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Animal Health Risk Analysis Framework for Biotechnology-Derived Animals

November 2004

INDEX

Acronyms

1. Introduction

The Animal Health Risk Analysis (AHRA) group within the Sciences Branch of the Canadian Food Inspection Agency (CFIA) is responsible for conducting risk analyses and providing scientific information and advice to the Animal Health and Production Division (AHPD) of the CFIA in support of the National Animal Health Program. Risk analysis includes the three interactive processes of risk assessment, risk management and risk communication (Covello et al., 1993).

The Risk Analysis Framework for Biotechnology-Derived Animals is a protocol used by AHRA and the Animal Biotechnology Unit (ABU) of the AHPD to conduct risk analyses from the perspective of animal health. The general design of the document is modelled after the Animal Health and Production Risk Analysis Framework (AHRA, 2004). The protocol describes the processes followed for conducting animal health risk analyses and provides guidelines for risk assessors and managers. The risk management and risk communication are the responsibility of the AHPD for the animal health and ultimately for Environment Canada and Health Canada which have legislative authority. However, when appropriate, all parties participating in the risk assessment should be involved in risk communication. This framework document will focus on the risk assessment process from an animal health perspective.

1.1 SCOPE

"The assessment of risk for many genetically engineered organisms may be dauntingly complex, combining as it does the micro-scale of molecular biology, biochemistry and physiology with the macro-scale complexity of ecology, population genetics, behaviour, biogeography, and evolutionary biology." (Scientist’s Working Group on Biosafety, 1998).

This framework is intended for the assessment of biotechnology-derived animal from the animal health perspective. It is anticipated that the regulated animals will principally include terrestrial mammalian and avian livestock species intended for release outside of research and development facilities. For import commodities (biotechnology-derived), the Animal Health and Production Risk Analysis Framework (AHRA, 2004) may be consulted, which complements this document.

Biotechnology-derived animals in Canada are, currently, almost exclusively produced from research and development activities of academic and commercial establishments. Under CEPA, such animals may be exempted from government regulation that apply to commercial production establishments, provided there is no release of the organism (or animal), its genetic material or toxic material from the organism into the environment. Further development of animal biotechnology research and applications leading to commercial use of biotechnology-derived animals can be expected in the future. It is important for the public to have confidence in regulations which have implications on animal health. To achieve this goal, regulatory assessments should be based on scientific knowledge and assessment procedures must be sensible and practical. Therefore, the need to develop an approach to conduct an animal health risk assessment for biotechnology-derived animal was addressed by AHRA.

The objective of this framework document is to provide guidance to perform risk assessments relating to biotechnology-derived animals. Although other considerations such as human health, environment implications, genetic diversity and sustainability are mentioned, the principal focus of this document is on the risks to animal health posed by the production of cloned, transgenic and other animals derived from biotechnology. Animal welfare considerations are also included in this document, reflecting the involvement of the CFIA in this area (CFIA , 2002; Doonan, 2002), and consistent with recommendations made by non-governmental advisory bodies (United States National Academy of Sciences, 2002).

The risks associated with biotechnology-derived animal must be assessed individually. This is warranted because of the large number of variables involved, these include:

• the species involved,
• the health status of the individuals and herds/ flocks involved,
• the techniques and materials employed in the production of biotechnology-derived animal,
• the transgene used,
• the potential for exposure to the environment (biological and ecological characteristics of the animal),
• the end use of the animal.

1.2 DEFINITION OF "BIOTECHNOLOGY" AND "BIOTECHNOLOGY-DERIVED ANIMALS"

In several Acts and Regulations of Parliament (e.g. Canadian Environmental Protection Act, 1999 (CEPA); the Health of Animal Regulations) biotechnology is defined as: "The application of science and engineering to the direct or indirect use of living organisms or parts or products of living organisms in their natural or modified forms".

The term "biotechnology-derived animals" is an extension of the definition of biotechnology. It refers to animals which have been generated through biotechnological methods. This term may include, but not be limited to, the following categories of animals (Adlakha-Hutcheon, 2001):

• genetically engineered or modified animals in which genetic material has been added, deleted, silenced or altered to influence the expression of genes and traits,
• clones of animals derived by nuclear transfer from embryonic or somatic cells,
• chimeric animals,
• interspecies hybrids,
• animals derived from in vitro cultivation such as maturation or manipulation of embryos.

