A Risk Assessment Model for Establishing Upper Intake Levels for Nutrients

http://www.fsis.usda.gov/OA/codex/ccnfsdu1.htm
U.S. Department of Agriculture, Food Safety and Inspection Service

Codex Alimentarius Commission

Adapted from the two DRI reports published to date: Dietary Reference Intakes for Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride (IOM, 1997), and Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline (IOM, 1998).

INTRODUCTION
The model for risk assessment of nutrients used to develop tolerable upper intake levels (ULs) is one of the key elements of the developing framework for Dietary Reference Intakes, which are dietary reference values for the intake of nutrients and food components by Americans and Canadians recently released by the U.S. National Academy of Sciences in a series of reports. The overall project is a comprehensive effort undertaken by the Standing Committee on the Scientific Evaluation of Dietary Reference Intakes (DRI Committee) of the Food and Nutrition Board (FNB), Institute of Medicine, National Academy of Sciences in the United States, with active involvement of Health Canada. The DRI project is the result of significant discussion from 1991 to l996 by the FNB regarding how to approach the growing concern that one set of quantitative estimates of recommended intakes, the Recommended Dietary Allowances (RDAs), was scientifically inappropriate to be used as the basis for many of the uses to which they had come to be applied. The lack of specific determinations of maximum or tolerable upper levels of intake was noted. It is expected that when evaluation of all groups of nutrients and food components are completed as part of this ongoing process, the model will have been fully developed and validated.

WHAT ARE DIETARY REFERENCE INTAKES?
Dietary Reference Intakes (DRIs) are reference values that are quantitative estimates of nutrient intakes to be used for planning and assessing diets for healthy people. They include both recommended intakes and ULs as reference values. Although the reference values are based on data, the data are often scanty or drawn from studies that had limitations in addressing the question.

Thus, scientific judgment is required in setting the reference values: Recommended Dietary Allowance (RDA): the average daily dietary intake level that is sufficient to meet the nutrient requirement of nearly all (97 to 98 percent) healthy individuals in a group. Adequate Intake (AI): a value based on observed or experimentally determined approximations of nutrient intake by a group (or groups) of health peopleCused when an RDA cannot be determined. Tolerable Upper Intake Level (UL): the highest level of daily nutrient intake that is likely to pose no risks of adverse health effects to almost all individuals in the general population Tolerable Upper Intake Level ULs are useful because of the increased interest in and availability of fortified foods and the increased use of dietary supplements. ULs are based on total intake of a nutrient from food, water, and supplements if adverse effects have been associated with total intake. However, if adverse effects have been associated with intake from supplements or food fortificants only, the UL is based on nutrient intake from those sources only, not on total intake. The UL applies to chronic daily use. The UL is the highest level of daily nutrient intake that is likely to pose no risks of adverse health effects to almost all individuals in the general population. As intake increases above the UL, the risk of adverse effects increases. For many nutrients, there are insufficient data on which to develop a UL. This does not mean that there is no potential for adverse effects resulting from high intake. When data about adverse effects are extremely limited, extra caution may be warranted. Terminology The term "tolerable" is chosen because it connotes a level of intake that can, with high probability, be tolerated biologically by individuals; it does not imply acceptability of that level in any other sense. The setting of a UL does not indicate that nutrient intakes greater than the RDA or AI are recommended as being beneficial to an individual. Many individuals are self-medicating with nutrients for curative or treatment purposes. It is beyond the scope of the model at this time to address the possible therapeutic benefits of higher nutrient intakes that may offset the risk of adverse effects. The UL is not meant to apply to individuals who are treated with the nutrient or food component under medical supervision. The term "adverse effect" is defined as any significant alteration in the structure or function of the human organism, or any impairment of a physiologically important function, in accordance with the definition set by the joint World Health Organization, Food and Agriculture Organization of the United Nations, and International Atomic Energy Agency Expert Consultation in Trace Elements in Human Nutrition and Health. In the case of nutrients, it is exceedingly important to consider the possibility that the intake of one nutrient may alter in detrimental ways the health benefits conferred by another nutrient. Any such alteration (referred to as an adverse nutrient-nutrient interaction) is considered an adverse health effect. When evidence for such adverse interactions is available, it is considered in establishing a nutrient's UL.

