Update Project Chapter 2: Analysis Draft May 2008

1 PRINCIPLES AND METHODS FOR THE OF CHEMICALS IN FOOD 2 3 CHAPTER 2: RISK ANALYSIS 4 5 Contents 6 7 CHAPTER 2: RISK ANALYSIS...... 1 8 2.1 INTRODUCTION...... 1 9 2.2 THE RISK ANALYSIS PARADIGM ...... 1 10 2.2.1 Definitions of and risk ...... 2 11 2.2.2 Role of ...... 3 12 2.2.3 Interactions between risk assessment and ...... 3 13 2.2.3.1 Problem formulation ...... 4 14 2.2.3.2 Priority setting for JECFA and JMPR ...... 4 15 2.2.4 The role of risk assessment in risk analysis...... 4 16 2.2.4.1 Hazard identification...... 5 17 2.2.4.2 Hazard characterization ...... 5 18 2.2.4.3 Exposure assessment...... 6 19 2.2.4.4 Risk characterization...... 6 20 2.3 REFERENCES...... 7 21 22 23 2.1 Introduction 24 JECFA and JMPR have provided scientific advice to Member States since 1956 and 1961, 25 respectively, and to the general subject committees of the CAC since its formation in 1963. 26 However, the structural framework for these interactions was quite informal until the 27 development of the risk analysis paradigm. 28 The first risk analysis paradigm for public was proposed by the United States 29 National Academy of Sciences (NAS) (NRC, 1983) and focused on assessing the risk of 30 cancer from chemicals in food. The decision process was divided into three major steps: 31 research, risk assessment and risk management. In the NAS paradigm, the principal steps 32 were considered to be sequential, with the decision process commencing with research and 33 concluding with the decision, but such an approach does not recognize the possible influence 34 of risk analysis on data needs or of the impact of political, social and economic objectives. 35 36 2.2 The risk analysis paradigm 37 Risk analysis has since been defined by the CAC as “a process consisting of three 38 components: risk assessment, risk management and risk communication” (CAC, 1997, 2006). 39 CAC (2006) goes on to define the three components of risk analysis as follows: 40 41 Risk assessment: A scientifically based process consisting of the following steps: (i) hazard 42 identification, (ii) hazard characterization, (iii) exposure assessment, and, (iv) risk characterization. 43 44 Risk management: The process, distinct from risk assessment, of weighing policy alternatives, in 45 consultation with all interested parties, considering risk assessment and other factors relevant for the 46 health protection of consumers and for the promotion of fair trade practices, and, if needed, selecting 47 appropriate prevention and control options. 48 49 Risk communication: The interactive exchange of information and opinions throughout the risk 50 analysis process concerning risk, risk-related factors and risk perceptions, among risk assessors, risk

1

Update Project Chapter 2: Risk Analysis Draft May 2008

1 managers, consumers, industry, the academic community and other interested parties, including the 2 explanation of risk assessment findings and the basis of risk management decisions. 3 4 The risk analysis paradigm (see Figure 2.1) is a formal representation of the risk 5 analysis process in which it is made clear that there is both functional separation of the three 6 components and at the same time a requirement for communication and interaction between 7 those with responsibility for each of the three components. Within risk analysis, a functional 8 separation between risk assessors and risk managers is necessary to ensure scientific 9 objectivity of the risk assessment process. Further background information on risk analysis 10 can be found in Kaferstein & Hueston (2000). 11 12 13 14 Figure 2.1. Risk analysis (from FAO/WHO, 1997b) 15 16 The use of risk analysis methodology facilitates consistent and orderly decision- 17 making. Risk assessment is undertaken by the Joint Expert Committees, like JECFA and 18 JMPR, rather than the Codex Committees. Joint Expert Committees base their evaluations on 19 scientific principles and ensure necessary consistency in their risk assessment determinations. 20 The respective Codex Committees take responsibility as risk managers in making the final 21 decisions on establishing maximum limits for pesticide residues, veterinary drugs, 22 contaminants and additives in food. The CAC recognized the need to revisit risk analysis 23 approaches applied by Codex Committees and the Joint Expert Committees. At the request of 24 the CAC, three consecutive Joint FAO/WHO Expert Consultations were held between 1995 25 and 1998 on the application of risk analysis to food standard issues (FAO/WHO, 1995, 26 1997b, 1999). 27 28 2.2.1 Definitions of hazard and risk 29 The Joint Expert Consultations were by and large devoted to the three components of risk 30 analysis: risk assessment, risk management and risk communication, respectively. The first 31 Consultation, held in 1995 in Geneva, explored the risk analysis domain and focused on risk 32 assessment (FAO/WHO, 1995). The Consultation was also aware of the need for uniform 33 terminology on risk analysis in the work of Codex and considered risk analysis definitions 34 from different sources. The Consultation drafted definitions of risk analysis terms related to 35 food safety and recommended them to the CAC. The CAC subsequently amended these 36 definitions, adopted them on an interim basis and published the definitions in the Procedural 37 Manual (FAO/WHO, 2001, and subsequent updates). The definition of two terms—hazard 38 and risk—should be mentioned in particular. These are fundamental in the risk analysis 39 process, but different words for these two terms do not exist in many languages other than 40 English. Codex has adopted the following definitions for hazard and risk in relation to food to 41 cover not only chemical agents, but also biological and physical agents (CAC, 1997, 2006): 42 43 Hazard: a biological, chemical or physical agent in, or condition of, food with the potential to cause an 44 adverse health effect. 45 46 Risk: a of the probability of an adverse health effect and the severity of that effect, 47 consequential to a hazard(s) in food. 48 49 The Codex definition of hazard differs from that of other bodies, for which a hazard is a 50 property associated with the chemical or agent rather than the chemical or agent itself. Thus, 51 a single chemical could represent multiple (e.g. it could be a reproductive toxicant