Appendix 1 (Introduction to the Generation of Biotechnology-Derived Animals) describes some techniques that are used to generate biotechnology-derived animals.

1.3 LEGISLATION

Currently in Canada, biotechnology-derived animals, such as transgenic and other biotechnology-derived livestock animals are regulated under the Canadian Environmental Protection Act, 1999 (CEPA) and its New Substances Notification Regulation (NSNR). CEPA is co-administered by Environment Canada (EC) and by Health Canada (HC). Part II.1 of the NSNR implements provisions of Part 6 of CEPA by prescribing the information as well as the timelines for notifying Environment Canada of the intent to manufacture or import such animal or its derived products. Environment Canada and Health Canada then assess for whether or not the animal is toxic or has potential of being "toxic". The Novel Foods Regulations under the Food and Drugs Act administered by Health Canada comes into effect if the product is sold or advertised for sale as food. The CFIA is working in collaboration with EC and HC to scientific and technical advise, including conducting animal health risk analyses. Under the authority of Health of Animals Act and Regulations and Feeds Act and Regulations the CFIA administers and enforces regulatory controls over animal health, animal products, veterinary biologics and livestock feeds.

On the basis of the end use for which an animal or its derived products is being assessed, different government departments may be responsible for the assessment. The end use of the product determines which department or agency may be responsible for conducting an assessment. For example (the following list is not exhaustive):

• If the animal or its derived products including semen, oocytes and embryos are going to be imported, the CFIA would be consulted (Health of Animals Act and Regulations).
• If the production of recombinant products from the living animal is intended for use in animal as veterinary biologic, the CFIA would be consulted for the assessment (Health of Animals Act and Regulations).
• If the production of recombinant products from the living animal is intended for medical devices, xenotransplantation, therapeutic biologicals, cosmetic, veterinary drug and industrial chemicals or biochemicals, Health Canada (Food and Drugs Act and Regulations) and Environment Canada would be consulted for the assessment (CEPA, 1999 and the NSNR).
• If any animal parts, by-products or rendering materials is intended to be used as livestock feed, or if intended to be used as a fertilizer the CFIA would be consulted (Feeds Act and Regulations and Fertilizers Act and Regulations).
• If any animal parts, by-products or rendering materials is intended to be used in cosmetics, Health Canada (Food and Drugs Act and Cosmetic Regulations) and Environment Canada would be consulted for the assessment (CEPA, 1999 and the NSNR).

Environment Canada, Health Canada and CFIA work together to ensure that both the food and the environmental safety and the health of the animal and the feed of the final product are evaluated.

2. The General Process of Conducting a Risk Analysis

Risk analysis is the process of identifying the elements that pose risk, analysing their likelihood and the significance of impacts, their management, and communicating them to applicants, stakeholders and the broader community. Risk analysis consists of three processes; risk assessment, risk management and risk communication. The Animal Health and Production Risk Analysis Framework (AHRA, 2004) may be consulted for further details.

3. Risk Analysis Procedures for Biotechnology-Derived Animals from an Animal Health Perspective

3.1 INITIATION PROCESS

Figure 1 describes the steps of such a risk analysis procedure. The risk analysis process is initiated by an applicant who makes an inquiry to Environment Canada and Health Canada. Depending on the end use, the CFIA is then asked to collaborate with EC and HC by providing scientific and technical advice from an animal perspective as to whether or not to authorize an animal to be used. Whether the authorization is to consist of a single, multiple use or on a continuous basis of an animal, the steps followed in the process of approving the commodity remain the same.

Within the CFIA, the risk analysis process is initiated by a decision of the Director of the Animal Health and Production Division to conduct a risk assessment. The Animal Biotechnology Unit (ABU) is responsible of filling a specific form to request a risk assessment (Appendix 2, Request for an Animal Health Risk Assessment of Biotechnology-Derived Animals). The request should be endorsed by the Director of the AHPD and sent to the Director of the Science Division, then on to the National Manager of the AHRA Unit. Conformity with this process allows AHRA to respond appropriately to the request. The Animal Health and Production Risk Analysis Framework (AHRA, 2004) may be consulted for further details of the steps following an inquiry.

