Environment Canada and Health Canada

Transcription

1 Environment Canada and Health Canada Framework for Science-Based Risk Assessment of Micro-Organisms Regulated under the Canadian Environmental Protection Act,

2 LIST OF ACRONYMS AND TERMS CEPA 1999 Canadian Environmental Protection Act, 1999 CEPA toxic Suspected of being toxic or capable of becoming toxic based on criteria described in Section 64 of CEPA DSL Domestic Substances List LC 50 Median Lethal Concentration EC 50 Median Effective Concentration IC 50 Median Inhibition Concentration ED 50 Median Effective Dose ID 50 Median Infective Dose LD 50 Median Lethal Dose NSNR (Organisms) New Substances Notification Regulations (Organisms) The Regulations New Substances Notification Regulations (Organisms) SNAc Significant New Activity as per section 106 or 110 of the CEPA 1999 PURPOSE AND SCOPE OF DOCUMENT This document outlines the systematic steps used by the Health Canada and Environment Canada Substances Assessment Programs to conduct science-based risk assessments of micro- organisms in which the assessment is based on a determination of toxic as defined under section 64 of the Canadian Environmental Protection Act, 1999 (see next page). In other words, it describes a framework of the basic concepts considered when conducting this assessment based on available information on hazard and exposure for both existing (i.e., those on the Domestic Substance List) and new micro-organisms (i.e., those notified under the New Substances Notification Regulations (Organisms) in order to determine whether any of the conditions described in section 64 will or could be met. OVERVIEW OF THE PROPOSED APPROACH TO MICROBIAL RISK ASSESSMENT The proposed approach (illustrated in Figure 1), describes a series of steps to be followed during the risk assessment of a micro-organism. The approach is structured to ensure that micro-organisms undergo a rigorous, consistent and expeditious analysis to determine whether or not they are toxic (see Risk Characterization ). This approach is based on the evaluation of toxic, as defined under section 64 of CEPA 1999, using the paradigm that risk is proportional to the product of hazard and exposure. Risk Hazard Exposure 2

3 In the context of the screening assessment of DSL micro-organisms, a prioritization was performed in order to ensure that micro-organisms with the greatest potential for hazard are assessed first. This process is described in detail in the Prioritization of Micro-organisms on the Domestic Substances List prior to the Screening Assessment under paragraph 74(b) of CEPA During risk assessment of DSL micro-organisms, the identification and determination of the severity of hazard are based on an exhaustive literature review and other sources such as experimental data from completed and ongoing research projects, decisions from other jurisdictions. For new micro-organisms, risk assessment is based on the information provided, as required under the New Substances Notification Regulations (Organisms). The determination of exposure sources and characterization of exposure levels are based on available information describing current known use patterns, proposed uses, or other potential uses. This risk is characterised as Low, Medium or High depending on the hazard severity and potential for exposure (see Risk Characterization ), and taking into consideration weight of evidence and scientific uncertainties (see Considerations for Science-Based Evaluations ). The outcome of the risk assessment will be used to determine whether or not the micro-organism meets the description of CEPA toxic, as defined under section 64 of CEPA A substance is toxic if it is entering or may enter the environment in a quantity or concentration or under conditions that: (a) have or may have an immediate or long-term harmful effect on the environment or its biological diversity; (b) constitute or may constitute a danger to the environment on which life depends; or (c) constitute or may constitute a danger in Canada to human life or health. The risk assessment will result in one of the three following conclusions: Not CEPA Toxic for all reasonably foreseeable use(s) or exposure scenario(s): no further action; Not CEPA Toxic for intended (proposed) use(s) or exposure scenario(s) but, under another significant new activity, may become toxic : application of the SNAc provision may be recommended to allow for the notification and assessment of new uses/activities; or 3

4 CEPA Toxic: appropriate control measures or risk management actions will be recommended to the Minister in order to mitigate the risk. Figure 1: Approach to risk assessment of micro-organisms Micro-organism Hazard Assessment Identification and characterization Exposure Assessment Sources of exposure and characterization Consider weight of evidence and address any remaining uncertainties Low Risk Medium Risk High Risk Not CEPA Toxic No further action Not CEPA Toxic for known, or intended use(s) but may be toxic for a significant new activity. Application of SNAc provisions recommended CEPA Toxic for known, forseeable or intended use(s) Risk management or control measure recommended 4