APPROACH FOR SETTING DIETARY REFERENCE INTAKES, INCLUDING TOLERABLE UPPER INTAKE LEVELS
The scientific data used to develop recommended intakes and ULs have come from observational and experimental studies. Studies published in peer-reviewed journals were the principal source of data. Life stage and gender were considered to the extent possible; but for some nutrients, the data did not provide a basis for proposing different requirements or upper levels for men and women or for adults in different age groups. Three of the categories of reference values (EAR, RDA, and AI) are defined by specific criteria of nutrient adequacy; the fourth (UL) is defined by a specific end point of adverse effect if one is available. In all cases, data were examined closely to determine whether reduction of risk of a chronic degenerative disease or developmental abnormality could be used as a criterion of adequacy. The quality of studies was examined, considering study design, methods used for measuring intake and indicators of adequacy, and biases, interactions, and confounding factors. After careful review and analysis of the evidence, including examination of the extent of congruence of findings, scientific judgment was used to determine the basis for establishing the values. Like all chemical agents, nutrients can produce adverse health effects if intakes from any combination of food, water, nutrient supplements, and pharmacologic agents is excessive. Some lower level of nutrient intake will ordinarily pose no likelihood (or risk) of adverse health effects in normal individuals even if the level is above that associated with any benefit. It is not possible to identify a single "risk-free" intake level for a nutrient that can be applied with certainty to all members of a population. However, it is possible to develop intake levels that are unlikely to pose risks of adverse health effects to most members of the general population, including sensitive individuals. For some nutrients or food components these intake levels may, however, pose a risk to subpopulations with extreme or distinct vulnerabilities.

MODEL FOR THE DERIVATION OF TOLERABLE UPPER INTAKE LEVELS
Given the current state of knowledge, any attempt to capture in a mathematical model all the information and scientific judgments that must be made to reach conclusions regarding ULs would not be consistent with contemporary risk assessment practices. Instead, the model for the derivation of ULs consists of a set of scientific factors that always should be considered explicitly. The framework under which these factors are organized is called risk assessment. Risk assessment is a systematic means of evaluating the probability of occurrence of adverse health effects in humans from excess exposure to an environmental agent (in this case, a nutrient or food component). The hallmark of risk assessment is the requirement to be explicit in all the evaluations and judgments that must be made to document conclusions.