Figure 1

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The request form (Appendix 2) includes required information such as the history, background and description of the commodity, including production protocols, the volume, quantity, frequency and time-frames of the proposed release. In addition to the request form, additional information, as described in Table 1 (for further details refer to Appendix 3, Information Required for Conducting an Animal Health Risk Assessment), is needed to conduct such assessment. This information will be supplied by EC and HC through the schedule XIX of the New Substances Notification Regulation (http://www.ec.gc.ca/substances/nsb/eng/B19ew_e.htm).

Table 1 Summary of Information Required

Note: additional information could be requested if necessary (through EC and HC)

3.2 RISK ASSESSMENT PROCESS

The first step in the animal health risk assessment process is the identification of hazards associated with the biotechnology-derived animal for which a request has been received. This process occurs through the collection of evidence, including consultation with officials both within Canada (CFIA and other Government Departments) and internationally on a case by case basis.

The risk assessment process involves four other interrelated assessment steps: release assessment, exposure assessment, consequence assessment and risk estimation. These steps clarify the stages of the risk assessment, describing them in terms of the events necessary for the identified potential risk(s) to occur, and facilitate understanding and evaluation of the outputs. Figure 2 illustrates the processes involved in a animal health risk assessment.

Figure 2

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Risk assessment principles:

• The risk assessment process should be flexible in order to deal with the complexity of real life situations. No single method is applicable in all cases. This is exemplified by the variety of animal commodities, methods and materials used to produce the animal, the multiple hazards that may be related to the method of production (biotechnology-derived animal), the different diseases’ epidemiology, detection and surveillance systems, exposure scenarios and types and amounts of data.
• Both qualitative and quantitative risk assessments have merit.
• An organizational arrangement that separates risk assessment from risk management decision-making is encouraged to ensure that the risk assessments are not influenced to fit prior regulatory conclusions.
• The risk assessment should be based on the best available information that is in accord with current scientific thinking. The assessment should be well documented and supported with references to the scientific literature and other sources, including expert information elicitation (Appendix 4, Source Materials for Use in Risk Assessments).
• Consistency and transparency in risk assessments should be encouraged to ensure fairness and rationality, comparison of risks and ease of understanding by all interested parties. Consistency may be limited to similar biotechnology-derived animal and depend on the types and amount of data available. Improvement in risk assessment methods should supersede consistency.
• Risk assessments should illustrate the uncertainty in the risk estimation output.
• In general, the risk estimate increases with increasing volume or quantity of the commodity (biotechnology-derived animal) released.
• The risk assessment should be amenable to updating when additional information becomes available.

3.2.1 Hazard Identification

A hazard is defined as an agent, element or event that poses potential harm, an adverse event or adverse outcome (AHRA, 2004). Hazard identification is a categorization step identifying biological agents and genotypic and phenotypic hazards, dichotomously as potential hazards or not, which could potentially be introduced with a commodity or activity and for which pathways exist for exposure of the agents to susceptible animals. The risk assessment is concluded if a hazard identification fails to identify potential hazards associated with the release.

AHRA is responsible for identifying the hazards associated with biotechnology-derived animals and their products, and conducting the risk assessment from an animal health perspective for each hazard. The risk assessment process involves collecting evidence and information and, on a case by case basis, consulting with experts nationally and internationally. Often, officials in the CFIA Centres of Expertise and the associated Biotechnology Testing Centers (Molecular Analysis and Testing Unit / MATU) are consulted:

Charlottetown Laboratory, Charlottetown, Prince Edward Island
St-Hyacinthe Laboratory, St-Hyacinthe, Quebec
Ottawa Laboratory (Carling), Ottawa, Ontario
Ottawa Laboratory (Fallowfield), Ottawa, Ontario
Sidney Laboratory, Sidney, British Columbia

