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SCIENTIFIC OPINION

Guidance on human health risk-benefit assessment of foods

EFSA Scientific Committee

European Food Safety Authority (EFSA), Parma, Italy

Abstract

The Scientific Committee of the European Food Safety Authority (EFSA) developed guidance for performing risk-benefit assessments of food. The document focuses on human health risks and human health benefits, and does not address social, economic and other considerations such as “cost-effectiveness” considerations. It is considered as essential that formulation of the problem precedes the risk-benefit assessment as such. Agreement between the risk-benefit assessor and the risk-benefit manager on the terms of reference should be reached in order to ensure that the outcome of the assessment is useful and relevant for the risk-benefit manager goals. A stepwise approach is recommended for the risk-benefit assessment, i.e. i) initial assessment, addressing the question whether the health risks clearly outweigh the health benefits or vice versa, ii) refined assessment, aiming at providing semi-quantitative or quantitative estimates of risks and benefits at relevant exposure by using common metrics, and iii) comparison of risks and benefits using a composite metric such as DALYs or QALYs to express the outcome of the risk-benefit assessment as a single net health impact value. The outcome of each step of the assessment should also include a narrative of the strengths and weaknesses of the evidence base and its associated uncertainties. After each step of the risk-benefit assessment, discussion should take place between the risk-benefit assessor and the risk-benefit manager on whether sufficient information has been provided or whether the terms of reference should be refined in order to proceed with the next step of the assessment. Two examples (selenium as an indispensable nutrient, and fish consumption) illustrate the proposed approach for risk-benefit assessment.

Summary

The European Food Safety Authority (EFSA) asked its Scientific Committee to prepare a guidance document for performing risk-benefit assessments of food related to human health risks and human health benefits.

Risk-benefit assessments are performed in different disciplines, under various perspectives and use a wide range of quantitative or semi-quantitative tools. In this opinion, guidance for performing riskbenefit assessments of food focuses on human health risks and human health benefits and does not address social, economic and other considerations such as “cost-effectiveness” considerations. The Scientific Committee notes that there is less experience with benefit assessment than with risk assessment and therefore proposes to mirror the risk assessment paradigm by introducing four steps for the benefit assessment, i.e. positive health effect identification, positive health effect characterisation (dose response assessment), exposure assessment and benefit characterisation. Following this approach will facilitate a transparent comparison of risks and benefits in the riskbenefit assessment.

Problem formulation should precede the risk-benefit assessment. Agreement on the terms of reference between the risk-benefit assessor and the risk-benefit manager is critical for ensuring a useful and relevant outcome for the risk-benefit manager goals.

After problem formulation, a stepwise approach is recommended using three steps: i) initial assessment, addressing the question whether the health risks far outweigh the health benefits or vice versa, ii) refined assessment, aiming at providing semi-quantitative or quantitative estimates of risks and benefits at relevant exposure by using common metrics, and iii) comparison of risks and benefits using a composite metric such as DALYs or QALYs to express the outcome of the risk-benefit assessment as a single net health impact value. At each of the three steps, both risk assessment and benefit assessment are usually performed at the population level. Where differences in the sensitivity to the agent under consideration exist or are assumed to exist in specific subpopulations, separate consideration of these subpopulations is needed.

After each step of the risk-benefit assessment, discussion should take place between the risk-benefit assessor and the risk-benefit manager on whether sufficient information has been provided or whether the terms of reference should be refined in order to proceed with the next step of the assessment. The outcome of each step of the assessment should also include a narrative of the strengths and weaknesses of the evidence base and its associated uncertainties. The overall magnitude of uncertainty associated with a risk-benefit assessment may often be large. This should not be regarded as implying a failure of the assessment; on the contrary, it provides essential information for decision-making and helps in identification of data needs.

A number of metrics which can be used in the risk-benefit assessment are described in the document. It should be noted that more than one metric will be needed to capture all dimensions of health for a risk-benefit assessment. It is important that the risk-benefit manager is aware of the limitations of the metrics used for measuring risks and benefits.

The Scientific Committee recommends that metrics used in risk-benefit assessment and weight factors associated to most common diseases should be internationally agreed upon in order to ensure harmonisation and recognition of the assessments.

The Scientific Committee recommends a close collaboration between risk assessors and benefit assessors in order to ensure that data generated by one or the other can be used in a broader riskbenefit assessment context. Furthermore, the development of hard biomarkers of effect for both risk and benefit is also needed.

