Guidance on Risk Assessment of Living Modified Organisms

PART I: ROADMAP FOR RISK ASSESSMENT OF LIVING MODIFIED ORGANISMS

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Background

This “Roadmap” provides guidance on assessing environmental risks of living modified organisms (LMOs), ¹ taking into account risks to human health, consistent with the Cartagena Protocol on Biosafety (hereinafter “the Protocol”) and in particular with its Article 15 and Annex III. ² Accordingly, this Roadmap supplements Annex III and may also supplement national biosafety policies and legislations. Specifically, the Roadmap is intended to facilitate and enhance the effective use of Annex III by elaborating on the steps and points to consider in environmental risk assessment and by pointing users to relevant background materials. The Roadmap may be useful as a reference for risk assessors when conducting or reviewing risk assessments and as a training tool in capacity-building activities.

This Roadmap provides information that is broadly relevant to the risk assessment of all types of LMOs and their intended uses within the scope and objective of the Protocol. However, it has been developed based largely on living modified (LM) crop plants because the experience to date with environmental risk assessments of LMOs has been mainly gained from these organisms. ³

The Roadmap may be applied to all types of environmental releases of LMOs, including those of limited duration and scale as well as large-scale releases. Nevertheless, the amount and type of information available and needed to support risk assessments of the different types of intentional release into the environment may vary from case to case.

Introduction

According to the Protocol, risk assessment of LMOs is a structured process conducted in a scientifically sound and transparent manner, and on a case-by-case basis in relation to the likely potential receiving environment. Its purpose is to identify and evaluate the potential adverse effects of LMOs, and their likelihood and consequences as well as to make a recommendation as to whether or not the estimated overall risk is acceptable or manageable, taking into consideration any relevant uncertainty. Risk assessments serve as an input for decision-making regarding LMOs. This Roadmap describes an integrated risk assessment process in three sub-sections: “Overarching Issues in the Risk Assessment Process”, “Planning Phase of the Risk Assessment”, and “Conducting the Risk Assessment”.

The potential effects caused by an LMO may vary depending on the characteristics of the LMO, on how the LMO is used, and on the environment exposed to the LMO. The effects may be intended or unintended, and may be considered beneficial, neutral or adverse depending on the impact on a protection goal.

What is considered an adverse effect as well as an “acceptable risk” depends on protection goals and their assessment endpoints. The choice of protection goals may be informed by the Party`s national policies and legislation as well as Annex I to the Convention on Biological Diversity as relevant to the Party responsible for conducting the risk assessment.

The Roadmap includes five steps drawn from Annex III that describe a tiered process in which the results of one step are relevant to the other steps. Importantly, the steps of a risk assessment may need to be conducted in an iterative manner, where certain steps may be revisited when new information arises or a change in circumstances has occurred that could change its conclusions. Similarly, issues included in the ‘Establishing the context and scope’ section below may be taken into consideration while conducting the risk assessment and again at the end of the risk assessment process to determine whether the objectives and criteria set out at the beginning of the risk assessment have been addressed.

Ultimately, the concluding recommendations derived from the risk assessment are taken into account in the decision-making process for an LMO. In the decision-making process, in accordance with the country’s policies and protection goals, other Articles of the Protocol or other relevant issues may also be taken into account and are listed in the last paragraph of this Roadmap: ‘Related Issues’.

The risk assessment process according to this Roadmap is illustrated in the Annex.

Section References:

Overarching Issues in the Risk Assessment Process

This section gives guidance on issues that are relevant to all the steps of the risk assessment. It focuses on provisions related to the quality and relevance of information to be considered in the risk assessment, as well as the means to identify and describe uncertainties that may arise.

Quality and relevance of information

An important question in a risk assessment is whether the information presented is of sufficient quality and relevance to characterize the risk posed by the LMO.

A number of issues are typically considered to ensure the quality and relevance of the information used as well as the outcome of the risk assessment. For example:

• Criteria for the quality of scientific information:
  • Information, including raw data, of acceptable scientific quality should be used in the risk assessment. Data quality should be consistent with the accepted practices of scientific evidence-gathering and reporting and may include independent review of the methods and designs of studies;

  • Appropriate statistical methods should be used where appropriate, to strengthen the scientific conclusions of a risk assessment and be described in the risk assessment report. Risk assessments frequently use data generated from multiple scientific fields;

  • Reporting of data and methods should be sufficiently detailed and transparent to allow independent verification and reproduction. This would include ensuring the accessibility of data used by the risk assessors (e.g., the availability of relevant data or information and, if requested and as appropriate, sample material), taking into account the provisions of Article 21 of the Protocol on the confidentiality of information.

