transfer of the new genetic material to other organisms.
  • Possible methods for decontamination of the area in case of unintended release.

1.7. Selecting laboratory class 

Laboratories where genetic engineering activities are to be carried out must be classified by the Danish Working Environment Authority. Classification is done into four classes. In Class 1 laboratories, only activities of the lowest risk may be carried out. Classification for Classes 2, 3 and 4 places increasing demands on design and safety measures. You can read more about classifications in the Danish Working Environment Authority's guidelines on this. (1)

Class 1

If it is assessed that the activities are of no or negligible risk, it must, as a minimum, be carried out in Laboratory Class 1.

As a general rule, work with micro-organisms classified in Risk Class 1 must take place in Laboratory Class 1.

Class 2

Activities of low risk, it must, as a minimum, be performed in Laboratory Class 2.

Work with micro-organisms or inserts from micro-organisms classified in Risk Class 2 must, as a general rule, take place in Laboratory Class 2.

For activities involving biologically active substances, special attention must be paid to the fact that the overall circumstances of the activities can often make it necessary for the activities to be carried out in a higher class than Class 1.

Class 3

Activities of moderate risk of serious or potentially fatal diseases, it must, as a minimum, be performed in Laboratory Class 3. The projects must be preapproved by the Danish Working Environment Authority.

As a general rule, activities involving micro-organisms or inserts from micro-organisms classified in Risk Class 3 must take place in Laboratory Class 3.

Basically, activities involving a high-expression eukaryotic viral vector of a highly biologically active gene product would have to be performed in Laboratory Class 3 if the viral vector can infect human cells and if the activities involve the presence of a helper virus with the same host specificity at the same time.

Class 4

Activities of high risk of serious or potentially fatal diseases, the activities must be carried out in Laboratory Class 4. The projects must be preapproved by the Danish Working Environment Authority.

As a general rule, activities involving micro-organisms or inserts from micro-organisms classified in Risk Class 4 must take place in Laboratory Class 4.

2. Risk Assessment in Practice

Risk assessment of a project must follow the guidelines described in Annex 3b to the Executive Order on Genetic Technology and the Work Environment. The examples in the Danish Working Environment Authority’s guidelines only cover the provisional classification of the biological system. In a final classification, other factors must also be included, such as the location of the laboratory in question and measures already taken.

2.1. Examples of project types

Not all aspects are equally relevant when assessing different projects. A distinction can be made between the following main types of projects:

A. Transfer of genetic material from micro-organisms to other micro-organisms. The most important thing is to assess:

  • Pathogenicity of the micro-organisms used.
  • How well-characterised the transferred genetic material is.
  • The presence of conjugative plasmids or generally transducing phages in the host-vector system.
  • Possible effects of gene products causing discomfort.

Projects involving shotgun cloning from pathogenic to apathogenic prokaryotes or lower eukaryotes must be assessed according to the risk class in which the donor organism is classified. This is because it is not yet known whether unwanted properties have been transmitted to individual clones. Classification can be done by later subcloning, or if the activities involve well-characterised material that does not code for products with effects that cause discomfort.

B. Transfer of genetic material from higher eukaryotes to micro-organisms. The most important assessments are largely analogous to A:

  • The pathogenicity of the microbial host.
  • How well-characterised the transferred genetic material is in terms of effects that cause discomfort.
  • The presence of conjugative plasmids or generally transducing phages.
  • Whether the transferred genetic material encodes either proteins that may have an effect on human cells from the outside, or proteins that exert an effect only if expressed in the human cell.

C. Transfer of genetic material from higher eukaryotes to cell cultures from higher eukaryotes including gene therapy. The most important thing is to assess:

  • Whether the transferred genetic material encodes products with biological or possibly pathogenic/toxic effects.
  • Promoter strength and possibly the strength of other regulatory sequences.
  • Whether the vector/virus used has human specificity.
  • Whether the vector/virus can infect or transform human cells.
  • Whether helper virus is present.

2.2. Examples of Laboratory Class 1 projects

Title 1: Preparation of human adrenocorticotropic hormone (ACTH).
Host: Bacillus subtilis, asporogenic strain.
Donor: cDNA library from Homo sapiens.
Vector: pUB110 and strong Bacillus promoter.
Insert: The ACTH gene.

Risk assessment

Host: Bacillus subtilis is not mentioned in the Executive Order on the list of biological agents. Asporogenic Bacillus subtilis 13; a reversal frequency for spore formation lower than 10-7 is considered to belong to Risk Class 1, since the risk of allergy is reduced due to the lack of spore formation and the organism is apathogenic and subtilisin free.

Donor: The donor material is from a human cDNA library. The donor material thus does not in itself present any risk.

Vector: The vector pUB110 is not mobilisable in Bacillus and does not carry resistance to antibiotics targeting pathogenic Bacillus species.

Insert: The transferred insert encodes ACTH of human origin. ACTH is a protein hormone and a highly biologically active substance, but it only has an effect on the adrenal cortex.

