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* Food Science and Nutrition Department, California Polytechnic State University, San Luis Obispo, CA, 93407; and North American Branch of the International Life Sciences Institute, Washington, DC, 20005
3 To whom correspondence should be addressed. Email: lberner{at}calpoly.edu.
Workshop speakers and participants valued the opportunity to discuss tolerable upper intake levels (ULs)4 and thereby contributed to the timely discussion of strategies to improve the science behind and communication about dietary reference intakes (DRI) and the DRI process as a whole. This article captures the outcome of the workshop on scientific issues, communications concerns, and additional issues surrounding the practical application of ULs. The workshop resulted in suggestions for steps that can be taken to improve the process for establishing ULs, the understanding of how to use ULs, and longer-term research needs.
Scientific challenges and research needs
The scientific challenges for improving applicability of UL values range from a simple need for more data, to better clarification of the UL definition and acronym, to examining more complex issues of methodology for deriving UL values.
Improved data, not just more data, are critical to refining the ULs. Dose-response data for nutrients with ULs should continue to be collected, and research should be initiated for those nutrients or population subgroups without established ULs. The UL concept is meant to apply to chronic nutrient intakes rather than acute toxicities. However, the acute and the chronic effects of high levels of nutrients need to be more clearly defined and distinguished. A pursuit of the development of biomarkers for early indicators of hazard can aid in defining responses. Determining the adverse responses that should be assessed is in itself a challenge and requires considerable attention. Another issue that the participants addressed involves the appropriate scaling factors that should be used when extrapolating data from studies of adults and applying them to children. Would it not be helpful to use consistent scaling factors from expert panel to expert panel and from one country to another? An understanding of the shapes and slopes of dose-response curves for particular adverse responses in lifestage and/or gender subgroups is important for gauging the potential seriousness of excursions beyond the UL.
Applying the toxicological approach to risk assessment for nutrients is complicated by the clear differences between how nutrients and most other agents are handled by the body. These include the homeostatic mechanisms that affect the absorption, metabolism, and excretion of nutrients, as well as nutrient interactions that can increase or decrease the severity of an adverse event by modulating exposure at the tissue level. The composition of the vehicle for delivery of the nutrient, or food matrix, may also complicate hazard identification as well as exposure assessment. Participants suggested the current risk assessment model may be weakened by a lack of sufficient data for the accurate characterization of current exposures.
Ultimately, a risk assessment model requires that hazard characterization be combined with exposure characterization to assess risk. Usual exposure characterization is improved by use of the Iowa State University method of adjustment when data for only a few days of intake are available. Nevertheless, real limitations in current exposure estimates remain, and no easy solution to these limitations is available at present. Critical research needs include: 1) methods for the assessment of intakes of nutrients from all sources, including foods, fortified foods, and supplements, and 2) biomarkers that can be used to estimate intakes and exposures.
Several workshop participants encouraged investigators to develop a unified framework for understanding both the risk of inadequate nutrient exposures and the risk of excess nutrient intakes. Although the outcome measures for deficiency and excess are often, if not usually, unrelated, it may be possible to develop models that can be used to consider and minimize both risks simultaneously. Such an approach would benefit ULs and the other DRIs as they are reviewed in the future. However, most discussants warned against abandoning the risk assessment model used for UL derivation simply because interested individuals have some problems and concerns with the first set of ULs that have been established. The first generation of ULs represented a unique approach to dietary recommendations and assessments, and discussants made it clear that an earnest attempt must be made to rectify situations in which the UL is lower than the typical intakes or recommendations for some age groups. Can the evidence-based medicine approach work in some instances, or can it be used to modify the messages?
Communications challenges and recommendations
Some points of confusion or misinterpretation regarding ULs can be addressed in the short term, as workshop participants pointed out. As a first step, it would be valuable for the panels developing UL recommendations to decide exactly for whom the numbers are intended. With the risk assessment concept, it would be risk managers who would decide how to use the findings from a risk analysis. For ULs, however, who are the risk managers? Should the values be presented to consumers when some consumers may still not fully understand the idea that essential nutrients may be toxic?
No matter what the audience for ULs is, the explanations accompanying them could be strengthened, simplified, and tailored for specific audiences by using language with which they are comfortable and understand. To start, a simple and clear explanation of how recommended dietary allowances and ULs differ in concept is needed. Also, workshop participants expressed concern that there has been discussion of prevalence of excess intakes when comparing population intakes to the UL. Yet the definition of UL precludes any discussion of the prevalence of excess intakes because we do not know if, indeed, the intake above the UL is harmful. Instead, we can only characterize the prevalence of safe intakes (i.e., intakes below the UL).
Then, to strengthen the explanations and understanding of ULs, simple and clear information should be provided in addressing the following concerns for each nutrient:
What the absence of a UL implies. Does the absence of a UL mean that the data are insufficient to establish a UL, even though there may well be significant problems with high intakes, or does it mean that no hazard has been identified, despite the availability of ample data from people chronically exposed to high intakes?