Two examples of the approach for risk-benefit assessment are given. The first one (selenium, an indispensable nutrient) illustrates the case where the risk and the benefit are associated with one single agent, while in the second example (fish), the risk is due to one selected contaminant in food (methylmercury), whilst the benefit is due to other food components. The examples highlight the complexity of risk-benefit assessment, already when entering the first steps of the assessment.

Background as provided by EFSA

Where a food or food substance is recognised to have the potential to exert both health benefits and health risks it is important for risk-benefit managers to be able to weigh the risks against the benefits on the basis of a qualitative or quantitative risk-benefit assessment. However, there is currently no agreement on general principles or approaches for conducting a risk-benefit analysis for food and the assessment of risk to human health of food substances or nutrients is usually conducted independently of possible health benefits.

EFSA organised a scientific colloquium on risk-benefit analysis of foods in July 2006 to have an open scientific debate on the methods and approaches for risk-benefit analysis of foods4. There was a general consensus that a risk-benefit analysis should mirror the approach already agreed upon in the risk analysis, namely consist of a risk-benefit assessment part, a risk-benefit management part, and a riskbenefit communication part. The risk-benefit assessment should be comprised of 3 elements, i.e. risk assessment, benefit assessment and risk-benefit comparison. As for the risk assessment paradigm which is well established, the benefit assessment should also include the following steps: positive health effect identification, positive health effect characterisation (dose-response assessment), exposure assessment, and benefit characterisation. Finally the risk-benefit comparison should contain a means, quantitative if possible, to compare/weigh the potential human health risks against the potential human health benefits. For this a common scale of measurement (“composite metric”) for the risk and the benefit would facilitate the communication of the results.

It is considered that the decision to initiate a risk-benefit analysis would best be made on a case-by-case basis and, given the resources required to carry out such an analysis, should only be undertaken when clearly needed. Therefore the formulation of the problem (“why is the risk-benefit analysis being done, why do we need it?”) is pivotal; furthermore, it is emphasised that the question asked by the risk-benefit manager to the risk-benefit assessor should be clearly understandable.

Regarding tools/data available or needed to quantify the human health risks and health benefits it is considered that tools for classification of risks and of benefits would need to be developed, together with tools for comparison and prioritisation of risks and benefits. Both tools and data should be available, together with a common scale of measurement for risk and benefit. In order to provide confidence in the outcome of a risk-benefit assessment, the assumptions made for the assessment as well as the uncertainties embedded in the outcome should be stated explicitly.

It has been proposed at the EFSA Scientific Colloquium4 that the “state-of-the-art” of risk-benefit assessment had advanced beyond the brainstorming stage and that it was now time to advance to the ”learning by doing” stage. Although it may be premature at present to develop a prescriptive framework for risk-benefit assessment, it is suggested that a guidance document should be developed with respect to methodology, approaches, tools and potential limitations in the risk-benefit assessment.

Terms of reference as provided by EFSA

EFSA requests the Scientific Committee to prepare a guidance document for performing risk-benefit assessments of food related to human health risks and human health benefits. To this end the document should give considerations to the following issues:

• Scope and objective of risk-benefit assessment;
• Identification of situations for which a risk-benefit assessment might be appropriate;
• Guidance on problem formulation particularly considering the type of risk-benefit analysis

needed;

• Development of a harmonised language to express risk and benefits;
• Usefulness of currently available toxicological, epidemiological and nutritional data to assess

risk-benefit;

• Consideration of methods and approaches needed to assess the risks and benefits and to

compare them, e.g. common scale of measurement for the comparison of human health risks and health benefits;

• Considerations on how animal and other data can be extrapolated to the human situation in

order to facilitate human risk-benefit comparison;

• Identification of potential limitations of any risk-benefit assessment;
• Ongoing research activities, such as DG RTD projects and activities undertaken by other

organisations in order to join efforts and aim at harmonised approaches for risk-benefit assessment;

• Recommendations on future initiatives to overcome current limitations.

Assessment

Introduction

In July 2006, EFSA organised a scientific colloquium on risk-benefit analysis of foods, during which it was proposed that the “state-of-the-art” of risk-benefit assessment had advanced beyond the brainstorming stage (van Kreijl et al., 2004) and that it was now time to advance to the “learning by doing” stage. Although it may be premature to develop a prescriptive framework for risk-benefit assessment, it was suggested that a guidance document should be developed with respect to methodology, approaches, tools and potential limitations in the risk-benefit assessment. Since then, several activities such as the Beneris, Qalibra, Brafo and Bepraribean projects, which EFSA has been following closely, have been commenced to address the issue of risk-benefit assessment. In February 2010, the EFSA Scientific Committee endorsed the draft guidance on “human health riskbenefit assessment of foods” for a 6-week public consultation. The 280 comments received from 19 interested parties were considered in April 2010 for finalising the present guidance document (EFSA, 2010).