Health aspects of the final GMO: The final GMO will be able to produce ATCH but will not be able to transfer the insert to intestinal bacteria.

Classification

No adverse effects due to the natural transfer of ATCH to other organisms could occur and the project can therefore be carried out in Laboratory Class 1.

Title: Oncogenic effect in mammalian cells.
Host: 3T3 mouse cell line.
Donor: Abelson murine leukaemia virus.
Vector: pCGBPV9.
Insert: The ABL oncogene

Risk assessment

Host: The host is a cell culture from a higher eukaryote and does not contain endogenous vectors with the ability to mobilise portions of the transferred genetic material.

Donor: Abelson murine leukaemia virus is an endogenous retrovirus in mice in the wild. It can infect mice, rats, and hamsters, but not humans, and it cannot transform human cells in vitro.

Vector: The pCGBPV9 vector is a composite vector with replicon from E. coli ColE1 and from Bovine papilloma virus. No part of the vector has human specificity.

Insert: The ABL oncogene is an isolated fragment and does not contain viral structural protein genes, so virus particles cannot develop.

Health aspects of the final GMO: The ABL oncogene does not act externally on cells, as the biological system does not contain elements with human specificity and thus cannot be established in humans.

Classification

Oncogenic products are highly biologically active substances, and this gives reason to consider whether the project should be carried out in a higher laboratory class than Class 1. However, as virus particles cannot be developed, the project can be carried out in Laboratory Class 1.

2.3. Examples of Laboratory Class 2 projects

Title 3: Raising antibodies against tuberculosis antigens.
Host: E. coli K12.
Donor: Mycobacterium tuberculosis.
Vector: pBR322.
Insert: Genes for M. tuberculosis antigens.

Risk assessment

Host: E. coli K12 is a well-known laboratory strain that has been shown by experience to be apathogenic, one of the reasons being the inability to colonise.

Donor: Mycobacterium tuberculosis is a Risk Class 3 organism, cf. the Executive Order on Biological Agents.

Vector: The vector is non-conjugable and contains antibiotic resistance to Ampicillin and Tetracycline. However, these are not transposable.

Insert: The transferred genes for M. tuberculosis antigens are not well-characterised as cloning is done using the shotgun method. Therefore, pathogenic properties may be imposed on the host.

Health aspects of the final GMO: Since the vector is non-conjugable, the genes will not have the ability to transfer to intestinal bacteria. However, there is a risk that some of the coli clones have acquired pathogenic properties.

Classification

The project cannot be carried out in Class 1, as there is uncertainty about the risks associated with the cloned genes. It is estimated that the final GMOs will not be as pathogenic as the donor organism. Therefore, the project can be carried out in Class 2 as a minimum.

One can consider downgrading to Laboratory Class 1 when individual clones are well-characterised with respect to the potentially adverse effect of the transferred gene and its product.

Title 4: Production of the neurotransmitter somatostatin using adenoviral vectors.
Host: 293 cell line as a replication cell line and a hamster cell line.
Donor: cDNA library from Homo sapiens.
Vector: Adenoviral vector, derived from Adenovirus type 5. The vector is deleted in the E1a and E1b regions relative to the wild-type Adenovirus genome.
Insert: The neurotransmitter somatostatin. The gene is expressed under the control of the CMV promoter.

The vector with the inserted gene is introduced into the 293 cell line, whereby recombinant adenovirus is generated and amplified. Recombinant adenovirus is used to transduce hamster cells in vitro.

Risk assessment

Host: The hamster cell line is a cell culture from a higher eukaryote. The 293 cell line is a human cell line that contains 14 percent of the adenovirus genome, including the E1 region.

Donor: The donor material is from a human cDNA library. The donor material therefore does not in itself present any risk.

Vector: The vector originates from adenovirus, which is a Risk Class 2 organism, cf. the Executive Order on Biological Agents.  It causes influenza in humans. The CMV promoter is a medium-strength promoter.

Insert: The cloned gene is a highly biologically active substance with the ability to exert an effect on the pituitary gland.

Health aspects of the final GMO: It cannot be ruled out that replication-competent viruses with broad host specificity can be formed, incl. human cells by recombination in the replication cell line.

Classification

The project must be carried out in Class 2 as a minimum, because replication-competent viruses with human specificity can be generated, and because it is a highly biologically active substance that can exert a local effect on pituitary cells, and which is expressed under the control of a medium-strength promoter.

2.4. Examples of Laboratory Class 3 project

Title 5: Expression in eukaryotic cells of gene encoding Fibroblast Growth Factor-like factor (FGF-like factor).
Host: Hamster cell line and Murine amphitropic package cell line.
Donor: cDNA library from Homo sapiens.
Vector: Retroviral vector, derived from murine leukaemia virus. The vector contains less than two-thirds of the retroviral genome and is replication-deficient. Contains the neomycin resistance gene.
Insert: FGF-like growth factor. The gene is expressed under the control of LTR19; s (Long Terminal Repeat) enhancer/promoter.