2

Update Project Chapter 2: Risk Analysis Draft May 2008

1 and a carcinogen). As part of the project for the Harmonization of Approaches to the 2 Assessment of Risk from Exposure to Chemicals, the IPCS (2004) has defined hazard and 3 risk assessment slightly differently from Codex: 4 5 Hazard: Inherent property of an agent or situation having the potential to cause adverse effects 6 when an organism, system or (sub) is exposed to that agent. 7 8 Risk: The probability of an in an organism, system or (sub)population caused under 9 specified circumstances by exposure to an agent. 10 11 It is these IPCS definitions that most clearly describe the approaches of JECFA and JMPR. 12 13 2.2.2 Role of exposure assessment 14 It should be kept in mind that in general, risk analysis principles apply irrespective of the 15 nature of the hazard. The definition of hazard relates to chemical and microbiological 16 contaminants as well as to changes in the condition of food as a result of genetic 17 modification. Several components of the risk analysis process were subject of additional Joint 18 Expert Consultations. Two Consultations focused on exposure assessment (FAO/WHO, 19 1997a, 2000). 20 With regard to chemical hazards, the Consultations pointed to the further need for 21 harmonized approaches to the risk assessment of food additives, contaminants and residues of 22 pesticides and veterinary drugs, particularly in the assessment of exposure. Different 23 approaches are currently applied by JECFA and JMPR in establishing standards for the 24 various classes of chemicals. These approaches sometimes differ for historical reasons only, 25 while in other cases they are fully justifiable. In view of the increased importance of Codex 26 standards under the WTO Agreement on the Application of Sanitary and Phytosanitary 27 Measures (the SPS Agreement), harmonization of these approaches should be pursued to the 28 extent possible. The Consultations made interesting recommendations with regard to 29 exposure assessment. Where necessary, exposure assessment should be expanded to take into 30 account differences in dietary patterns and should include estimates of intake by potentially 31 vulnerable groups. It was recognized that information on food consumption by the general 32 population and by subgroups of interest is frequently lacking. Food consumption data are a 33 prerequisite for a consistent risk assessment of chemicals, and governments were encouraged 34 to generate such information and to make it available to the international organizations in 35 order to ensure that risk assessments are conducted on the basis of the state of 36 knowledge. 37 38 2.2.3 Interactions between risk assessment and risk management 39 More recent examinations of risk assessment/analysis methodology have paid much closer 40 attention to the influence of risk management on the risk assessment process (NRC, 1994, 41 1996; Presidential Commission, 1997; WHO, 2000; Renwick et al., 2003). While it is 42 necessary to separate the functional activities of risk assessment from those of risk 43 management in order to ensure scientific independence, it is acknowledged that risk 44 managers should communicate and interact with risk assessors during the process to establish 45 the scope of the analysis, particularly during problem formulation or risk profiling. Thus, the 46 relationship between risk assessment and risk management is an interactive, often iterative 47 process (see Figure 2.2). 48 49 50 Figure 2.2: Interactions of risk assessment with risk management 51