RISK ASSESSMENT AND FOOD SAFETY
Basic Concepts Risk assessment is a scientific undertaking having as its objective a characterization of the nature and likelihood of harm resulting from human exposure to agents in the environment. The characterization of risk typically contains both qualitative and quantitative information and includes a discussion of the scientific uncertainties in that information. In the present context, the agents of interest are nutrients, and the environmental media are food, water, and nonfood sources such as nutrient supplements and pharmacologic preparations. Performing a risk assessment results in a characterization of the relationships between exposure(s) to an agent and the likelihood that adverse health effects will occur in members of exposed populations. Scientific uncertainties, an inherent part of the risk assessment process, are (1) those related to data and (2) those associated with inferences that are required when directly applicable data are not available. Deciding whether the magnitude of exposure is "acceptable" in specific circumstances is not a component of risk assessment; this activity falls within the domain of risk management. Risk management decisions depend on the results of risk assessments but may also involve the public health significance of the risk, the technical feasibility of achieving various degrees of risk control, and the economic and social costs of this control. Because there is no single, scientifically definable distinction between "safe" and "unsafe" exposures, risk management necessarily incorporates components of sound, practical decision making that are not addressed by the risk assessment process. A risk assessment requires that information be organized in rather specific ways but does not require any specific scientific evaluation methods. Rather, risk assessors must evaluate scientific information using what they judge to be appropriate methods; and they must make explicit the basis for their judgments, the uncertainties in risk estimates, and when appropriate, alternative interpretations of the available data that may be scientifically plausible. Options for dealing with uncertainties are discussed in detail in Appendix II of the report. Steps in the Risk Assessment Process The organization of risk assessment is based on a model proposed by the NRC; that model is widely used in public health and regulatory decision making. The steps of risk assessment as applied to nutrients are as follows: Step 1. Hazard identification involves the collection, organization, and evaluation of all information pertaining to the dverse effects of a given nutrient. It concludes with a summary of the evidence concerning the capacity of the nutrient to cause one or more types of toxicity in humans. Step 2. Dose-response assessment determines the relationship between nutrient intake (dose) and adverse effect (in terms of incidence and severity). This step concludes with an estimate of the ULCit identifies the highest level of daily nutrient intake that is likely to pose no risks of adverse health effects to almost all individuals in the general population. Different ULs may be developed for various life-stage groups. Step 3. Intake assessment evaluates the distribution of usual total daily nutrient intakes among members of the general population. Step 4. Risk characterization summarizes the conclusions from Steps 1 through 3 and evaluates the risk. Generally, the isk is expressed as the fraction of the exposed population, if any, having nutrient intakes (Step 3) in excess of the estimated UL (Steps 1 and 2). If possible, characterization also covers the magnitude of any such excesses. Scientific uncertainties associated with both the UL and the intake estimates are described so that risk managers understand the degree of scientific confidence they can place in the risk assessment. The risk assessment contains no discussion of recommendations for reducing risk; these are the focus of risk management. Thresholds Thresholds vary among members of the general population. For any given adverse effect, if the distribution of thresholds in the population could be quantitatively identified, it would be possible to establish ULs by defining some point in the lower tail of the distribution of thresholds that would be protective for some specified fraction of the population. However, data are not sufficient to allow identification of the distribution of thresholds for all but a few, well-studied nutrients and compounds found in food (for example, acute toxic effects or for chemicals such as lead, where the human database is very large). The model method for identifying thresholds for a general population is designed to ensure that almost all members of the population will be protected, but it is not based on an analysis of the theoretical (but practically unattainable) distribution of thresholds. By using the model to derive the threshold, however, there is considerable confidence that the threshold, which becomes the UL for nutrients or food components, lies very near the low end of the theoretical distribution, and is the end representing the most sensitive members of the population. For some nutrients, there may be subpopulations that are not included in the general distribution because of extreme or distinct vulnerabilities to toxicity. Such distinct groups, whose conditions warrant medical supervision, may not be protected by the UL. When possible, the UL is based on a no-observed-adverse-effect level (NOAEL), which is the highest intake (or experimental oral dose) of a nutrient at which no adverse effects have been observed in the individuals studied. This is identified for a specific circumstance in the hazard identification and dose-response assessment steps of the risk assessment. If there are no adequate data demonstrating a NOAEL, then a lowest-observed-adverse-effect level (LOAEL) may be used. A LOAEL is the lowest intake (or experimental oral dose) at which an adverse effect has been identified. The derivation of a UL from a NOAEL (or LOAEL) involves a series of choices about what factors should be used to deal with uncertainties. Uncertainty factors are applied in an attempt both to deal with gaps in data and with incomplete knowledge regarding the inferences required (for example, the expected variability in response within the human population). The problems of both data and inference uncertainties arise in all steps of the risk assessment. A discussion of options available for dealing with these uncertainties is presented in the report and in greater detail in the Appendix II. A UL is not, in itself, a description of human risk. It is derived by application of the hazard identification and dose-response evaluation steps (Steps 1 and 2) of the risk assessment model. To determine whether populations are at risk requires an intake or exposure assessment (Step 3, evaluation of their intakes of the nutrient) and a determination of the fractions of those populations, if any, whose intakes exceed the UL. In the intake assessment and risk characterization steps (Steps 3 and 4), the distribution of actual intakes for the population is used as a basis in determining whether and to what extent the population is at risk.