In contrast to conventional import risk assessments, hazards associated with biotechnology-derived animals include consideration not only of hazards associated with infectious pathogens, but also hazards related to the impact of the genetic modification on animal health and welfare and hazards that have potential impacts on genetic diversity and sustainability. However, as mentioned previously, the principal focus of this document is on the risks to animal health posed by the production of cloned, transgenic and other animals derived from biotechnology. Criteria to identify infectious hazards are described in the Animal Health and Production Risk Analysis Framework (AHRA, 2004). Genetic hazards are identified based on the scientific evidence found in the literature. In the following table (Table 2) an attempt is made to list potential hazards related to the techniques and methods used (more details are presented in Appendix 5: Hazards Associated with Biotechnology-Derived Animals). These lists are not exhausted, other hazards may be added when identified. Because of the broad scope of this document, the large volume of the literature and the rapid pace of advancement in this field, the references cited should not be interpreted as all inclusive. In a field as new as animal biotechnology, genotypic and phenotypic hazards have not been completely identified and characterized.

Table 2 Hazards Related to the Techniques and Methods Used in production of Biotechnology-derived animals

The generation of a biotechnology-derived animal represents a sequential series of events that cannot be viewed in isolation. For a biotechnology-derived animal that is a transgenic, it begins with the generation of transgenic founder animals and ends with the production of a group of transgenic animals exhibiting the desired trait. Risk must be evaluated throughout this process to the production of at least one generations, and should include consideration of whether or not the transgene is present in a heterozygous or homozygous state. Cloned animals must be evaluated from the generation of the initial cloned animal to the production of progeny.

In Appendix 6 (Adverse Effects Associated with Hazards of Biotechnology-Derived Animals) an attempt is made to identify some adverse effects associated with the hazards. This appendix also presents the techniques, types of biotechnology-derived animal which can potentially express the effects, the release and the exposure pathways associated with the hazards.

3.2.2 Risk Assessment Steps

Release Assessment

Release assessment consists of describing and quantifying the potential of a risk source (the animal) to release or otherwise introduce a hazard into an environment accessible to animal population, including the risk to the animal derived from biotechnology itself or its progeny in subsequent generations.

With respect to the hazards posed by animals derived from biotechnology, release assessment involves consideration of the prevalence of the hazard, the point at which the hazard can be detected and the methods used to detect the hazard. The release assessment typically describes the types, amounts, timing and probabilities of the release of the hazard. In addition, the release assessment will include consideration of how these attributes might change as a result of various actions, events or measures.

In a risk assessment for biotechnology-derived animals, the various types of hazards — infectious, genetic — dictate the variety of inputs that need to be considered in the release assessment. In addition, any assessment of the release of a hazard from a biotechnology-derived animal must include consideration of the effects posed by animal waste products.

Exposure Assessment

Exposure assessment consists of describing and quantifying the relevant conditions and characteristics of animal exposure to hazards produced or released by a given risk source. The exposure assessment typically describes the amount, timing, frequency, duration of exposure, routes of exposure, and the number, species and characteristics of the animal population that might be exposed.

Detailed information concerning the release and exposure assessment in relation to identified hazards is presented in Appendix 6 (Adverse Effects Associated with Hazards of Biotechnology-Derived Animals).

Consequence Assessment

Consequence assessment consists of describing and quantifying the relationship between specified exposures of a biological agent and the economic consequences of those exposures. A causal process must exist by which exposures produce adverse animal health or environmental consequences. The consequence assessment typically includes a specification of the impact on health in the animal populations sustained under given exposure scenarios. In conventional import related risk assessments, consequences are related to infectious pathogens, and may include, but not be limited to:

• animal mortality and morbidity
• production losses (e.g. decreased reproductive efficiency, feed conversion etc.)
• costs associated with disease control (e.g. veterinary fees, vaccination, antibiotics, depopulation, decontamination etc.)
• reduced markets (e.g. domestic or export, live animal or products)
• human health implications (e.g. zoonotic disease).