3

Update Project Chapter 2: Risk Analysis Draft May 2008

1 2.2.3.1 Problem formulation 2 As a general rule, formal risk assessments are preceded by a preliminary consideration 3 of the necessity for and objective of a risk assessment. These are usually subjective and 4 informal and may be initiated from inside or outside the risk management, risk assessment 5 and scientific communities. The transition process from preliminary considerations to formal 6 risk assessments has been described as problem formulation (or risk profiling) (Renwick et 7 al., 2003). It is an iterative process that facilitates the critical interface between risk 8 assessment and risk management. Communication with other interested parties (stakeholders) 9 is particularly important during the period of problem formulation. 10 Problem formulation describes a food safety problem and its context, in order to 11 identify those elements of the hazard or risk relevant to various risk management decisions. 12 Problem formulation would include identifying aspects of hazards relevant to prioritizing and 13 setting the risk assessment policy and aspects of the risk relevant to the choice of acceptable 14 levels of risk and management options. A typical problem formulation might include the 15 following: 16 17 • a brief description of the situation, product or commodity involved; 18 • the issues expected to be affected (e.g. human health, economic concerns) and the 19 potential consequences; 20 • consumer perception of the risk assessment; and 21 • the distribution of and benefits. 22 23 The output is a plan for the risk assessment process, which can be changed as the risk 24 assessment progresses. The desired outcomes of problem formulation are 1) the questions 25 that need to be answered under risk characterization to meet the needs of the risk manager, 2) 26 determination of the resources that are needed and available, and 3) the timeframe for 27 completing the assessment. 28 29 2.2.3.2 Priority setting for JECFA and JMPR 30 The selection of new or existing chemicals for consideration by JECFA or JMPR and 31 recommending priorities for review are the responsibility of FAO and WHO, their Member 32 countries and the CAC, through its committees. For JECFA, these committees include 33 CCFAC, which in 2006 was divided into two separate committees, the Codex Committee on 34 Food Additives (CCFA) and the Codex Committee on Contaminants in Food (CCCF), 35 together with the CCRVDF. For JMPR, the primary source of input is the CCPR. The 36 protection of human health should be the main criterion for prioritization for risk assessment. 37 The exposure levels and toxicity of the substance and the existence of particularly susceptible 38 are key determinants that impact human health. However, the lack of available 39 data may also be a factor in prioritization for risk assessments. The FAO and WHO Joint 40 Secretaries for JECFA and JMPR, as representatives of their respective organizations, have 41 the final responsibility and authority for the determination of the priorities of substances to be 42 evaluated in their respective areas. This can be dependent in part on available resources. 43 44 2.2.4 The role of risk assessment in risk analysis 45 The risk assessment process within risk analysis forms one of the key components of the 46 work of JECFA and JMPR. Accordingly, it is examined here in more detail. The other two 47 components of risk analysis—namely, risk management and risk communication—are not 48 further discussed in this monograph, but the interested reader is referred to other publications 49 (see, for example, FAO/WHO, 1997b, 1999).