APPLICATION OF THE RISK ASSESSMENT MODEL TO NUTRIENTS
This section provides guidance for applying the risk assessment framework (the model) to the derivation of ULs for nutrients. Special Problems Associated with Substances Required for Human Nutrition Although the risk assessment model outlined above can be applied to nutrients to derive ULs, it must be recognized that nutrients possess some properties that distinguish them from the types of agents for which the risk assessment model has originally developed. In the application of accepted standards for assessing risks of environmental chemicals to the risk assessment of nutrients and food components, a fundamental difference between the two categories must be recognized: within a certain range of intakes, many nutrients are essential for human well-being and usually for life itself. Nonetheless, they may share with other chemicals the production of adverse effects at excessive exposures. Because the consumption of balanced diets is consistent with the development and survival of humankind over many millennia, there is less need for the large uncertainty factors that have been used in the typical risk assessment of nonessential chemicals. In addition, if data on the adverse effects of nutrients are available primarily from studies in human populations, there will be less uncertainty than is associated with the types of data available on nonessential chemicals. There is no evidence to suggest that nutrients consumed at the recommended intake (the RDA or AI) present a risk of adverse effects to the general population. It is clear, however, that the addition of nutrients to a diet, either through the ingestion of large amounts of highly fortified food or nonfood sources such as supplements, or both, may (at some level) pose a risk of adverse health effects. The UL is the highest level of daily nutrient intake that is likely to pose no risks of adverse health effects to almost all individuals in the general population. As intake increases above the UL, the risk of adverse effects increases. If adverse effects have been associated with total intake, ULs are based on total intake of a nutrient from food, water, and supplements. For cases in which adverse effects have been associated with intake only from supplements and/or food fortificants, the UL is based on intake from those sources only, rather than on total intake. The effects of nutrients from fortified foods or supplements may differ from those of naturally occurring constituents of foods because of several factors: the chemical form of the nutrient, the timing of the intake and amount consumed in a single bolus dose, the matrix supplied by the food, and the relation of the nutrient to the other constituents of the diet. Nutrient requirements and food intake are related to the metabolizing body mass, which is also at least an indirect measure of the space in which the nutrients are distributed. This relation between food intake and space of distribution supports homeostasis, which maintains nutrient concentrations in that space within a range compatible with health. However, excessive intake of a single nutrient from supplements or fortificants may compromise this homeostatic mechanism. Such elevations alone may pose risks of adverse effects; imbalances among the concentrations of mineral elements (for example, calcium, iron, zinc, an copper) can result in additional risks. These reasons and those discussed previously support the need to include the form and pattern of consumption in the assessment of risk from high nutrient intake. Consideration of Variability in Sensitivity This risk assessment model outlined in this paper is consistent with classical risk assessment approaches in that it must consider variability in the sensitivity of individuals to adverse effects of nutrients. Variability in the context of nutritional risk assessment deals with Physiological changes and common conditions associated with growth and maturation that occur during an individual's ifespan may influence sensitivity to nutrient toxicity. Even within relatively homogeneous life-stage groups, there is a range of sensitivities to toxic effects. The model accounts for normally expected variability in sensitivity, but it excludes ubpopulations with extreme and distinct vulnerabilities that are better served through the use of public health screening, product labeling, or other individualized health care strategies. Bioavailability (accessibility to normal metabolic and physiological processes) influences a nutrient's beneficial effects at hysiological levels of intake and also may affect the nature and severity of toxicity due to excessive intakes. Factors that affect bioavailability include the concentration and chemical form of the nutrient, the nutrition and health of the individual, and excretory losses. Adverse health effects that can result when there is an imbalance in the intake of two or more nutrients that significantly levates or reduces bioavilability. Excessive intake of one nutrient may interfere with absorption, excretion, transport, storage, function, or metabolism of a second nutrient. Individual nutritional status influences the absorption and utilization of most minerals, trace elements, and some vitamins. Form of intake influences the absorption of minerals and trace elements; they are less readily absorbed when they are part of a meal than when taken separately or when present in drinking water. The opposite is true for fat-soluable vitamins whose absorption depends on fat in the diet.