5 RISK ASSESSMENT FRAMEWORK HAZARD ASSESSMENT A hazard assessment characterizes the micro-organism and identifies the potential adverse effects on the environment and/or human health and predicts the extent and duration of these effects. The hazards may be posed by the micro-organism itself, its genetic material, or its toxins, metabolites or structural components. Hazard information considered in the assessment may be for the specific microorganism being assessed, or a suitable surrogate, if there is insufficient information on the specific micro-organism and the choice of surrogate is supported by a sound scientific rationale. Factors affecting the degree of hazard may be strain specific and therefore the assessment must address the factors known or suspected to be produced by the notified or nominated strain, as well as those known or suspected to be produced by other strains of the species (or genus). The degree of hazard may also be affected by the life stage of the organism. For this reason, all stages of the life cycle of the micro-organism and their potential effects must be considered. Sources of hazard information include, but are not limited to: information and data supplied by the notifier [in the case of new micro-organisms covered under the NSNR (Organisms)] or nominator (in the case of existing micro-organisms), the scientific literature, and any completed or ongoing research studies. Characterization of the micro-organism Taxonomic identification: The accurate identification of a micro-organism is the key element in a microbial hazard assessment. Strong and defensible identification, preferably to the strain level, is important for the hazard characterization of the micro-organism. This will allow a more effective distinction from related pathogenic micro-organisms. No single method is sufficient for an accurate identification. A combination of classical and molecular methods is often necessary. Strain history: From its original source of isolation until final product development, history of the strain is also considered in the assessment. This information includes any strain bank accession numbers and the history of isolation, storage, culturing conditions, adaptations, selection conditions and modifications to the micro-organism, as well as the life stage of the microorganism in the final product. Genetic Modifications: For genetically modified micro-organisms, information on all directed or intentional changes made to the organism is assessed. This would include the type of genetic manipulation (e.g., mutagenesis, genetic recombination) source, nature and function of any inserted genetic material, methods used to modify the organism, and stability of the modifications. 5

6 Horizontal Gene Transfer: The assessment considers the capacity for transfer of genetic material between organisms, including the mechanisms of possible transfer (including transformation, transduction or conjugation) and the elements involved (such as plasmids, bacteriophages, integrative conjugative elements, transposons, insertion sequences, integrons, gene cassettes and genomic islands). Biological and Ecological Properties of the Organism: Information about the biology of the organism contributing to the assessment of hazard may include the following: o Physiological properties, include growth parameters (e.g., temperature, ph, osmotic minima, maxima and optima), redox potential, nutritional dependence and susceptibility to antibiotics, metals and environmental factors such as sunlight and desiccation, to help determine conditions required for and conditions that limit survival, growth and replication; o Unusual properties of the notified or nominated strain that differ from the classical description of the species; o Description of the life cycle of the organism, including the characteristics of various different forms and mechanisms of microorganism dispersal; o Natural occurrence, including information on geographical distribution, habitats, ecological niches, preferred or obligate hosts (for symbiotic, saprophytic or pathogenic relationships) and level of natural occurrence in the environment; o Mode of action in relation to known, intended or predicted uses; History of Safe Use: A documented history of safe use of (or prior environmental exposure to) a micro-organism over significant time periods lends confidence, in the absence of evidence of effects, to a determination of low hazard. However, the particulars of exposure associated with a history of safe use (life stage of the micro-organism, environmental dose/concentration, route of exposure) must be fully considered to ensure that the exposure history compares to exposures likely from proposed or predicted uses. Effects Pathogenicity/Toxicity Under this heading, the ability of a micro-organism to cause lethal or sublethal adverse effects on living plants or animals, including humans, is assessed. 6