4

Update Project Chapter 2: Risk Analysis Draft May 2008

1 Risk assessment, comprising the four steps of hazard identification, hazard 2 characterization (including dose–response assessment), exposure assessment and risk 3 characterization, is a conceptual framework that, in the context of risk analysis in the area of 4 food safety, provides a mechanism for the structured review of information relevant to 5 estimating health outcomes in relation to exposure to chemicals present in food. Risk 6 assessment generally includes a key component in which the probability of harm is estimated. 7 As a probability calculation, a risk assessment will include both a statement of the nature of 8 the harm and the basis for the assertion that the harm may occur (i.e. the probability). 9 10 2.2.4.1 Hazard identification 11 Hazard identification is defined as follows: “The identification of biological chemical and 12 physical agents capable of causing adverse health effects and which may be present in a 13 particular food or group of foods” (CAC, 2006). 14 The purpose of hazard identification is to evaluate the of evidence for adverse 15 health effects, based on assessment of all available data on toxicity and mode of action. It is 16 primarily designed to address two questions: 1) the nature of any health hazard to humans 17 that an agent may pose, and 2) the circumstances under which an identified hazard may be 18 expressed. Hazard identification is based on analyses of a variety of data, ranging from 19 observations in humans or domestic animals, studies in laboratory animals and in vitro 20 laboratory studies, through to analysis of structure–activity relationships. From the range of 21 studies and observations available, the nature of any toxicity or adverse health effect 22 occurring and the affected (target) organ(s)/tissue(s) are identified. The outcome of hazard 23 identification is a scientific judgement as to whether the chemical being evaluated could, 24 under given exposure conditions, cause an adverse effect in humans. 25 26 2.2.4.2 Hazard characterization 27 Hazard characterization (also known as dose–response assessment) is defined as follows: 28 “The qualitative and/or quantitative evaluation of the nature of the adverse health effects 29 associated with biological, chemical and physical agents which may be present in food. For 30 chemical agents, a dose–response assessment should be performed. For biological or physical 31 agents, a dose-response–assessment should be performed if the data are available” (CAC, 32 2006). 33 The critical effect—that is, the first significant adverse effect observed as the 34 dose/exposure is increased—is also determined. Hazard characterization describes the 35 relationship between the administered dose of, or exposure to, a chemical and the incidence 36 of an adverse health effect. For most types of toxic effect, it is generally considered that there 37 is a dose below which adverse effects will not occur (i.e. a threshold). Such a dose is 38 described as the no-observed-adverse-effect level (NOAEL) or no-observed-effect level 39 (NOEL) and can be considered as a first approximation of the threshold for that particular 40 chemical for that particular effect. The NOAEL or NOEL for the critical effect is usually 41 used as a starting point or reference point for the risk characterization (see below). More 42 recently, the option of modelling of the dose–response data for potential critical effects has 43 been introduced to derive a benchmark dose (BMD) and its lower confidence limit (BMDL) 44 for a particular incidence of effect (e.g. a 5% or 10% incidence). Comparisons of the BMDL 45 values for different effects can be used to define the critical effect, with the lowest BMDL 46 used as a starting point for risk characterization (FAO/WHO, 2006). 47 In contrast to threshold-type effects, for some other types of toxic effect it is assumed 48 that there is some probability of harm at any level of exposure (i.e. that no biological 49 threshold exists). At the present time, this assumption is primarily applied in the case of 50 mutagenicity and genotoxic carcinogenicity. In the case of genotoxic carcinogenicity, the

5

Update Project Chapter 2: Risk Analysis Draft May 2008

1 BMDL derived from animal studies may be used as a point of departure for risk 2 characterization. 3 4 2.2.4.3 Exposure assessment 5 Exposure assessment is defined as follows: “The qualitative and/or quantitative evaluation of 6 the likely intake of biological, chemical and physical agents via food as well as exposure 7 from other sources if relevant” (CAC, 2006). 8 9 Intake/exposure assessment is the third step in risk assessment, in which the extent of 10 human exposure to the chemical (actual or anticipated) is determined. In the case of food 11 chemicals, exposure assessment takes into consideration the occurrence and of 12 the chemical in the diet, the consumption patterns of the foods containing the chemical and 13 the likelihood of consumers large amounts of the food(s) in question (high consumers) 14 and of the chemical being present in these foods at high levels. Usually a range of 15 intake/exposure estimates will be provided (e.g. for average consumers and for high 16 consumers) and may be broken down by subgroup of the population (e.g. infants, children, 17 adults). 18 19 2.2.4.4 Risk characterization 20 Risk characterization is defined as follows: “The qualitative and/or quantitative estimation, 21 including attendant uncertainties, of the probability of occurrence and severity of known or 22 potential adverse health effects in a given population based on hazard identification, hazard 23 characterization and exposure assessment” (CAC, 2006). 24 Risk characterization is the final step in the risk assessment process in which the 25 information from the intake/exposure assessment and the hazard characterization are 26 integrated into advice suitable for decision-making in risk management. It provides estimates 27 of the potential risk to human health under different exposure scenarios. It should include all 28 key assumptions and describe the nature, relevance and magnitude of any risks to human 29 health. The advice to risk managers may be qualitative or quantitative. 30 Qualitative advice may include: 31 32 • statements/evidence that the chemical is of no toxicological concern owing to the absence 33 of toxicity even at high exposure levels; 34 • statements/evidence that the chemical is safe in the context of specified use(s); and 35 • recommendations to avoid, minimize or reduce exposure. 36 37 Quantitative advice may include: 38 39 • health-based guidance values; 40 • estimates of risks at different levels of exposure; and 41 • risks at minimum and maximum intakes (e.g. nutrients). 42 43 The risk characterization statement should include a clear explanation of any 44 uncertainties in the risk assessment resulting from gaps in the science base. It should also 45 include, where relevant, information on susceptible subpopulations, including those with 46 greater potential exposure and/or specific predisposing physiological conditions or genetic 47 factors. The advice to risk managers can be in the form of a comparison of the relative risks 48 among risk management options. 49 The risk assessment is followed by either a risk management decision or a request for 50 further analysis, which may influence any further research that is conducted. The record