• The relevance of information for the risk assessment:
  • Information, including data, may be considered relevant if they are linked to protection goals or assessment endpoints, contribute to the identification and evaluation of potential adverse effects of the LMO, or if they can affect the outcome of the risk assessment or the decision;

  • Relevant information may be derived from a variety of sources such as new experimental data, data from relevant peer reviewed scientific literature, as well as data, experience and outcomes from previous risk assessments if regarded as of acceptable scientific quality, in particular for the same or similar LMOs introduced in similar receiving environments; ⁴

  • Information from national and international standards and guidelines may be used in the risk assessment, as well as knowledge and experience of, for example, farmers, growers, scientists, regulatory officials, and indigenous and local communities depending on the type of LMO, its intended use and the likely potential receiving environment;

  • The information that is relevant to perform a risk assessment will vary from case to case depending on the nature of the modification of the LMO, on its intended use, and on the scale and duration of the environmental introduction. In cases of environmental releases whose objective is to generate information for further risk assessments and where exposure of the environment to the LMO is limited, such as for some early-stage experimental releases and trials, less information may be available or required when performing the risk assessment. The uncertainty resulting from the limited information available in such cases may be addressed by risk management and monitoring measures.
• Additional considerations with regard to scientific information:
  • The process of risk assessment may give rise to the need for further relevant information about specific subjects, which may be identified and requested during the assessment process;

  • Whether independent experts with the relevant background in the different scientific disciplines are available to conduct risk assessments or to provide input into the risk assessment process.

Identification and consideration of uncertainty

Uncertainty is an inherent and integral element of scientific analysis and risk assessment. According to the Protocol, “where there is uncertainty regarding the level of risk, it may be addressed by requesting further information on the specific issues of concern or by implementing appropriate risk management strategies or monitoring the living modified organism in the receiving environment” ⁵. Whether and to what extent there is scientific uncertainty is therefore critical in the context of risk assessment. There is no internationally agreed definition of “scientific uncertainty”, nor are there internationally agreed general rules or guidelines to determine its occurrence. The issue of uncertainty is dealt with – sometimes differently – in each international instrument incorporating precautionary measures ⁶.

Considerations of uncertainty strengthen the scientific validity of a risk assessment. These include considerations of its source and nature, and focuses on uncertainties that can have a significant impact on the conclusions of the risk assessment.

For each identified uncertainty, the nature of the uncertainty may be described as arising from: (i) lack of information, (ii) incomplete knowledge, and (iii) biological or experimental variability, for example, due to inherent heterogeneity in the population being studied or to variations in the analytical assays. Uncertainty resulting from lack of information includes, for example, information that is missing and data that is imprecise or inaccurate (e.g., due to study designs, model systems and analytical methods used to generate, evaluate and analyze the information).

In some cases more information will not necessarily contribute to a better understanding of potential adverse effects, therefore risk assessors should look to ensure that any further information requested will contribute to better evaluations of the risk(s). Although uncertainties originating from lack of information may be reduced by further research, uncertainties arising from incomplete knowledge or from inherent variability may be irreducible. In such cases, instead of reducing uncertainty, the provision of additional information may actually give rise to new uncertainties.

The various forms of uncertainty are considered and described in each step of the risk assessment. In addition, when communicating the results of a risk assessment, it is important to describe, quantitatively or qualitatively, what impact uncertainty may have on the estimated level of risk and on the conclusions and recommendations of the risk assessment.

In cases where the nature of the uncertainty implies that it cannot be addressed through the provision of more data during the risk assessment, where necessary, it may be dealt with by risk management and/or monitoring in accordance with paragraphs 8(e) and 8(f) of Annex III to the Protocol (see step 5 and Part III).

Section References:

Planning Phase of the Risk Assessment

Establishing the context and scope

Risk assessments are carried out on a case-by-case basis in relation to the LMO, its intended use and the likely potential receiving environment. Each risk assessment starts by establishing its context and scope in a way that is consistent with the country’s protection goals, assessment endpoints, risk thresholds, risk management strategies and policies.

Establishing the context and scope for a risk assessment, in line with the country’s policies and regulations, may involve an information-sharing and consultation process with risk assessors, decision-makers and various stakeholders prior to conducting the actual risk assessment, to identify protection goals, assessment endpoints and risk thresholds relevant to the assessment. It may also involve identifying questions to be asked that are relevant to the case being considered. The risk assessors should, at the outset of the process, have knowledge of national requirements for risk assessment and criteria for acceptability of risks. They may also use questions or checklists designed for the case under consideration to assist in the subsequent steps.