Such consequences still apply with respect to B-D animals. In addition, other consequences related to unique genotypic and phenotypic hazards, such as the following, should be considered:

• perinatal mortality and morbidity
• costs associated with genotypic and phenotypic changes in B-D animals (e.g. immune function effects)
• loss of genetic diversity (e.g. in host and related species)
• costs associated with tracing B-D animals and their products
• effects related to commercial markets and consumer acceptance
• welfare concerns (repetitive invasive procedures, handling and restraint) (Appendice 7: Animal Welfare in Canada and the Codes of Practice: Backgrounder and Appendix 8: Welfare Evaluation in Three Successive Stages of a Transgenic Animal Production Program),
• adverse consequences to the environment, including disruption of ecosystems and native species extinctions
• costs associated with the control and eradication costs,
• quarantine and isolation costs,
• cleaning and disinfection costs,
• treatment costs,
• vaccination costs.

Risk Estimation

Risk estimation consists of integrating the results from the release, exposure and consequence assessments to produce quantitative measures of animal health. The final outputs of this process are estimates of the magnitude of possible adverse animal health consequences, including a characterization of the probabilities, uncertainties or degree of confidence associated with these estimates. Therefore, a risk estimation takes into account the entire risk pathway from hazard identification to unwanted outcome. A qualitative risk assessment is thus a summation of the findings of the release, exposure and consequence assessments.

For quantitative assessments, the final outputs may include:

• estimated numbers of herds, flocks, animals experiencing adverse health and other impacts of various severities over time,
• probability distributions, confidence intervals and other means for expressing the uncertainties in these estimates,
• portrayal of the variance of all model inputs,
• a sensitivity analysis to rank the inputs as to their contribution to the variance of the risk estimation output,
• analysis of the dependence and correlation between model inputs.

3.3 PEER REVIEW

A draft of the animal health risk assessment document is produced and subsequently distributed for peer review on a case by case basis. The importance of peer review, particularly for risk assessments related to biotechnology, has been highlighted in several reports and studies (e.g.: Canadian Biotechnology Advisory Committee, 2002).

The participants in a peer review are selected based upon nature of the risk assessment. They may include:

• CFIA staff, including those of the CFIA Animal Biotechnology Unit,
• other Government of Canada staff,
• non-governmental specialists in industry and academia.

Comments received from reviewers, when appropriate are incorporated into the risk assessment document.

3.4 ANIMAL RELEASE PROTOCOL

Recommendations of a release protocol from an animal health perspective for biotechnology-derived animals are the responsibility of Animal Biotechnology Unit (ABU). The recommendation are base on the tolerability of the estimated risk provided in the risk assessment document.

Development of those recommendations protocol may involve further consultation with CFIA expertise including the ABU, the AHRA Unit, Laboratory staff, Legal Services, etc.

It is important to recognize that, the final decision regarding release into the environment of a biotechnology-derived animals or animal products is the responsibility of Environment Canada and Health Canada.

Considerations associated with the release protocol and risk management options may include, but not be limited to:

• biocontainment requirements for the animal or product (semen, embryo...)
• any breeding restrictions,
• allowable uses for the product,
• domestic or international use,
• requirements for labelling,
• requirements for traceability,
• monitoring requirements – gene stability, health effects, gene expression, etc.,
• effect of release on natural populations and on the ecosystem.

3.5 ANIMAL HEALTH AND PRODUCTION DIVISION - RISK MANAGEMENT DECISION

When finalized and approved by the Director of AHPD, recommendations from an animal perspective to to accept (or not) the release of a biotechnology-derived animal into the environment are sent to Environment Canada and Health Canada.

4. Risk Management

Options are provided to risk managers to continue in the risk management process. Risk management comprises a number of measures, however not all are necessarily included in every risk analysis. The elements of risk management include:

• Risk evaluation: the aspect of risk management concerned initially with the decision to request a risk assessment, and secondly, with interpreting, comparing, judging the significance of and deciding the tolerability of the risk as estimated in a risk assessment document.
• Option evaluation: the process of identifying, evaluating the efficacy and feasibility, and selecting risk mitigation measures (in addition to those that may have been considered in the initial risk assessment) in order to reduce the animal health risk associated with biotechnology-derived animals. The efficacy is the degree to which an option reduces the likelihood and magnitude of adverse biological and economic consequences. Evaluating the efficacy is an iterative process that involves incorporation into the initial risk assessment, which is then re-evaluated to determine the degree of risk reduction. The evaluation for feasibility normally focuses on technical, operational and economic factors affecting the implementation of the risk management options.
• Implementation: proper actions are taken following the risk management decision on acceptance or refusal of the release.
• Monitoring and review: the ongoing process to observe the release and conduct a review, if necessary, of the risk assessment, the risk mitigation measures and the risk management decision.