6

Update Project Chapter 2: Risk Analysis Draft May 2008

1 produced by a risk assessment stands as a scientific basis for any risk management decision at 2 that time. However, the risk assessment/analysis may be reopened—for example, if additional 3 information be becomes available. 4 5 2.3 References 6 CAC (1997) Report of the Twenty-second Session of the Codex Alimentarius Commission, Geneva, 23-28 June 7 1997. (Available at: http://www.codexalimentarius.net/web/archives.jsp?year=97. ALINORM 97/37). 8 Appendix III: Definitions of risk analysis terms related to food safety. 9 CAC (2006) Codex Alimentarius Commission Procedural Manual. 16th edition. Joint FAO/WHO Food 10 Standards Programme. Available at ftp://ftp.fao.org/codex/Publications/ProcManuals/Manual_16e.pdf 11 (accessed 29-08-07). 12 FAO/WHO (1995) Application of risk analysis to food standards issues. Report of a Joint FAO/WHO Expert 13 Consultation, Geneva, 13-17 March 1995 (Unpublished WHO document FNU/FOS/95.3). Avaialable at 14 http://www.who.int/foodsafety/publications/micro/en/march1995.pdf. 15 FAO/WHO (1997a) Food consumption and exposure assessment of chemicals. Report of a FAO/WHO 16 Consultation, Geneva, Switzerland, 10-14 February 1997 (Unpublished WHO document 17 WHO/FSF/FOS/97.5). 18 FAO/WHO (1997b) Risk management and food safety. Report of a Joint FAO/WHO Consultation, Rome, 27-31 19 January 1997 (FAO Food and Nutrition Paper No. 65) 20 FAO/WHO (1999) The application of risk communication to food standards and safety matters. Report of a 21 Joint FAO/WHO Expert Consultation, Rome, 2-6 February 1998 (FAO Food and Nutrition Paper No. 70). 22 FAO/WHO (2000) Methodology for exposure assessment of contaminants and toxins in food. Report of a Joint 23 FAO/WHO Workshop, 7-8 June 2000, Geneva, Switzerland. WHO, Geneva. 24 FAO/WHO (2001) Joint FAO/WHO Food Standards Programme. Codex Alimentarius Commission. Procedural 25 Manual, Twelfth edition, Food and Agriculture Organization of the United Nations/World Health 26 Organization, Rome. 27 FAO/WHO (2006) Evaluation of certain food contaminants. Sixty-fourth report of the Joint FAO/WHO Expert 28 Committee on Food Additives (WHO Technical Report Series No. 930). 29 IPCS (2004). IPCS Risk Assessment Terminology. Harmonization Project Document No. 1. World Health 30 Organization, Geneva. Available at: 31 http://www.who.int/ipcs/methods/harmonization/areas/ipcsterminologyparts1and2.pdf (Accessed 1 Jan 32 2008). 33 Kaferstein, F, and Hueston, W (2000) Risk assessment Analysis: The New Paradigm in Food safety Assurance. 34 Presentation at JIFSAN 2000 Seminar. 35 Available at http://www.foodriskclearinghouse.umd.edu/powerpoint/JIFSAN_3_14_00/ (accessed 29-08- 36 07) (from WHO at http://www.who.int/foodsafety/micro/riskanalysis/en/). 37 NRC (1983). Risk Assessment in the Federal Government: Managing the Process, National Research Council. 38 National Academy of Sciences Press, Washington DC, USA. 39 NRC (1994) Science and Judgement in Risk Assessment, NAS Press, Washington, DC, USA. 40 NRC (1996) Understanding Risk: Informing Decisions in a Democratic Society. NAS Press, Washington, DC, 41 USA. 42 Presidential Commission (1997) Risk Assessment and Risk Management in Regulatory Decision-Making, Vol. 43 2, The Presidential/Congressional Commission on Risk Assessment and Risk Management. Washington, 44 DC, USA. 45 Renwick AG, Barlow, SM, Hertz-Picciotto I, Boobis AR, Dybing E, Edler L, Eisenbrand G, Grieg, JB, Kleiner 46 J, Lambe J, Müller DJG, Smith MR, Tritscher A, Tuijtelaars S, van den Brandt PA, Walker R, and Kroes R 47 (2003) Risk chacterization of chemicals in food and diet, Food Chem. Toxicol., 41:1211-1271. 48 WHO (2000) The Interaction between Assessors and Managers of Microbiological Hazards in Food. Report of a 49 WHO Expert Consultation, Kiel, Germany, 21 to 23 March 2000. Geneva.

7