7 Relatedness of the microorganism to known pathogens is considered, as is the presence or absence virulence factors that enable it to infect, establish itself, multiply, inflict injury or damage or cause disease or adverse immunological effects in a host. Key elements relating to the assessment of pathogenicity and toxicity include the following: Pathogenicity refers to the ability of an organism to cause harm or disease to the host. This ability is a property of the pathogen and the extent of damage done to the host depends on host-pathogen interactions. Virulence refers to the degree of pathogenicity. Different species or strains of microorganism may exhibit different level of virulence. Virulence factors are any genetic, biochemical or structural features that enable the microorganism to cause disease or harm to the host. Pathogenicity of microorganisms is generally the result of two processes that may or may not be linked: the ability to infect the host (invasion, adherence, colonization, evasion of the immune system) and toxigenesis (the production of toxins that may or may not play role in the infectious process). A toxin is a substance produced by a micro-organism that may have a harmful effect on a living organism, irrespective of the presence of the living micro-organism (endotoxins, exotoxins, structural components or metabolites). Toxins are some of the major determinants of virulence. They can have cytotoxic activity towards a narrow or wide range of cells and can induce death of specific cell types or general tissue damage. Some toxins can be lethal to the target organisms. Infectivity refers to the ability of a microorganism to cross or evade natural host barriers to infection. This term describes the capability of the microorganisms to escape clearance measures and to invade and persist in a viable state or multiply within or on an organism, with or without disease manifestation. It also refers to its capacity for horizontal transmission (how readily a pathogen is passed from one individual or group to a previously uninfected individual or group). Toxicity refers to the degree to which a substance (toxin) or an organism can cause harm to living organism as a whole, its tissue or its cells. Live microorganisms need not necessarily be present for a toxic effect to occur (e.g., in toxin-mediated food poisoning or for toxic products of microorganisms used in industrial applications). Ideally, in vivo test data are used to evaluate the effects of the organism, including: o pathogenicity and/or toxicity test on aquatic plants, vertebrates and invertebrates species o pathogenicity and/or toxicity test on terrestrial plants, vertebrates and invertebrates species 7

8 o pathogenicity and/or toxicity test in laboratory mammals, as a surrogate for potential effects on human health For micro-organisms, in vivo pathogenicity/toxicity testing typically starts with a single dose or concentration test at a maximum hazard (challenge) dose or concentration (Environment Canada, Report EPS 1/RM/44, March 2004). If adverse effects are reported at this dose or concentration, a range of lesser challenges may be used to establish a dose-response relationship, and ideally to identify an appropriate statistical endpoint, such as median infective, effective or lethal dose or concentration (ID50/IC50, ED50/EC50, LD50/LC50) (Environment Canada, Report EPS 1/RM/46, March 2005). If in vivo tests are not possible or available, in vitro pathogenicity/toxicity testing in plant, animal or human cell culture (primary or cell line) could be used to determine toxic and infectious properties of a micro-organism toward higher organisms. Determination of the appropriate model is dependent on the micro-organism itself and the effects tested. A review of case reports and outbreaks in the scientific literature is another key element in the assessment of pathogenicity and toxicity. In evaluating documented effects on the environment and human health, host range is considered, including differential susceptibility of human populations and the range of plant or animal hosts, as well as incidence, morbidity and mortality and effects at the population or ecosystem level. Other Ecological Effects Other ecological effects are considered in the assessment of hazard such as the ability of the micro-organism to adversely alter biotic and abiotic components of the ecosystem (e.g. loss of biodiversity, loss of habitat). Hazard Characterization Hazard severity can be characterized as low, medium or high. While these categories are qualitative, they are convenient for communicating the relative degree of concern associated with micro-organisms, especially as there is generally a paucity of quantitative data on the hazards posed by many micro-organisms. Environment Environmental hazard level determination considers the diversity of living organisms and habitats that could be affected by the known, proposed and predicted releases of the micro-organism, taking into account its environmental expression and fate, and differential susceptibility of the organisms and ecosystems likely to be exposed. Table 1 describes considerations for each of the environment hazard severity categories used in the risk assessment of micro-organisms. 8

