State of the art in benefit–risk analysis: Food and nutrition

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This page (including the files available for download at the bottom of this page) contains a draft version of a manuscript, whose final version is published and is available in the Food and Chemical Toxicology 50 (2012) 5–25. If referring to this text in scientific or other official papers, please refer to the published final version as: M.J. Tijhuis, N. de Jong, M.V. Pohjola, H. Gunnlaugsdóttir, M. Hendriksen, J. Hoekstra, F. Holm, N. Kalogeras, O. Leino, F.X.R. van Leeuwen, J.M. Luteijn, S.H. Magnússon, G. Odekerken, C. Rompelberg, J.T. Tuomisto, Ø. Ueland, B.C. White, H. Verhagen: State of the art in benefit–risk analysis: Food and nutrition. Food and Chemical Toxicology 50 (2012) 5–25 doi:10.1016/j.fct.2011.06.010 .

Title

Editing State of the art in benefit–risk analysis: Food and nutrition

Authors and contact information

M.J. Tijhuis, correspondence author

(mariken.tijhuis@rivm.nl)

(National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands)

(Maastricht University, School of Business and Economics, Maastricht, The Netherlands)

N. de Jong

(National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands)

M.V. Pohjola

(National Institute for Health and Welfare (THL), Kuopio, Finland)

H. Gunnlaugsdóttir

(Matís, Icelandic Food and Biotech R&D, Reykjavík, Iceland)

M. Hendriksen

(National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands)

J. Hoekstra

(National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands)

F. Holm

FoodGroup Denmark & Nordic NutriScience, Ebeltoft, Denmark

N. Kalogeras

(Maastricht University, School of Business and Economics, Maastricht, The Netherlands)

O. Leino

(National Institute for Health and Welfare (THL), Kuopio, Finland)

F.X.R. van Leeuwen

(National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands)

J.M. Luteijn

University of Ulster, School of Nursing, Northern Ireland, United Kingdom

S.H. Magnússon

(Matís, Icelandic Food and Biotech R&D, Reykjavík, Iceland)

G. Odekerken

(Maastricht University, School of Business and Economics, Maastricht, The Netherlands)

C. Rompelberg

(National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands)

J.T. Tuomisto

(National Institute for Health and Welfare (THL), Kuopio, Finland)

Ø. Ueland

(Nofima, Ås, Norway)

B.C. White

(University of Ulster, Dept. of Pharmacy & Pharmaceutical Sciences, School of Biomedical Sciences, Northern Ireland, United Kingdom)

H. Verhagen i,j

(National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands)

(Maastricht University, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht, The Netherlands)

(University of Ulster, Northern Ireland Centre for Food and Health (NICHE), Northern Ireland, United Kingdom)

Article info

Article history: Available online 12 June 2011

=Abstract

Benefit–risk assessment in food and nutrition is relatively new. It weighs the beneficial and adverse effects that a food (component) may have, in order to facilitate more informed management decisions regarding public health issues. It is rooted in the recognition that good food and nutrition can improve health and that some risk may be acceptable if benefit is expected to outweigh it. This paper presents an overview of current concepts and practices in benefit–risk analysis for food and nutrition. It aims to facilitate scientists and policy makers in performing, interpreting and evaluating benefit–risk assessments.

Historically, the assessments of risks and benefits have been separate processes. Risk assessment is mainly addressed by toxicology, as demanded by regulation. It traditionally assumes that a maximum safe dose can be determined from experimental studies (usually in animals) and that applying appropriate uncertainty factors then defines the ‘safe’ intake for human populations. There is a minor role for other research traditions in risk assessment, such as epidemiology, which quantifies associations between determinants and health effects in humans. These effects can be both adverse and beneficial. Benefit assessment is newly developing in regulatory terms, but has been the subject of research for a long time within nutrition and epidemiology. The exact scope is yet to be defined. Reductions in risk can be termed benefits, but also states rising above ‘the average health’ are explored as benefits. In nutrition, current interest is in ‘optimal’ intake; from a population perspective, but also from a more individualised perspective.

In current approaches to combine benefit and risk assessment, benefit assessment mirrors the traditional risk assessment paradigm of hazard identification, hazard characterization, exposure assessment and risk characterization. Benefit–risk comparison can be qualitative and quantitative. In a quantitative comparison, benefits and risks are expressed in a common currency, for which the input may be deterministic or (increasingly more) probabilistic. A tiered approach is advocated, as this allows for transparency, an early stop in the analysis and interim interaction with the decision-maker. A general problem in the disciplines underlying benefit–risk assessment is that good dose–response data, i.e. at relevant intake levels and suitable for the target population, are scarce.