The vector with the inserted gene is introduced into the package cell line, resulting in the formation of retrovirus particles with broad host specificity. The harvested virus is used to infect hamster cells in vitro.

Risk assessment

Host: The hosts are cell cultures from higher eukaryotes. The murine package cell line contains the genes necessary for the formation of retroviral particles from the vector.

Donor: The donor material is from a human cDNA library. The donor material thus does not in itself pose a risk.

Vector: Murine retrovirus virus can infect mice, rats, and hamsters, but not humans, and it cannot transform human cells in vitro. Neomycin resistance in eukaryotic cells can be selected with G418.

Insert: The cloned gene encodes a highly biologically active substance which, at a physiological concentration of a few pg/ml, has the ability to exert an effect on cells. The cloned gene is expressed under the control of the LTR promoter, i.e. under non-physiological conditions.

Health aspects of the final GMO: It cannot be ruled out that, by recombination in the package cell line, replication-competent viruses with broad host specificity can be formed, incl. human cells.

Classification

The project must be carried out in a Laboratory Class 2 as a minimum because replication-competent viruses with broad host specificity can be generated. In addition, as it is a highly biologically active substance which exerts an external effect on cells at an exceptionally low concentration and which is expressed under the control of a medium-strength promoter, the project must be carried out in Laboratory Class 3 as a minimum.

3. Integrating the Risk Assessment into the Company's Workplace Assessment

Companies that have a duty to prepare a workplace assessment can choose to integrate the risk assessment into the company's workplace assessment instead of both carrying out a risk assessment in accordance with the Executive Order and preparing a workplace assessment. It is a prerequisite that all elements from both the risk assessment and the workplace assessment are included in the integrated assessment.

This way, the company can make an overall identification of all risks to human safety and health as well as to the external environment. It must be assumed that the risk assessment will largely meet the requirements for workplace assessment, and it can therefore normally replace the workplace assessment for the area in question.

The parts of the overall assessment of the activities that originate from the risk assessment and from the workplace assessment, respectively, can be updated/revised independently of each other. There is no requirement for the risk assessment to be revised every three years as is required for workplace assessments.

4. Glossary

The glossary explains special technical terms as defined in the Danish Working Environment Authority’s guidelines. Not all technical terms are found in the glossary because it is assumed that certain basic terms in microbiology and genetic engineering are known.

Allergenicity: The ability to induce a hypersensitivity reaction.

Amphotropic (polytropic) virus: Virus that can infect many (all) species by binding to several different receptors on the host cells. Viruses can thus cross species barriers.

Asporogenic: Not spore-forming.

Biological system: All biological materials used, i.e. all cells, tissue, organisms, viruses, and plasmids used as donor, host, vector, or genetically engineered organisms.

Colonisation ability: The ability to establish and reproduce in a host without necessarily invading or destroying tissue.

Communicability: Transfer mechanism between hosts.

Conjugation: The transfer of DNA from one bacterium to another through pili.

Differentiation: Modification of cell function and morphology from stem cell to specialised cell.

Donor: The organism, cell, or cell material from which the genetic material used originates.

Ectotrophic virus: A virus that can infect only a single species (e.g. mice) by binding to species-specific receptors. Thus, the virus cannot cross species barriers – it is host-specific.

Genetic engineering activities: Use of genetic engineering techniques or use, handling and storage of genetically engineered cells, organisms or viruses and tissue of such organisms.

Habitat: Habitat of an organism, e.g. soil or human intestine.

Highly biologically active substances: Substances that have signal function in the human organism, e.g. hormones and lymphokines.

Host: The cell or organism into which the genetic material is introduced. When using cell hybridisation techniques where there is no meaningful distinction between donor and host, the cell types used must all be perceived as hosts.

Host range: The breadth of organisms that can act as hosts.

Host specificity: The specific organisms that can act as hosts.

Indigenous (endogenous) vectors: Vectors originating from inside the cell.

Insert: Material inserted into the vector, gene or other.

Invasiveness: The ability to penetrate tissue barriers.

Non-permissive conditions: Conditions that do not allow optimal cell growth and division of the culture.

Oncogenes: Genes that can transform cells in vitro.

Pathogen: Disease-causing.

Pathological: Pathological.

Prophylaxis:Disease prevention.

Proto-oncogenes: Normal cell genes related to oncogenes.

Secernate: Excrete:

Transformation: Cell change.

Transmission capability: The transferability of the pathogenic organism.

Vector: The biological material that can be used to introduce genetic material (insert) into a host.

Virulence: Degree of pathogenic ability (pathogenicity) and ability to colonise the host.

Xenotropic virus: Viruses that can infect many species, except the species in which they are formed, by binding to specific receptors. This means that they can infect many species other than the one in which they originated.