9 Table 1: Considerations for hazard severity (environment) Hazard Considerations High Considerations that may result in a finding of high hazard include a microorganism that: Is known as a frank pathogen. Has irreversible adverse effects (e.g., loss of biodiversity, loss of habitat, serious disease). Has significant uncertainty in the identification, characterization or possible effects. Medium Considerations that may result in a finding of medium hazard include a micro-organism that: Is known as an opportunistic non-human pathogen or for which there is some evidence in the literature of pathogenicity/toxicity. Has some adverse but reversible or self-resolving effects. Low Considerations that may result in a finding of low hazard include a microorganism that: Is not known to be a non-human pathogen. Is well characterized and identified with no adverse ecological effects known. May have theoretical negative impacts for a short period but no predicted long term effect for microbial, plant and/or animal populations or ecosystems. Has a history of safe use over several years. Combinations of the factors within each generalized environmental hazard level above are possible and would affect the overall assessment. Human Health Elements that are used in determining the hazard severity of a micro-organism towards humans include: Virulence Infectivity Severity of effects (including toxicity) Duration Sequelae Reversibility (self-limiting or requiring treatment) Potential community burden of disease Potential for horizontal transmission 9

10 Incidence and prevalence i.e., morbidity, mortality rates in the general population The circumstances in which humans have been exposed to the micro-organism or its close relatives (history of safe use, prior environmental exposure) may also be considered, particularly where there is an absence of case reports in the scientific literature. Table 2 defines each of the human health hazard severity categories used in the risk assessment of micro-organisms. Table 2: Considerations for hazard severity (human health) Hazard Considerations High Considerations that may result in a finding of high hazard include a microorganism for which: disease in healthy humans is severe, of longer duration and/or sequelae may result; Disease in susceptible humans may be lethal; Potential for horizontal transmission/community-acquired infection; Lethal or severe effects in laboratory mammals at maximum hazard/challenge dose trigger multiple-dose testing Medium Considerations that may result in a finding of medium hazard include: Case reports of human disease in the scientific literature are limited to susceptible populations or are rare, localized and rapidly self-resolving in healthy humans; Low potential for horizontal transmission; Effects at maximum hazard/challenge dose in laboratory mammals are not lethal, and are limited to invasive exposure routes (i.e., intraperitoneal, intravenous, intratracheal) or are mild and rapidly self-resolving. Low Considerations that may result in a finding of low hazard include: No case reports of human disease in the scientific literature, or case reports associated with predisposing factors are rare and without potential for secondary transmission and any effects are mostly mild, asymptomatic, or benign No adverse effects seen at maximum challenge dose in laboratory mammals by any route of exposure. 10

11 EXPOSURE ASSESSMENT An exposure assessment identifies the mechanisms by which a micro-organism is introduced into a receiving environment, considers its environmental expression and fate, and estimates the likelihood, magnitude, frequency, duration, and/or extent of human and environmental exposure. Sources of Exposure Exposure to the micro-organism may be direct (e.g., through contact with consumer or industrial products) or indirect. Indirect exposure assessment considers how the micro-organism is released into the environment through known, proposed or predicted uses, and the environmental fate of the micro-organism, its genetic material, toxins, metabolites and structural components. Environmental release is assessed from known, proposed or predicted: sites of release (including geographical location(s), environmental compartments into which release is expected); nature of release (e.g., aerial spray, ground application, deep well injection, emissions, or wastes); quantity, duration, and frequency of release. Assessment of the environmental expression and fate of the micro-organism considers the biology and life cycle of the organism, which may be used to predict: the ability of the micro-organism to survive, persist, disperse, proliferate and become established in the environment to which it is released; potential for dispersal or transport to other environmental sites or compartments; for genetic material, the potential for dispersal of traits; for toxins, metabolites and structural components, the potential for persistence and bio-accumulation; In relation to the exposed plants, animals, humans or ecosystems, the following factors are considered: magnitude of exposure (quantity, duration); the life stage of the micro-organism at the time of exposure (vegetative cells or spores, live or dead); exposure to toxins, metabolites and/or structural components; routes of exposure (ingestion, inhalation, dermal, etc.); Exposure Characterization Exposure to a micro-organism, its toxins, metabolites, structural components or genetic material, is categorised as low, medium or high. While these categories are qualitative, they are convenient for communicating the predicted degree of exposure. 11