5. Risk Communication

Risk communication takes place throughout the risk analysis process. The interactive exchange of information on risk occurs among risk analysts, risk managers and other interested parties. It begins when a risk analysis is requested and continues after the implementation of the decision (acceptance or refusal) on the animal. Risk communication is an integral component of the risk analysis and risk management process, and should not be considered an "add-on". Risk communication with stakeholders is principally the responsibility of the Environment Canada and Health Canada, however risk communication should be carried out by all parties involved in the risk assessment, when appropriate.

The widespread and deep interest of the public in biotechnology makes it imperative that risk communication is a priority. In 2001, the CFIA Public and Regulatory Affairs Branch produced a discussion paper entitled "Risk Communication and Government: Theory and Application for the Canadian Food Inspection Agency".

Once reviewed and approved, the animal health risk assessment for biotechnology-derived animal documents will be available via the CFIA website.

5.1 PRINCIPLES OF RISK COMMUNICATION

• The communication of risk should be an open, interactive and transparent exchange of information that may continue after the decision on release.
• The principal recipients of risk communication include, in addition to the applicant and the other Government Departments, the authorities and other stakeholders such as domestic and foreign industry groups, domestic livestock producers and consumer groups.
• Peer review should represent a component of risk communication in order to obtain scientific and analytical critiques, and to ensure the validity of the scientific data, methods and assumptions.
• The uncertainty in the model, model inputs and the risk estimates of the risk assessment should be communicated.

REFERENCES

Adlakha-Hutcheon, G., (2001). "Transgenic Animal Safety Assessments: Transgenic Avian Species / Internal Report", Animal Biotechnology Unit , Animal Health and Production Division, Internal report, CFIA.

Animal Health Risk Analysis Unit (AHRA), (2004). "Animal Health and Production Risk Analysis Framework", AHRA, Science Division, CFIA. (http://www.inspection.gc.ca/english/sci/ahra/rianfrwk/rianfrwke.shtml)

Canadian Biotechnology Advisory Committee, (2002). "Improving the Regulation of Genetically Modified Foods and Other Novel Foods in Canada." Report to the Government of Canada, Biotechnology Ministerial Coordinating Committee. (http://cbac-cccb.ca/epic/internet/incbac-cccb.nsf/vwGeneratedInterE/ah00186e.html#sum)

Canadian Food Inspection Agency, (2002). Draft: "Farm Animal Welfare Infrastructure." CFIA Performance Measurement and Program Support, Animal Health and Production Division, CFIA.

Canadian Food Inspection Agency, (2001). "Risk Communication and Government: Theory and Application for the Canadian Food Inspection Agency." CFIA Public and Regulatory Affairs Branch. (http://www.inspection.gc.ca/english/corpaffr/publications/riscomm/riscomme.shtml)

Covello, V.T. and Merkhofer, M.W., (1993). Risk assessment methods: Approaches for assessing health and environmental risks. Plenum Press, New York, 319 p.

Doonan, G., (2002). "So what does a food inspection agency have to do with animal welfare?" CFIA Officer Training Program, CFIA.

Scientist’s Working Group on Biosafety, (1998). Manual for Assessing Ecological and Human Health Effects of Genetically Engineered Organisms. The Edmonds Institute, Washington DC, (http://www.edmonds-institute.org/manp1os.pdf)

United States National Academy of Sciences, (2002). Animal Biotechnology: Science-based concerns., Chapter 6, National Academy Press, Washington, DC, USA.

GLOSSARY OF TERMS

Sources:

PDB Thain, M. And Hickman, M. (2000). Penguin Dictionary of Biology, 10th Edition. Penguin Books, London UK.
CAG Passarge, E. (2001). Colour Atlas of Genetics, Second Edition. Thieme, Stuttgart.