The issue of dose as it is related to form or matrix. For some nutrients, current DRI reports stipulate that adverse effects can be expected only from supplemental forms of a nutrient. Confusion apparently exists, however, about when this is the case; moreover, the issue of matrix becomes relevant with fortified foods.
The severity of the adverse effect. It would be helpful to emphasize how serious the consequences of excursions beyond the UL can be (perhaps with a classification system that highlights nutrients with particular degrees of risk from excessive exposure). Is the endpoint irreversible neurological damage, gastric irritation, diarrhea, or a fishy body odor? Although the panelists and workshop participants regarded no endpoint as trivial, they believed that it is critical to make a distinction between relatively benign consequences and much more serious consequences.
Certainty surrounding the ULs. Because of the amount and quality of data available to DRI panels, some ULs are based on fairly sophisticated scientific judgments, whereas others depend on more crude analyses. It would be fair and valuable to share that level of certainty. As one participant asked, Is the UL number a bright line or a flashing yellow light? There was agreement that, at present, the answer may vary from nutrient to nutrient (on the basis of the certainty surrounding the hazard characterization, the severity of the potential adverse response, and the shape of the dose-response curve).
Simplification of messages will be crucial if ULs are to have increased practical use. For example, a health professional such as a physician might be a frontline risk manager when it comes to addressing excessive nutrient intakes. The physician needs a one-page take-home message, not a lengthy document that might be better suited to dietitians or other nutritionists. The tailoring of messages for health professionals might require the adoption of language from evidence-based medicine rather than from a toxicologist's lexicon, and communications with other audiences would need to be similarly customized.
Additional issues and recommendations
Several individuals believed that it is both timely and important for regulatory agencies to examine fortification policies, and at the same time, for other government groups to examine the broad impact of their nutrient requirements or standards. For example, the Supplemental Food Program for Women, Infants, and Children requires that cereals be fortified with iron, which provides the incentive for manufacturers to fortify cereals with iron. While this may benefit the intended age and gender groups, it could possibly contribute to excessive intakes by others in the population (such as men). A discussion on nutrient standards for school lunch programs would also be relevant. Because controversy surrounds specific ULs, some participants urge the use of caution. Specifically, regulatory agencies and nutrition scientists should consider the risks and benefits of making rules and recommendations without data (or without good data).
A practical issue for the food industry and related groups is whether consideration should be given to placing ULs on food labels. The discussants clearly believe that ULs are "not ready for prime time" on food labels, and that the focus should instead be on educating health professionals. [Recently, the Institute of Medicine Committee on Use of Dietary Reference Intakes in Nutrition Labeling said it does "not recommend including the ULs, their representation, or a statement mentioning them" on nutrition labels for conventional foods (1). However, the committee did recommend that consideration be given to including UL information on dietary supplement labels.]
In sum, the workshop participants identified long-term research needs to improve the science behind the derivation of ULs and shorter-term directives for improving communication about ULs. As these gaps are closed, it may signal the appropriate time to revise the nutrient-specific UL values as well as some concepts pertaining to ULs. It will be important to consider how much new data, for example, is sufficient to re-evaluate a UL. It may be necessary to put such re-evaluations on a schedule, or prioritize nutrients with incomplete data to accomplish timely revisions. Such examples of triggers to initiate the review of ULs are also relevant to the other DRI categories and are critical to the fundamental analysis of the DRI process, as the framework itself is refined and possibly restructured. Furthermore, as new dietary components are discovered to play important roles in the maintenance of health and prevention of disease, they are likely to be increasingly available in fortified foods and supplements. Thus, it may be prudent to develop intake recommendations and other reference values for safe and beneficial levels of intake. Important considerations are: how well such components fit in with the existing DRI framework; how the DRI framework might need to be revised for their inclusion, or whether a novel paradigm is required to consider nonessential nutrients; and ultimately what criteria could trigger their review for inclusion into any framework to establish relevant recommendations. The Food and Nutrition Board of the Institute of Medicine is currently seeking advice from the nutrition community for improving the review process for all DRIs; the outcome of this workshop pointed out ways to strengthen the science, the intents, and the practical applications of the ULs.
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FOOTNOTES |
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2 Author Disclosure: No relationships to disclose.
4 Abbreviations used: DRI, dietary reference intakes; UL, tolerable upper intake level.
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LITERATURE CITED |
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 TOP LITERATURE CITED |
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1. Committee on Use of Dietary Reference Intakes in Nutrition Labeling, Food and Nutrition Board, Institute of Medicine. Dietary Reference Intakes: guiding principles for nutrition labeling and fortification. Washington, DC: National Academies Press; 2003. Available from: http://books.nap.edu/catalog/10872.html.
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