Several points may be taken into consideration, as appropriate, that are specific to the Party involved ⁷ and to the particular risk assessment. These include:

• Existing environmental and health policies and strategies based on, for instance:
  1. Regulations and international obligations of the Party involved;
  2. Guidelines or regulatory frameworks that the Party has adopted; and
  3. Protection goals, assessment endpoints, risk thresholds and management strategies as laid down, for instance, in relevant legislation of the Party;

• Intended handling and use of the LMO, including practices related to the use of the LMO, taking into account user practices and habits;

• The nature and level of detail of the information that is needed (see above), which may, among other things, depend on the biology/ecology of the recipient organism, the intended use of the LMO and its likely potential receiving environment, and the scale and duration of the environmental exposure (e.g., whether it is for import only, field testing or for commercial use). For small-scale releases, especially at early experimental stages or in the early steps of environmental releases of LMOs that are conducted in a step-wise manner, the nature and detail of the information that is required or available may differ compared to the information required or available for large scale or commercial environmental release;

• Identification of methodological and analytical requirements, including requirements for review mechanisms, that must be met to achieve the objective of the risk assessment as specified, for instance, in guidelines published or adopted by the Party that is responsible for conducting the risk assessment (i.e., typically the Party of import according to the Protocol);

• Experience and history of use of the non-modified recipient organism, taking into account its ecological function.

• Approaches for describing potential adverse effects of the LMO and terms used for describing the likelihood (step 2), the magnitude of consequences (step 3) and risks (step 4), and the acceptability or manageability of risks (step 5).

Some risk assessment frameworks combine the process of establishing the context and scope of the risk assessment with the identification of potential adverse effects associated with the modifications of the LMO into a single step called “Problem formulation” (see step 1).

Section References:

The choice of comparators

Risks associated with an LMO should be considered in the context of the risks posed by the non-modified recipients or parental organisms in the likely potential receiving environment ⁸.

A comparative approach aims at identifying changes between an LMO and its comparator(s) that may lead to adverse effects. The choice of comparators can have large effects on the relevance, interpretation and conclusions drawn from the risk assessment process. Therefore, the one or more comparators that are chosen should be selected on the basis of their capacity to generate information that is consistent and relevant for the risk assessment.

To account for variation due to interaction with the environment, the LMO and its comparator(s) should ideally be evaluated at the same time and location, and under the same environmental conditions.

Choosing the appropriate comparator(s) may, in some cases, be difficult or challenging.

Some risk assessment approaches use a non-modified genotype with a genetic background as close as possible to the LMO being assessed, e.g., a (near-)isogenic line as the primary choice of comparator. In such risk assessment frameworks where the use of a (near-)isogenic non-modified recipient organism as the comparator is required, additional comparators may prove useful depending on the biology of the organism and types of modified traits under assessment. In practice, the (near-)isogenic non-modified organism is used in step 1 and throughout the risk assessment. When the likelihood and potential consequences of adverse effects are evaluated, broader knowledge and experience with additional comparators such as defined non-modified reference lines may also be taken into consideration, as appropriate, along with the non-modified recipient organism. Results from experimental field trials or other environmental information and experience with the same or similar LMOs in the same or similar receiving environments may also be taken into account. In other risk assessment approaches, the choice of an appropriate comparator will depend on the specific LMO being considered, the step in the risk assessment and on the questions that are being asked.

In some cases, the non-modified recipient organisms or the parental organisms alone may not be sufficient to establish an adequate basis for a comparative assessment. In such cases, additional approaches and/or comparators may be necessary (for concrete examples and more guidance, please refer to Part II of this Guidance).

Section References:

Conducting the Risk Assessment

To fulfil the objective under Annex III of the Protocol, as well as provisions under other relevant articles, a risk assessment is conducted in steps, in an integrated process and in an iterative manner, as appropriate. Paragraph 8 of Annex III describes the key steps of the risk assessment process. Paragraph 9 of Annex III lists and describes points to consider in the process for risk assessment of LMOs depending on the particular case.