Risk-benefit assessments are performed in different disciplines, under various perspectives (government, industry, patients) and using a wide range of quantitative and semi-quantitative tools. Examples are human medicine (e.g. assessment of the benefits and risks in the context of a new drug application) and engineering. Many of such assessments include socioeconomic considerations or aspects beyond human health that are not directly comparable and require value judgments to be compared.

The classic case where value judgments are needed is when the risk or benefit assessment is used as the basis of a cost-benefit analysis. In this case risks and benefits are given monetary values reflecting market prices directly or indirectly. The use of economic methods such as willingness to pay studies or co-joint analyses could be helpful in eliciting information on the consumer or citizen preferences and valuing the benefits and risks. The direct and indirect monetary costs of years of life lost through, and years of life spent with diet-related diseases, like cardiovascular diseases or cancer can be calculated based on morbidity and mortality statistics. The EFSA’s Scientific Committee, given EFSA’s remit, excluded social, economic and other considerations such as “cost-effectiveness” from its considerations. In this opinion, guidance for performing risk-benefit assessments of food related to human health risks and human health benefits is provided. The result of such an assessment will enable risk-benefit managers to take decisions and to formulate a strategy, taking into account other considerations such as social, economic or “cost-effectiveness” aspects.

Risk assessment - Definition

Risk assessment is "a process intended to calculate or estimate the risk to a given (sub)population, including the identification of attendant uncertainties, relating to exposure to a particular agent, taking into account the inherent characteristics of the agent of concern as well as the characteristics of the specific target system" (IPCS, 2004). For the purpose of this opinion the agent will be a food itself or a constituent of a food (incl. contaminants, microbes), and the target system is the human body.

Different organisations use different definitions of risk, depending on the focus of their activities. In the context of this opinion, the following definition of risk will be used:

Risk: The probability of an adverse effect in an organism, system9, or (sub)population in reaction to exposure to an agent (IPCS, 2004).

The terms hazard and adverse health effect have been defined for the use in risk assessment:

Hazard: Inherent property of an agent or situation having the potential to cause adverse effects on health when an organism, system, or (sub)population is exposed to that agent (slightly modified from IPCS, 2004).

Adverse (health) effect: a change in morphology, physiology, growth, development, reproduction or life span of an organism, system9 or (sub)population that results in an impairment of functional capacity, an impairment of the capacity to compensate for additional stress, or an increase in susceptibility to other influences (IPCS, 2004; FAO/WHO, 2006).

Notably hazard describes the exposure dependent potential of an agent to cause harm which in this context consists of an adverse effect on health. Therefore, adverse health effects caused by an insufficient intake, e.g. of an indispensable (essential) nutrient are not attributable to a hazardous property of that nutrient; while adverse health effects caused by excessive intake are. Accordingly, the evaluation of a nutrient could be done as a risk-risk comparison, by comparing the risk of inadequacy (deficiency or absence of a beneficial effect) to the risk of excessive intake (toxicity) (Renwick et al., 2004, EFSA, 2006a).

Benefit assessment - Definition

In common language a benefit provides an advantage, a help or an aid and beneficial is something which is helpful or good for something or someone. This means that risk and the term benefit in its conventional sense would not be a pair of corresponding opposite terms, while adverse health effect and positive effect on health are. There is also no term for the inherent potential of an agent (food) to cause beneficial effects on health which would correspond to the term hazard as applied in risk assessment.

In the context of this opinion and in line with the definition of risk, benefit is considered to consist of the probability of a positive effect on health (see box on “Benefit”). The reduction of a risk will also be considered as a benefit. Consequently, the following definition of benefit is used:

Benefit: The probability of a positive health effect and/or the probability of a reduction of an adverse health effect in an organism, system, or (sub)population, in reaction to exposure to an agent.

In contrast to risk assessment there is not much guidance published on how to perform benefit assessment of foods and food constituents. It is proposed in this opinion that positive health effects of nutrients, foods or constituents of food are assessed in a similar way to hazards, that is potential benefits should be identified, described, weighed and arranged according to their magnitude, and their doseresponse relationship should be characterised (see right side of Figure 1). Several concepts for assessing evidence for beneficial effects have been developed (Aggett et al., 2005; WHO/FAO, 2003; WCRF/AICR, 2007).