It is concluded that, provided it is clearly explained, benefit–risk assessment is a valuable approach to systematically show current knowledge and its gaps and to transparently provide the best possible science- based answer to complicated questions with a large potential impact on public health.

Abbreviations

ADI, acceptable daily intake; AICR, Association for International Cancer Research; ALARA, as low as reasonably achievable; AR, Average Requirement; ATBC, alpha-tocopherol, beta carotene cancer prevention (trial); BCRR, Benefit Cancer Risk Ratio; BENERIS, benefit–risk assessment for food: an iterative value-of-information approach; BMD, benchmark dose; BMDL, lower one-sided confidence limit on the BMD; BNRR, Benefit Noncancer Risk Ratio; BRA, Benefit–risk analysis; BRAFO, benefit risk analysis of foods; CARET, beta-carotene and retinol efficacy trial; DALY, disability adjusted life years; EAR, Estimated Average Requirement; EFSA, European Food Safety Authority; FAO, [United Nations] Food and Agriculture Organization; FOSIE, food safety in Europe: risk assessment of chemicals in the food and diet; FUFOSE, Functional Food Science in Europe; ILSI, International Life Sciences Institute; JECFA, Joint FAO/WHO Expert Committee on Food Additives; LLAB, lower level of additional benefit; LOAEL, Lowest Observed Adverse Effect Level; MOE, margin of exposure; NOAEL, No Observed Adverse Effect Level; OECD, Organisation for Economic Co-operation and Development; PAR, population attributable risk; PASSCLAIM, process for the assessment of scientific support for claims on foods; POD, point of departure; PRI, population reference intake; RDA, recommended dietary allowance; RfD, Reference Dose; RIVM, [Dutch] National Institute for Public Health and the Environment; RR, relative risk; SCF, Scientific Committee on Food; (P)TDI/WI/MI, (provisional) tolerable daily/weekly/monthly intake; UL, tolerable upper intake level; ULAB, upper level of additional benefit; WHO, World Health Organization; QALIBRA, quality of life – integrated benefit and risk analysis; QALY, quality adjusted life years; WCRF, World Cancer Research Fund.

Keywords

Keywords: Benefit–risk, Benefit, Risk, Food, Nutrition

Introduction to the scope of this paper

Food and nutrition are in essence necessary and beneficial to, but may also have adverse effects on, human health. Public health professionals have realized, while acknowledging the success of the current food safety system, that the health loss due to unhealthy food and nutrition is many times greater than that attributable to unsafe food; and that the health gains to be made through the consumption of certain foods are many times greater than the health risks involved (van Kreijl et al., 2006). The beneficial and adverse effects may occur concurrently through a single food item (for example fish or whole grain products) or a single food component (for example folic acid or phytosterols), within the same population range of dietary intake. This means that any policy action directed at the adverse effects also affects the degree of beneficial effects. The challenge in the relatively new field of benefit–risk assessment in food and nutrition is to scientifically measure and weigh these two sides.

Historically, the assessments of benefits and risks have been separate processes, where by far most attention has been directed at the assessment of risks, as required by regulation (EU, 2000, 2002b). Focus has been on food safety, with precaution as a risk management option (EC, 2000a) surrounded by much debate as to when and how it should be applied. Worded differently, it is a political decision whether or not to include benefits. From a public health perspective, however, a decision-making process which strives for the lowest risk does not by definition lead to the optimal population health outcome. If the benefits are high enough, some risk may be acceptable. As such, there is a broader picture to be assessed.

The benefit–risk assessment approach entails a paradigm shift from traditional risk analysis, as known from toxicology, to benefit– risk analysis. Essentially, it brings together different scientific disciplines, which have their own history, perspective, tools and uncertainties:

• Toxicology, the discipline that traditionally investigates the risk

of ‘too much’ (acute or chronic adverse effects), as required by the regulatory process.

• Nutrition, a younger discipline that investigates the risk of ‘too

little’ (nutritional deficiencies), the risk of ‘too much’ (nutritional intoxications or affluence-associated problems) and the benefits of optimal nutrient intakes.

In benefit–risk assessment, there is an important role for epidemiology, the methodology-oriented discipline that investigates associations between (real-life human) exposures and health outcomes, adverse or beneficial.

In order to weigh the risks and benefits of foods or their components, they must be evaluated and expressed in a comparable way. Methodologies have been developed and applied to actual cases. New grounds have been explored, yet consensus on the general principles or approaches for conducting benefit– risk analysis for foods and food components still needs to be reached.