The steps of risk assessment under the Protocol are similar to those used in other risk assessment frameworks. Although the terminology may differ between the various approaches, in general terms, risk assessment is defined as a science-based process that includes at least the following common components (corresponding to the steps 1 to 4 respectively): “hazard identification”, “exposure assessment”, “hazard characterization”, and “risk characterization”

In this section, the steps indicated in paragraph 8(a)-(e) of Annex III are described in further detail and points to consider are provided for each step. Some points to consider are taken from paragraph 9 of Annex III. Additional points to consider were added on the basis of commonly used methodologies of LMO risk assessment and risk management insofar as they were in line with the principles of Annex III. The relevance of each point to consider will depend on the case being assessed. The guidance provided below on the steps in risk assessment is not exhaustive, thus additional guidance and points to consider may be relevant, as appropriate. Lists of background documents relevant to each section are provided through the links.

Section References:

STEP 1: “An identification of any novel genotypic and phenotypic characteristics associated with the living modified organism that may have adverse effects on biological diversity in the likely potential receiving environment, taking also into account risks to human health.” ⁹

Rationale:

The purpose of this step is to identify changes in the LMO, resulting from the use of modern biotechnology, that could cause adverse effects on the conservation and sustainable use of biological diversity, taking also into account risks to human health. The potential adverse effects may be direct or indirect, immediate or delayed ¹⁰.

The question that risk assessors ask in this step is what adverse effects could occur, why and how. This step is very important in the risk assessment process as the questions raised will determine what risk scenarios are considered in all subsequent steps. This step may also be referred to as “hazard identification” – the difference between the concepts of “hazard” and “risk” is important and must be understood by the risk assessor. In many cases, this step is performed as part of a problem formulation process when establishing the context and scope of the risk assessment. In that case, this step is not limited to the identification of hazards, but also takes into account protection goals and appropriate assessment endpoints. Whether step 1 and “establishing the context and scope” are done in parallel or in sequence, together these actions are among the most important in a risk assessment as they form the basis for the subsequent steps.

In this step, risk assessors identify scientifically plausible scenarios and risk hypotheses to predict if the LMO could have an adverse effect on the assessment endpoints. In doing so, risk assessors analyse what novel characteristics of the LMO, as well as its transfer, handling and use, could give rise to adverse effects in an interaction with the likely potential receiving environment. For example, if the protection goal is maintenance of biodiversity, a risk hypothesis could assess what novel characteristics of the LMO might affect specific “targets” such as a component of the food web or the population size of certain species in the likely potential receiving environment. The targets are called assessment endpoints, and their unambiguous specification is crucial to focus the risk assessment.

It is important to define a causal link or pathway between a characteristic of the LMO and a possible adverse effect, otherwise the risk assessment may generate information that will not be useful for decision-making (see also steps 2 and 3). Depending on the LMO, its intended use and the likely potential receiving environment, possible changes that could lead to adverse effects may include, but are not limited to, the potential of the LMO to: (i) affect non-target organisms, (ii) cause unintended effects on target organisms, (iii) become persistent or invasive or develop a fitness advantage in ecosystems with limited or no management, (iv) transfer genes to other organisms/populations, and (v) become genotypically or phenotypically unstable.

In this step, a comparison of the LMO should be considered in the context of the non-modified recipient or parental organisms in the likely potential receiving environment, taking into consideration the new trait(s) of the LMO (see ‘The choice of comparators’ in the chapter entitled ‘Planning Phase of the Risk Assessment’).

The novel characteristics of the LMO to be considered can be described in genotypic and phenotypic terms. These include any changes in the LMO, ranging from the nucleic acid (including any deletions), to gene expression level to morphological changes.

The LMO may cause adverse effects which may be direct or indirect, immediate or delayed, combinatorial or cumulative, as well as predicted or unpredicted. For example, an adverse effect may also be caused by changes in the expression levels of endogenous genes as a result of the genetic modification or by combinatorial effects of two or more genes, gene products or physiological pathways.

Points to consider regarding characterization of the LMO:

1. Relevant characteristics of the non-modified recipient organism, such as:
   1. its biological characteristics, in particular those that, if changed or resulting in an interaction with the new gene products or traits of the LMO, could lead to changes that may cause adverse effects;
   2. its taxonomic relationships;
   3. its origin, centres of origin and centres of genetic diversity;
   4. ecological function; and
   5. whether it is a component of biological diversity that is important for the conservation and sustainable use of biological diversity in the context of Article 7(a) and Annex I of the Convention;

2. Characteristics related to the transformation method, including the characteristics of the vector such as its identity, source or origin and host range, and information on whether the transformation method results in the presence of (parts of) the vector in the LMO, including any marker genes;

3. Relevant characteristics of the genes and of other functional sequences, such as promoters, that have been inserted into the LMO (e.g., functions of the gene and its gene product in the donor organism with particular attention to characteristics in the recipient organism that could cause adverse effects);

4. Molecular characteristics of the LMO related to the modification, such as characteristics of the modified genetic elements; insertion site(s) and copy number of the inserts; stability, integrity and genomic organization in the recipient organism; specificity of the genetic elements (e.g., transcription factors); levels of gene expression and intended and unintended gene products;

5. Genotypic (see point (d) above) and phenotypic changes in the LMO, either intended or unintended, in comparison with the non-modified recipient, considering those changes that could cause adverse effects. These may include changes in native/endogenous gene expression and regulation at the transcriptional, translational and post-translational levels.