12 For micro-organisms, exposure is generally estimated qualitatively due to capacity of micro-organisms to increase or decrease in numbers, and the general paucity of models or environmental fate data for micro-organisms. Exposure to a toxin, metabolite or structural component can sometimes be estimated quantitatively using established chemical models. Table 3 describes the considerations for assessing the likelihood of exposure for both environmental and human health endpoints. Table 3: Considerations/examples for levels of exposure (environment and humans) Exposure Considerations High Considerations that may result in a finding of high exposure include a micro-organism for which: the release quantity, duration and/or frequency are high. the organism is likely to survive, persist, disperse proliferate and become established in the environment. dispersal or transport to other environmental compartments is likely. the nature of release makes it likely that susceptible living organisms or ecosystems will be exposed and/or that releases will extend beyond a region or single ecosystem. In relation to exposed organisms, routes of exposure are permissive of toxic or pathogenic effects in susceptible organisms. Medium Considerations that may result in a finding of medium exposure include a micro-organism for which: It is released into the environment, but quantity, duration and/or frequency of release is moderate. It may persist in the environment, but in low numbers. The potential for dispersal/transport is limited. The nature of release is such that some susceptible living organisms may be exposed. In relation to exposed organisms, routes of exposure are not expected to favour toxic or pathogenic effects. Low Considerations that may result in a finding of low exposure include a microorganism for which: It is no longer in use. It is used in containment (no intentional release). The nature of release and/or the biology of the micro-organism are expected to contain the micro-organism such that susceptible populations or ecosystems are not exposed. Low quantity, duration and frequency of release of micro-organisms that are not expected to survive, persist, disperse or proliferate in the environment where released. 12

13 Combinations of the factors within each generalized exposure level above are possible and would affect the overall exposure assessment. RISK CHARACTERIZATION For the determination of CEPA toxic, the outcomes of the hazard assessment and exposure assessment are combined to determine the likelihood that an exposure will or may impact on the environment and/or human health as described in section 64 of the Act. Risk is typically described as the probability of an adverse effect occurring based on hazards and a particular exposure scenario, a proportional relationship which is usually expressed as: Risk Hazard Exposure As emphasized throughout this document, in order for a micro-organism to be considered CEPA toxic,, the following must be true: there must (or there is likely to) be a hazard related to the micro-organism to human health or the environment; there must (or there is likely to) be exposure to humans or the environment to that hazard; there must be some likelihood that an adverse effect to human health or the environment will result from exposure to the identified hazard. Estimation of Risk The assessment of the magnitude of risk is based on the assumption that the hazard will be realized due to environmental exposure, based on estimates taking into account known or proposed/foreseeable uses and/or assumptions. The text below outlines three categories of risk, based on the severity of the hazard and the potential for exposure as described above. Note that hazard severity and level of exposure are defined in isolation. However the specifics of the hazard assessment may modify the significance of a particular exposure scenario. For example, an organism that is innocuous on oral ingestion or dermal contact may be pathogenic on inhalation, so the likelihood of aerosol formation on release or dispersal of the organism may cause the estimation of risk to change relative to the scheme outlined above, and may also affect the selection of control measures and/or risk management approaches. In addition, other considerations modifying hazard and exposure, as outlined in the next section (Considerations for Science-Based Evaluations), also play a role in estimating risk and linking it to an assessment conclusion as described in Figure 1. The following three categories are considered to estimate the risk level: 13