This paper presents an overview of current approaches to an integrated weighing of benefits and risks, a state of the art in benefit– risk analysis, in the field of food and nutrition. In this, most attention is directed at the assessment phase, but benefit–risk management and benefit–risk communication are also recognized as an integral part of the benefit–risk paradigm. The perspective is broad, rather than technical. The aim is to facilitate scientists and policy makers in carrying out and judging benefit–risk assessments, to eventually come to better informed decisions about food-related health issues.

We start with an overview of key terms in the field. We then describe risk assessment and benefit assessment separately to build up to a description of current approaches to combine the two. This is illustrated by an overview of benefit–risk case studies and followed by a brief description of benefit–risk management and communication. We end with conclusions and recommendations.

Key terms in benefit–risk assessment of food and nutrition

As benefit–risk assessment of food and nutrition involves different disciplines using different scientific jargon, we first define the key terms as they are used in this review: food, nutrition, risk, benefit and benefit–risk assessment.

In this review, food is defined as any substance or product, whether processed, partially processed or unprocessed, intended to be, or reasonably expected to be ingested by humans (EU, 2002a). Foods are made up of many different components affecting body functions. ‘‘Food’’ and ‘‘food component’’ are viewed as a broad concept: macronutrients, micronutrients, bioactive nonnutrients, additives, contaminants, residues, phyto/phyco/mycotoxins, micro-organisms, allergens, supplements, whole foods and novel foods. The total of these components that are ingested via food, naturally occurring or added, can be seen as nutrition. Notably, ‘nutritious’ has the connotation of ‘healthy’. As a science, ‘‘nutrition’’ studies the total of processes by which food or its components are ingested, digested, absorbed, metabolized, utilized, needed and excreted, and the interactions between these components and between these processes, and their effect on human health and disease.

In the food and nutrition context, we see risk as the probability and severity of an adverse health effect occurring to humans following exposure (or lack of exposure) to a food or food component. In risk assessment, a distinction is made between ‘‘risk’’ and ‘‘hazard’’. In this context, the intrinsic potential of a food (component) to result in adverse health effects is called a hazard. A hazard, then, becomes a risk if there is sufficient exposure. Risk can result from both action and lack of action and both can be analyzed (Wilson and Crouch, 2001). An ‘‘adverse health effect’’ is defined by the WHO as ‘a change in morphology, physiology, growth, development or life span of an organism, which results in impairment of functional capacity or impairment of capacity to compensate for additional stress or increase in susceptibility to the harmful effects of environmental influences’ (WHO, 1994). A ‘‘beneficial health effect’’ can analogously be seen as ‘an improvement of functional capacity or improvement of capacity to deal with stress or decrease in susceptibility to the harmful effects of environmental influences’ in the above definition (Palou et al., 2009). On the benefit side, no parallel words exist for ‘‘hazard’’ and ‘‘risk’’. In order to make the parallel distinction on the benefit side but also have similarity in nomenclature, we will use ‘‘adverse health effects’’ and ‘‘beneficial health effects’’ instead of hazards and benefits. In this review we use benefit analogously to ‘‘risk’’, as the probability and degree of a beneficial health effect occurring to humans following exposure (or lack of exposure) to a food (component). Beneficial health effects may postpone the onset of disease and thus benefit can also be measured as a reduction of risk.

Benefit–risk assessment is seen here as a science-based process intended to estimate the benefits and risks for humans following exposure (or lack of exposure) to a particular food or food component and to integrate them in comparable measures, thus facilitating better informed decisions by decision-makers.

Risk assessment

Risk assessment is an established field, that is mainly addressed by toxicology (Faustman and Omenn, 2008). The traditional risk assessment paradigm (EC, 2000b) consists of

• hazard identification (what effect?),
• hazard characterization (at what dose? how?),
• exposure assessment (how much is taken in?) and
• risk characterization (what is the probability and severity of the effect?).

A risk assessment framework specifically for food has been developed in the context of the FOSIE project (Food Safety in Europe, www.ilsi.org/Europe) (Smith, 2002). The basic concepts and approaches to risk assessment in toxicology will be addressed in Section 3.1. A separate paragraph is dedicated to micronutrients, which is placed under toxicology for practical reasons. There is an additional (not yet clearly defined) role for epidemiology, which will be addressed in Section 3.2. Focus will be on those characteristics where the most pronounced differences exist between toxicology, epidemiology and later benefit assessment, and which need to be considered when integrating the different disciplines. Table 1 presents a summary of some of the characteristics of toxicological and epidemiologic risk assessment.