Points to consider regarding the intended use and the likely potential receiving environment:

6. Protection goals and assessment endpoints relevant to the likely potential receiving environment (see “Planning phase of the risk assessment”, “Establishing the context and scope”);

7. Availability of sufficient data to establish a meaningful baseline for the likely receiving environment which will serve as a basis for the risk assessment;

8. The intended spatial scale, duration and level of confinement (such as biological confinement) of the environmental release, taking into account user practices and habits;

9. Characteristics of the likely potential receiving environment including relevant ecosystem functions and services, in particular its attributes that are relevant to potential interactions of the LMO that could lead to adverse effects (see also paragraph (k) below) ¹¹, taking into account the characteristics of the components of biological diversity, particularly in centres of origin and centres of genetic diversity;

10. Potential adverse effects concerning target organisms such as pests developing resistance to the target trait and weeds developing resistance to the herbicide.

Points to consider regarding the potential adverse effects resulting from the interaction between the LMO and the likely potential receiving environment:

11. Characteristics of the LMO in relation to the likely potential receiving environment (e.g., information on phenotypic traits that are relevant for its survival, or its potential adverse effects – see also paragraph (e) above);

12. Considerations for unmanaged and managed ecosystems, concerning the use of an LMO, that are relevant for the likely potential receiving environment. These include potential adverse effects resulting from the use of an LMO, such as changes in farm management practices; dispersal of the LMO through mechanisms such as seed dispersal or outcrossing within or between species, or through transfer into habitats where the LMO may persist or proliferate; as well as effects on species distribution, food webs and changes in bio-geochemical characteristics;

13. Potential for outcrossing and transfer of transgenes, via vertical gene transfer, from an LMO to other sexually compatible species that could lead to introgression of the transgene(s) into populations of sexually compatible species, and whether these would lead to adverse effects;

14. Whether horizontal gene transfer of transgenic sequences from the LMO to other organisms in the likely potential receiving environment could occur and whether this would result in potential adverse effects. With regard to horizontal gene transfer to micro-organisms (including viruses), particular attention may be given to cases where the LMO is also a micro-organism;

15. Potential adverse effects on non-target organisms such as toxicity, allergenicity and multi-trophic effects which can affect the survival, development, or behaviour of these organisms;

16. Potential adverse effects of the incidental exposure of humans to (parts of) the LMO (e.g., exposure to modified gene products in pollen), and the toxic or allergenic effects that may ensue taking into account the agricultural practices that may be used with the LMO, such as type of irrigation, number and amount of herbicide applications, methods for harvesting and waste disposal, etc;

17. Cumulative effects with any other LMO present in the environment.

Section References:

STEP 2: “An evaluation of the likelihood of adverse effects being realized, taking into account the level and kind of exposure of the likely potential receiving environment to the living modified organism.”

Rationale:

To determine and characterize the overall risk of an LMO (step 4), risk assessors evaluate the likelihood that each of the potential adverse effects identified in step 1 will occur. The evaluation of likelihood may be undertaken at the same time as the evaluation of the consequences should the adverse effects be realized (step 3) or in an inverse order.

This step may be referred to as “exposure assessment” where plausible pathways of a hazard leading to adverse effects are identified. It aims to determine whether the receiving environment will be exposed to an LMO that has the potential to cause adverse effects, taking into consideration the intended transfer, handling and use of the LMO, and the expression level, dose and environmental fate of transgene products.

For each of the risk hypotheses or scenarios identified in step 1, the route of exposure to the LMO being assessed (or its products) should be determined. Furthermore, when possible the causal link between the LMO and the potential adverse effect should be established. This can be achieved by building conceptual models describing relationships between the LMO, pathways of exposure and potential adverse effects in the environment, taking also into account risks to human health. For example, for an LMO producing a potentially toxic gene product, oral, respiratory or dermal exposure pathways could be relevant.