14 High risk: A determination of high risk implies that severe, enduring or widespread adverse effects are probable for exposure scenarios predicted from known, foreseeable or intended uses. A conclusion of CEPA-toxic would result from this determination of risk level and control measures or risk management would be recommended. Medium risk: A determination of medium risk implies that adverse effects predicted for probable exposure scenarios may be moderate and self-resolving. The conclusion (CEPA-toxic or not) is determined based on the particulars of the case. In the case where the conclusion is not CEPA-toxic, for intended (proposed) use(s) or exposure scenario(s) but, under another significant new activity, may become CEPA-toxic, application of the SNAc provision may be recommended to allow for the assessment of new uses/activities should those new activities be proposed. Low risk: A determination of low risk implies that any adverse effects predicted for probable exposure scenarios are rare, or mild and self-resolving. The conclusion would be not CEPA-toxic, and SNAc provisions may or may not be applied. CONSIDERATIONS FOR SCIENCE-BASED EVALUATIONS Quantitative Data Quantitative risk assessment for micro-organisms is made difficult by their ability to proliferate in the environment and their host-specificity, among other factors. Although laboratory testing in a suitable animal model may provide quantitative values for potential pathogens, such data are rarely available to evaluators. Qualitative Data and Information In the absence of quantitative evidence, a qualitative approach is used, considering several lines of evidence, including: Literature searches for information, including epidemiology and clinical case reports and information on the biology (e.g., virulence factors, toxin production), physiology (e.g., growth requirements) and ecology of the microorganism being assessed and suitable surrogates. Decisions from other domestic and international jurisdictions and experts History of safe use, and likelihood of prior environmental exposure for relevant life stages of the micro-organism Weight of Evidence Under CEPA 1999, risk assessments incorporate the precautionary principle and a weight of evidence approach. Weight of evidence considers several component lines of evidence to reduce overall uncertainty. Lines of evidence are weighted based on the net persuasiveness of many factors, including: The number of studies supporting a particular line of evidence Study design (multivariate, randomized, statistical analysis) 14

15 Number of tested hypotheses Sample size Validity and degree of extrapolation (spatiotemporal, species extrapolation) Data quality Scope relative to the risk assessment (same or closely related strain, climate of study area, etc.) Effect size The Precautionary Principle The precautionary principle is one of the guiding principles set out in the preamble of the CEPA 1999, and states that "where there are threats of serious or irreversible damage, lack of full scientific certainty shall not be used as a reason for postponing cost-effective measures to prevent environmental degradation." Sound scientific information remains the cornerstone of all assessments. In situations where sound scientific information is limited but where the impacts could potentially be important, the approach to risk management measures is prudent, in order to protect the environment and human health. Scientific Uncertainties Risk estimates always contain some level of uncertainty resulting from the limited availability of scientific data, and the challenge of extrapolating available data to real situations. The effect of these uncertainties on risk estimates must be thoroughly considered and documented, including: Identification of major data gaps and, where appropriate, indication of whether more data would enhance the overall confidence in the assessment conclusion Assumptions used to bridge data gaps, and the bases for those assumptions Identification of any unacceptable uncertainties requiring application of the precautionary principle until new data become available to resolve the uncertainty Experts and Peer Reviewers If the necessary expertise cannot be found within the Government, scientific experts may be sought out to provide advice. In addition, risk assessment reports may be reviewed by third party experts to ensure a high degree of rigor and quality in the report. Professional Judgement The minister of the Environment and the Minister of Health share the ultimate authority and accountability for any decision arising from the risk assessment of micro-organisms under CEPA Professional judgement is used to make risk management decisions in the face of uncertainty or conflicting lines of evidence. 15

16 CONTEXT The Canadian Environmental Protection Act, 1999 (CEPA 1999) takes a proactive and preventative cradle to grave approach to pollution prevention and protecting the environment and human health by regulating new and existing substances. Substances include chemicals, polymers, and living organisms, and in the context of this document, living organisms refers to micro-organisms. Definition of micro-organism For the purposes of CEPA 1999, a micro-organism is defined in subsection 1(1) of the New Substances Notification Regulations (Organisms) as: a microscopic organism that is: a. classified in the Bacteria, the Archaea, the Protista, which includes protozoa and algae, or the Fungi, which includes yeasts; b. a virus, virus-like particle, or sub-viral particle; c. a cultured cell of an organism not referred to in paragraphs (a) and (b), other than a cell used to propagate the organism; or d. any culture other than a pure culture. A consortium, which is a complex unformulated natural combination of microorganisms, is regarded as any culture other than a pure culture. Existing versus New Substances Existing substances are substances that are listed on the Domestic Substances List (DSL). The DSL for living organisms is a compilation of all reported living organisms that were either (i) in Canadian commerce between January 1, 1984, and December 31, 1986, or (ii) that were added to the DSL in accordance with CEPA 1999 after assessment of the information outlined in Schedule 1 (micro-organisms) of the Regulations. Substances listed on the DSL do not require notification prior to manufacture or import. As of September 2010, there were 67 microbial strains and 1 complex microbial culture (i.e., consortium) on the DSL because they met criterion (i) or (ii) (see for more information). Under paragraph 74(b) of CEPA 1999, the Minister of the Environment and the Minister of Health are required to conduct a screening assessment of these organisms based on information gathered or generated by the Government of Canada. New substances are substances that are not listed on the DSL. New microorganisms require pre-import and pre-manufacture notification under subsection 106 (1) of CEPA 1999 and are assessed under subsection 108(1) of CEPA The Regulations outline notification and information requirements for these (see for more information). For new living organisms, information supporting the assessment originates with the proponent, but other relevant information may be 16