STEPS IN THE DEVELOPMENT OF THE TOLERABLE UPPER INTAKE LEVEL
Step 1. Hazard identification involves the collection, organization, and evaluation of all information pertaining to the adverse effects of a given nutrient. It concludes with a summary of the evidence concerning the capacity of the nutrient to cause one or more types of toxicity in humans. Human data provide the most relevant kind of information for hazard identification, and, when they are of sufficient quality and extent, are given greatest weight. Animal data provides the majority of the available data used in regulatory risk assessments. However, cross species differences make the usefulness of animal data for establishing ULs problematic. The report addresses the following key issues in the data evaluation of human and animal studies. Evidence of adverse effects in humans. Causality. Relevance of experimental data. Mechanisms of toxic action. Quality and completeness of the database. Identification of distinct and highly sensitive subpopulations. Step 2. Dose-response assessment determines the relationship between nutrient intake (dose) and adverse effect (in terms of incidence and severity). This step concludes with an estimate of the ULCit identifies the highest level of daily nutrient intake that is likely to pose no risks of adverse health effects to almost all individuals in the general population. Different ULs may be developed for various life-stage groups. The following components of the dose-response assessment are addressed in the report. Data selection. Identification of no-observed-adverse-effect level (NOAEL) or lowest-observed-adverse-effect level (LOAEL) and critical endpoint. Uncertainty assessment. Derivation of a UL. Characterization of the estimate and special considerations. Step 3. Intake assessment evaluates the distribution of usual total daily nutrient intakes among members of the general population. Step 4. Risk characterization summarizes the conclusions from Steps 1 through 3 and evaluates the risk. Generally, the isk is expressed as the fraction of the exposed population, if any, having nutrient intakes (Step 3) in excess of the estimated UL (Steps 1 and 2). If possible, characterization also covers the magnitude of any such excesses. Scientific uncertainties associated with both the UL and the intake estimates are described so that risk managers understand the degree of scientific confidence they can place in the risk assessment. Identification of NOAEL (or LOAEL) and Critical Endpoint A nutrient can produce more than one toxic effect (or endpoint), even within the same species or in studies using the same or different exposure durations. The NOAELs and (LOAELs) for these effects will differ. The critical endpoint used to establish a UL is the adverse biological effect exhibiting the lowest NOAEL (for example, the most sensitive indicator of a nutrient or food component's toxicity). The derivation of a UL based on the most sensitive endpoint will ensure protection against all other adverse effects. For some nutrients, there may be inadequate data on which to develop a UL. The lack of reports of adverse effects following excess intake of a nutrient does not mean that adverse effects do not occur. As the intake of any nutrient increases, a point (A) is reached at which intake begins to pose a risk. Above this point, increased intake increases the risk of adverse effects. For some nutrients, and for various reasons, there are inadequate data to identify point A, or even to make any estimate of its location. Because adverse effects are almost certain to occur for any nutrient at some level of intake, it should be assumed that such effects may occur for nutrients for which a scientifically documentable UL cannot now be derived. Until a UL is set or an alternative approach to identifying protective limits is developed, intakes greater than the RDA or AI should be viewed with caution. Uncertainty Assessment Several judgments must be made regarding the uncertainties and thus the uncertainty factor (UF) associated with extrapolating from the observed data to the general population (see Appendix II). Applying a UF to a NOAEL (or LOAEL) results in a value for the derived UL that is less than the experimentally derived NOAEL, unless the UF is 1.0. The larger the uncertainty, the larger the UF and the smaller the UL. This is consistent with the ultimate goal of the risk assessment: to provide an estimate of a level of intake that will protect the health of the healthy population. Although several reports describe the underlying basis for UFs, the strength of the evidence supporting the use of a specific UF will vary. Because the imprecision of these UFs is a major limitation of risk assessment approaches, considerable leeway must be allowed for the application of scientific judgment in making the final determination. Since data are generally available regarding intakes of nutrients and food components in human populations, the data on nutrient toxicity may not be subject to the same uncertainties as with nonessential chemical agents resulting in UFs for nutrients and food components typically less than 10. They are lower with higher quality data and when the adverse effects are extremely mild and reversible. In general, when determining a UF, the following potential sources of uncertainty are considered and combined into the final UF: Interindividual variation in sensitivity. Small UFs (close to 1) are used if it is judged that little population variability is expected for the adverse effect, and larger factors (close to 10) are used if variability is expected to be great. Experimental animal to human. A UF is generally applied to the NOAEL to account for the uncertainty in extrapolating animal data to humans. Larger UFs (close to 10) may be used if it is believed that the animal responses will underpredict average human responses. LOAEL to NOAEL. If a NOAEL is not available, a UF may be applied to account for the uncertainty in deriving a UL from the LOAEL. The size of the UF involves scientific judgment based on the severity and incidence of the observed effect at the LOAEL and the steepness (slope) of the dose response. Subchronic NOAEL to predict chronic NOAEL. When data are lacking on chronic exposures, scientific judgment is necessary to determine whether chronic exposure is likely to lead to adverse effects at lower intakes than those producing effects after subchronic exposures (exposures of shorter duration). Characterization of the Estimate and Special Considerations ULs are derived for various life-stage groups using relevant databases, NOAELs and LOAELs, and UFs. In cases where no data exist with regard to NOAELs or LOAELs for the group under consideration, extrapolations from data in other age groups and/or animal data are made on the basis of known differences in body size, physiology, metabolism, absorption, and excretion of the nutrient. If the data review reveals the existence of subpopulations having distinct and exceptional sensitivities to a nutrient's toxicity, these subpopulations should be explicitly discussed and concerns related to adverse effects noted; however the use of the data is not included in the identification of the NOAEL or LOAEL upon which the UL for the general population is based.

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Abridged Version
Food and Nutrition Board Institute of Medicine National Academy of Sciences Washington, DC
June 1998. Copyright© 1998, National Academy of Sciences. All rights reserved. Unabridged document available contact: Elizabeth Yetley, U.S. Food and Drug Administration, Washington, D.C. 20204. Phone: (202)205-4168; FAX (202)205-5295; EYetley@bangate.fda.gov.