Experimental studies and models may be used for an assessment of the potential level and type of exposure, combined with the use of statistical tools relevant for each case. Past experience with similar situations (e.g., same recipient organism, LMO, trait, receiving environment, etc), if available, may also be used in assessing the level and type of exposure, taking into account user practices and habits.

In some circumstances, particularly when there is a high level of uncertainty in assessing the likelihood, it may be difficult to assess the likelihood of adverse effects being realized. In such cases, it may be useful to assign a likelihood of 100% that an adverse effect will occur and concentrating on the evaluation of its consequences.

Likelihood may be expressed quantitatively or qualitatively. For example, qualitative terms could include ‘highly likely’, ‘likely’, ‘unlikely’, and ‘highly unlikely’. Parties may consider describing these terms and their uses in risk assessment guidelines published or adopted by them.

Points to consider:

1. The relevant characteristics of the likely potential receiving environment that may be a factor in the occurrence of the potential adverse effects (see also step 1 (f), (g) and (i)), taking into account the variability of the environmental conditions and long-term adverse effects related to the exposure to the LMO;

2. Levels of expression in the LMO and persistence and accumulation in the environment (e.g., in the food chain) of substances with potentially adverse effects newly produced by the LMO, such as toxins, allergens and some insecticidal proteins. In the case of field trials, the level of persistence and accumulation in the receiving environment may be low depending on the scale and temporary nature of the release, and the implementation of management measures;

3. Information on the location of the release and the receiving environment (such as geographic and biogeographic information, including, as appropriate, geographic coordinates);

4. Factors that may affect spread of the LMO, such as its ecological range and ability to move; its reproductive ability (e.g., numbers of offspring, time to set seed, abundance of seed and vegetative propagules, dormancy, pollen viability); and its ability to spread using natural means (e.g., wind, water) or anthropogenic mechanisms (e.g., rearing or cultivation practices, seed saving and exchange, etc);

5. Factors that affect presence or persistence of the LMO that may lead to its establishment in the environment, such as, in the case of LM plants, lifespan, seed dormancy, ability of LM seedlings to establish among existing wild or cultivated vegetation and to reach reproductive stage, or the ability to propagate vegetatively;

6. When assessing the likelihood of outcrossing from the LMO to sexually compatible species, the following issues are relevant:
   1. the biology of the sexually compatible species;
   2. the potential environment where the sexually compatible species may be located;
   3. Persistence of the LMO in the environment;
   4. Introgression of the transgene into the sexually compatible species;

7. Persistence of the transgene in the ecosystem; and

8. Expected type and level of exposure in the environment where the LMO is released, and mechanisms by which incidental exposure could occur at that location or elsewhere (e.g., gene flow, incidental exposure due to losses during transport and handling, intentional spread by people, or unintentional spread by people via machinery, mixed produce or other means).

Section References:

STEP 3: “An evaluation of the consequences should these adverse effects be realized.”

Rationale: This step, which may also be referred to as “hazard characterization”, describes an evaluation of the magnitude of the consequences of the possible adverse effects, based on the risk scenarios established in step 1, paying special attention to protected areas and centres of origin and centres of genetic diversity, and taking into account protection goals and endpoints of the country where the environmental release may take place. As discussed in the previous step, the evaluation of consequences of adverse effects may be undertaken at the same time as the evaluation of likelihood (step 2) or in an inverse order.

In this step, results of tests conducted under different conditions, such as laboratory experiments or experimental releases, may be considered. The scale and duration of the intended use (e.g., small or large) may influence the severity of potential consequences and should therefore be taken into account.

The evaluation of consequences of adverse effects should be considered in the context of the adverse effects caused by the non-modified recipients or parental organisms in the likely potential receiving environment (see Planning Phase of the Risk Assessment). The evaluation of consequences may also consider the adverse effects associated with the existing practices or with practices that will be introduced along with the LMO (such as various agronomic practices, for example, for pest or weed management).

It is important to also assess in this step the duration of the potential adverse effect (i.e., short or long term), the scale (i.e., are implications local, national or regional), the mechanisms of effect (direct or indirect), the reversibility (or lack thereof) of effects, and the expected ecological scale (i.e., individual organisms – for example of a protected species – or populations).

The evaluation of the consequence of adverse effects may be expressed qualitatively or quantitatively. For instance, qualitative terms such as ‘major’, ‘intermediate’, ‘minor’ or ‘marginal’ may be used. Parties may consider describing these terms and their uses in risk assessment guidelines published or adopted by them.