Risk-benefit assessment - Definition

The EFSA scientific colloquium on Risk-Benefit Analysis of Food (EFSA, 2006b) concluded that a risk-benefit analysis should mirror the approach agreed upon for risk analysis (IPCS, 2004; Codex Alimentarius Commission, 2005; FAO/WHO, 2006), and therefore should include a risk-benefit assessment, a risk-benefit management and a risk-benefit communication part. This opinion focuses on the risk-benefit assessment.

In the risk-benefit assessment, the probability of an adverse health effect or harm (both incidence and severity) as a consequence of exposure can be weighed against the probability of benefit, if both are known to be possible.

The Scientific Committee proposes the following terms and their counterparts for the assessment of the probability of harm (= risk) and of the assessment of the probability of the positive health effects (= benefit).

Figure 1 illustrates the proposed procedure for a risk-benefit assessment which consists of two separate and independent arms of assessing the risk and the benefit, respectively. Both assessments include four steps on both sides that are comparable: identification of the possible hazards and positive / reduced adverse health effects together with their biological mechanisms if possible; characterisation of the identified hazards and positive / reduced adverse health effects with respect to severity, reversibility and dose-response relationship; and characterisation of the risk and the benefit, that is the probability of each identified hazard or positive health effect to occur in a population or population group. The exposure assessment is positioned as a central part of the risk-benefit assessment and should take into account all relevant dietary and non-dietary sources. Finally, the risk-benefit comparison will weigh the risks against the benefits.

Figure 1: The risk-benefit assessment paradigm, as recommended by the EFSA Scientific Committee and based on the discussions of the EFSA scientific colloquium on risk-benefit analysis of foods.

Different scenarios for the risk-benefit assessment can be foreseen due to the nature of the benefits and risks. The different scenarios for different risks and benefits connected with one food and concerning the same or different populations are outlined in Section 2.1.

Proposed approach for risk-benefit assessment

The guidance is primarily designed for the need of the EFSA Scientific Panels and Committee, as well as for Member States’ Competent Authorities who have to provide scientific advice to risk-benefit managers. However, the stepwise approach proposed in this section is also useful for other parties, e.g. academia or industry.

Examples of situations for which a risk-benefit assessment might be appropriate

Risk-benefit assessment would be appropriate in situations, such as, but not restricted to:

• Where a single compound or food constituent has both positive and negative health effects.

These effects may occur: i) in the same population, e.g. for zinc, vitamin A, phytosterols, iron; ii) in different populations e.g. for folic acid fortified food, where the prevention of neural tube defects in the unborn child should be compared with potential hazards, such as masking of vitamin B12 deficiency in the elderly, dementia or colon cancer.

• Where similar levels of dietary exposures can be associated with both risk and benefit.
• Where positive and negative health effects, either in the same or different populations result

from different components in the same food e.g.: i) fatty fish, where the main potential beneficial effects related to prevention of cardiovascular diseases by n3 fatty acids need to be compared with the potential negative health effects of environmental pollutants such as dioxins or PCBs, or ii) consumption of vegetables, where the positive effects such as supplying of micronutrients and prevention of certain types of cancer should be weighed against the potential hazards of the presence of nitrates, such as methaemoglobinaemia in infants and formation of carcinogenic nitrosamines. Before the start of an intervention, such as folic acid fortification, or fluoridation of drinking water.

• Where a significant change of dietary consumption patterns has occurred or may occur in the

future, e.g. substituting sugar by low-calorie sweeteners.

• Where chemicals are used to reduce microbial contamination, e.g. use of disinfection processes.
• Where the beneficial effect, such as enhanced retention of nutritional value resulting from

improved processing procedures, requires to be assessed against the negative effects associated with a greater survival of foodborne pathogens.

• Where new knowledge emerges with major implications for either the risk(s) or the benefit(s) in

a previous risk assessment, benefit assessment or risk-benefit assessment. For example the possible association between folic acid consumption and colon cancer.

It is to be noted that risk-benefit assessment does not replace procedures required by existing European legislation, e.g. safety assessment and authorisation of a food additive.

Key words

Risk, benefit, assessment, problem formulation, risk-benefit assessment paradigm, stepwise approach, metrics

Full 40 pages document:

File:EFSA Guidance for risk-benefit asssments July 2010.pdf