17 gathered for use in the assessment. The government is bound to the assessment timelines as prescribed in the Regulations. Additional background information More information about micro-organisms assessment under CEPA 1999 is found at the Living Organisms (Biotechnology) section of the New Substances website ( and Guidelines for the Notification and Testing of New Substances: Organisms ( More information about risk management of chemical substances under CEPA 1999 can be found at for chemical new substances, visit 17

18 REFERENCES Environment Canada. A guide to understanding the Canadian Environmental Protection Act, CEPA Environmental Registry report En84-11/2004E. Available at Environment Canada Advisory Note on Streamlining the notification process for naturally occurring micro-organisms with a low hazard potential. October 2, New Substances Program. Available at Environment Canada. Environmental assessment best practice guide for wildlife at risk in Canada. 1 st Ed. February Available at Environment Canada. Guidance document for testing the pathogenicity and toxicity of new microbial substances to aquatic and terrestrial organisms. Report EPS 1/RM/44, March Available at: BD3E-9B Environment Canada, Guidance Document on Statistical Methods for Environmental Toxicity Tests, Report EPS 1/RM/46, March Available at: 4DDB-8A67-5EDB2A4FB4B5 Environment Canada. Guidance Manual: The Science Behind Environmental Assessments of Priority Substances under the Canadian Environmental Protection Act. Existing Substances Division Available at: Environment Canada. Guidelines for the Notification and Testing of New Substances: Organisms. December Available at newsubs/default.asp?lang=en&xml=42a1cc66-bcca-cf00-5c87- C57E1D9D25B0 Environment Canada. Living Organisms (Biotechnology) website. New Substances Program. Reviewed December

19 Environment Canada. Organisms Assessment Guidance Manual. February Biotechnology Evaluation Section. New Substances Division Commercial Chemicals Evaluation Branch. Environment Canada. Overview of the Ecological Assessment of Substances under the Canadian Environmental Protection Act, Existing Substances Division and New Substances Division, June Available at Environment Canada. Use of the weight of evidence approach for the ecological assessment of existing substances under CEPA Draft: April 11, Last revised: September 8, Existing Substances Program. Environment Canada and Health Canada. Prioritization of Micro-organisms on the Domestic Substances List prior to the Screening Assessment under paragraph 74(b) of the CEPA Available at: Environment Canada and Health Canada. (2008). Guidance for Identification of Micro-organisms in the Context of the New Substances Notification Regulations (Organisms) (Draft). European Commission. Environmental Risk Assessment for Immunological Veterinary Medicinal Products. March Available at 6/ne_en_doc/vol6c_env_risk_gmo_200603_en.pdf Haas, C.N., Rose, J.B. and Gerba, C.P. Quantitative Microbial Risk Assessment. John Wiley & Sons, Inc. New York Health Canada Decision-Making Framework for Identifying, Assessing, and Managing Health Risks. August Available at Health Canada. Determination of "Toxic" for the Purposes of the New Substances Provisions (chemicals and polymers) under the Canadian Environmental Protection Act - Human Health Considerations. February, New Substances Assessment and Control Bureau. Available at OECD. Guidance document on the use of taxonomy in risk assessment of microorganisms: bacteria. OECD Series on Harmonisation of Regulatory Oversight in Biotechnology. 2003; Report ENV/JM/MONO(2003)13. Available at 01,00.html 19

20 Privy Council Office. A Framework for the Application of Precaution in Sciencebased Decision Making about Risk Available at ution/precaution_e.htm 20