Points to consider:

1. Relevant knowledge and experience with the non-modified recipient or parental organisms, or current use of the organism, in the likely potential receiving environment, and their interactions with other species, including sexually compatible species. This may include the effects of:
   1. agricultural practices on the level of inter- and intra-species gene flow; dissemination of the recipient organism; abundance of volunteers in crop rotation; change in abundance of pests, beneficial organisms such as pollinators, decomposers, organisms involved in biological control or soil microorganisms involved in nutrient cycling;
   2. pest management affecting non-target organisms through pesticide applications or other management approaches while following accepted agronomic practices;
   3. the behaviour of populations of other species, including interactions between predators and prey, their role in food webs and other ecological functions, disease transmission, allergies and interaction with humans or other species;

2. Consequences resulting from combinatorial and cumulative effects in the likely potential receiving environment;¹²

3. Relevant knowledge and experience with the LMO in similar receiving environments;

4. Results from laboratory experiments examining, as appropriate, dose-response relationships or particular effect levels (e.g., EC50, LD50, NOEL) for acute, chronic or sub-chronic effects including immunogenic effects;

5. Results from field trials evaluating, for instance, potential invasiveness; and

6. Possible consequences of transgene introgression resulting from outcrossing/interbreeding to sexually compatible species.

Section References:

STEP 4: “An estimation of the overall risk posed by the living modified organism based on the evaluation of the likelihood and consequences of the identified adverse effects being realized.”

Rationale:

The purpose of this step, which may also be referred to as “risk characterization”, is to determine and characterize the overall risk of the LMO. This can be achieved by characterising and analysing individual risks on the basis of an analysis of the potential adverse effects completed in step 1, their likelihood (step 2) and consequences (step 3), and combining them into an estimation of the overall risk, taking into consideration any relevant uncertainty that was identified in each of the preceding steps and how it could affect the estimation of the overall risk of the LMO (see “Identification and consideration of uncertainty” under “Overarching issues in the risk assessment process” above).

To date, there is no universally accepted approach for estimating the overall risk but rather a number of approaches are available for this purpose. For example, the characterization of the overall risk often derives a best estimate of risk from multiple lines of evidence. These lines of evidence may be quantitatively or qualitatively weighted and combined. Risk matrixes, risk indices or models may be used for this purpose ¹³.

A description of the risk characterization may be expressed qualitatively or quantitatively. Qualitative terms such as ‘high’, ‘medium’, ‘low’, ‘negligible’ or ‘indeterminate’ (e.g., due to uncertainty or lack of knowledge) have been used to characterize the overall risk of an LMO. Parties could consider describing these terms and their uses in risk assessment guidelines published or adopted by them.

The outcome of this step should include a description explaining how the estimation of the overall risk was performed.

Points to consider:

1. The identified potential adverse effects (step 1);

2. The assessments of likelihood (step 2);

3. The evaluation of the consequences should the adverse effects be realized (step 3);

4. Individual risks and any interaction among them, such as synergism or antagonism;

5. Any risk management strategies (see step 5) that may affect risk estimates if implemented;

6. Broader ecosystem and landscape considerations, including cumulative effects due to the presence of various LMOs in the receiving environment.

Section References:

STEP 5: “A recommendation as to whether or not the risks are acceptable or manageable, including, where necessary, identification of strategies to manage these risks”

Rationale:

In step 5, risk assessors prepare a report summarizing the risk assessment process, identified individual risks and the estimated overall risk, and provide recommendation(s) as to whether or not the risks are acceptable or manageable and, if needed, recommendation(s) for risk management options that could be implemented to manage the risks associated with the LMO. The recommendation is made in the context of criteria for the acceptability of risk that were identified in the planning phase of the risk assessment, taking into account established protection goals, assessment endpoints and risk thresholds, as well as risks posed by the non-modified recipient organism and its use.

This step is an interface between the process of risk assessment and the process of decision-making. Importantly, while the risk assessor provides a recommendation as to whether or not the risks are acceptable or manageable, the ultimate decision about whether or not to approve the LMO notification is a prerogative of the decision maker. Moreover, the “acceptability” of risks is typically decided at a policy level and may vary from country to country.

In evaluating the acceptability of the overall risk of the LMO, it is important to consider whether risk management options can be identified that could address identified individual risks and the estimated overall risk as well as uncertainties. The need, feasibility and efficacy of the management options, including the capacity to enact them, should be considered on a case-by-case basis. If such measures are identified, the preceding steps of the risk assessment may need to be revisited in order to evaluate how the application of the proposed risk management measures would change the outcome of the steps.

The recommendation on the acceptability of risk(s) should take into account any available scientific analysis of potential benefits for the environment, biodiversity, and human health (e.g., change in the use of crop protection products, reduction of infections in the case of mosquitoes), and should also take into account risks associated with other existing user practices and habits.

Further, the sources and nature of uncertainty that could not be addressed during the preceding steps of the risk assessment should be described in relation to how they could affect the conclusions of the risk assessment. For assessments where uncertainties could not be addressed, difficulties encountered during the risk assessment should be made transparent to the decision makers. In such cases, it may also be useful to provide an analysis of alternative options to assist the decision makers.

In accordance with Annex III paragraph 8(f) “where there is uncertainty regarding the level of risk, it may be addressed by requesting further information on the specific issues of concern or by implementing appropriate risk management strategies and/or monitoring the living modified organism in the receiving environment”.

Monitoring can be a means to reduce uncertainty, to address assumptions made during the risk assessment, to validate conclusions of the assessment on a wider (e.g., commercial) level of application, and to establish a causal link or pathway between LMOs and adverse effects. Monitoring may also be used to evaluate whether risk management strategies are being implemented effectively, including whether those strategies are able to detect potential adverse effects before the consequences are realized. Monitoring can also be applied as a tool to detect effects that were not anticipated in the risk assessment and long-term adverse effects.

The issues mentioned in the section ‘Establishing the context and scope’ may be taken into consideration again at the end of the risk assessment process to evaluate whether the objectives that were set out at the beginning of the risk assessment have been met.

The recommendation(s) are submitted, typically as part of a risk assessment report, for consideration in the decision-making process.

Points to consider related to the risk management strategies:

1. Existing management practices, if applicable, that are in use for the non-modified recipient organism or for other organisms that require comparable risk management and that might be appropriate for the LMO being assessed (e.g., physical containment, isolation distances to reduce outcrossing potential of the LMO, modifications in herbicide or pesticide management, crop rotation, soil tillage);

2. Methods to detect and identify the LMO, and their specificity, sensitivity and reliability in the context of environmental monitoring (e.g., monitoring for short- and long-term, immediate and delayed effects; specific monitoring on the basis of scientific hypotheses and supposed cause/effect relationship as well as general monitoring), including plans for appropriate contingency measures to be applied if warranted based on monitoring results;

3. Management options and their feasibility in the context of the intended and expected use (e.g., isolation distances to prevent outcrossing, and the use of refuge areas to minimize the development of resistance to insecticidal proteins); and

4. Methods for evaluating the proposed risk management and monitoring strategies for feasibility, efficacy and effectiveness.

Points to consider related to the acceptability of risks:

5. Established criteria and thresholds for determining risk acceptability, including those set out in national legislation or guidelines;

6. Protection goals and assessment endpoints as identified when establishing the context and scope for a risk assessment;

7. Any relevant experience with the non-modified recipient organism(s) or other reference line(s) (including practices associated with their use in the likely potential receiving environment) which were used to establish the baseline for the risk assessment;

8. Scientific benefit analyses, carried out using similar principles of sound science as those used throughout the risk assessment;

9. Ability to identify, evaluate, manage and confine adverse effects in the event that the LMO is released into the environment, as well as to take appropriate response measures.

Section References:

Related Issues

Risk assessment is one input to decision-making regarding LMOs. Other issues that may be part of the decision-making process, as appropriate, and that are mentioned in other articles of the Protocol, include:

• Risk Management (Article 16);
• Capacity-building (Article 22);
• Public Awareness and Participation (Article 23);
• Socio-economic Considerations (Article 26);
• Liability and Redress (Article 27).

A number of other issues, which are not mentioned in the Protocol (e.g., co-existence, ethical issues), may also be taken into account in the decision-making process regarding an LMO in accordance with a country’s policies and regulations.

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Annex: Flowchart for the Risk Assessment Process

Figure 1. The Roadmap for Risk Assessment. The flowchart illustrates the risk assessment process, which includes “Overarching issues”, “Planning phase of the risk assessment” and ”Conducting the risk assessment”, to identify and evaluate the potential adverse effects of LMOs on the conservation and sustainable use of biological diversity in the likely potential receiving environment, taking also into account risks to human health. As results are gathered at each step and new information arises, risk assessments may need to be conducted in an iterative manner, where certain steps may be revisited as shown by the solid and double-headed arrows. The box around steps 2 and 3 shows that these steps may sometimes be considered simultaneously or in reverse order. Dotted arrows indicate the flow to and from issues outside the risk assessment process.

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