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Supplement: 3rd Amino Acid Workshop

The Basis for Setting the Upper Range of Adequate Intake for Regulation of Macronutrient Intakes, Especially Amino Acids¹

Direction of Risk Assessment for Nutrition and Food Safety, French Food Safety Agency, 94701 Maisons-Alfort Cedex, France

² To whom correspondence should be addressed. E-mail: a.martin{at}afssa.fr.

	ABSTRACT

TOP ABSTRACT LITERATURE CITED

 
The comparison of actual intakes of essential amino acids to the dietary reference intakes indicates that amino acid supply is likely not a public health concern in industrialized countries. This fact does not preclude the interest in specific amino acid intake in some physiological or pathological situations in targeted subgroups of the population. Thus, the addition of amino acids to some food vehicles to create functional foods will be regulated by public authorities in different ways according to the regulatory contexts specific to each country. The main issues to be considered are, however, the same: safety of the product and justification of the health claim accompanying the product's promotion. In addition to classical scientific data, the use of Monte Carlo simulations can be a useful tool to support the choice of the food vehicle and the amounts added to this food, and to demonstrate both safety and possible efficacy of the functional food in the targeted population.

KEY WORDS: • amino acids • intake • functional foods • safety • health claim • Monte Carlo simulation

The regulation of nutrient intakes at a population level is generally based on a science-derived set of values known as "dietary reference intakes" (DRI) in the United States (1) or their equivalents in other countries, such as the "Apports Nutritionnels Conseillés" in France (2). DRIs include upper limits (ULs), estimated average requirements (EARs) for assessing nutritional status of a population, and recommended dietary allowances (RDAs) used as individual references. It is noteworthy that, in several Western countries, these recent revisions of DRIs shifted from the initial goal, detection, and prevention of deficiencies, to a more positive approach, promotion of health. This also includes the promotion of better and longer aging to reduce the risk of disease. This shift principally concerned micronutrients and, among macronutrients, was essentially applied to some fatty acids [(n-6) and (n-3)] through the consideration of their consequences on cardiovascular diseases and cancer. For this purpose, the results of numerous observational or interventional studies were taken into account. Large improvements remain to be done in the amino acid area for the determination of health-promoting DRIs in the case of a healthy population.

The basis for health-nutrition policies

Many consumers are aware of the links between nutrition (or foods) and health and, as a consequence, they adapt their food choices to real or perceived health benefits. But, health promotion through nutrition must also be considered at a population level, using various nonexclusive means: i) nutrient-based actions, used by industry or public authorities and ii) diet- or food-based actions, more often used by public authorities. Nutritional education of consumers or of health professionals and the regulation of industry initiatives in the health-food connection are complementary tools in implementing these actions. In most countries, the addition of nutrients to specific foods at the initiative of public authorities is made on the basis of demonstrated and generalized public health necessity. It is limited to some micronutrients (iodine, fluoride, vitamin D, folic acid, etc.) and to some widespread basic food vehicles (salt, flour, milk, etc.). For other nutrients, the level of scientific proofs is low or the insufficient intake is restricted to subgroups of the population, so that a general public solution is not convenient. In these last cases, the addition of nutrients is often made at the initiative of the industry and leads to the development of the so-called "functional foods," sometimes also known as nutraceuticals, pharmafoods, etc.

The distribution of intakes of two indispensable amino acids in the French population was estimated from the last representative dietary survey conducted in France in 1999, which included 2000 adults (>15 y old) and 1000 3- to 15-y-old children (3). Food consumption was recorded with a 7-d diary; ingested quantities were estimated using a photographic book of servings, validated for the French cohort SU.VI.MAX (4). We used the food data base for amino acids published by Paul et al. (5). We only studied intakes of methionine and lysine, because they are often considered as limiting amino acids for the nutritional quality of proteins. After the exclusion of adult underreporters, the distributions of intakes were obtained for 1434 adults and the 1000 children (Fig. 1). Compared to the reference values proposed by the Massachusetts Institute of Technology in 1998 (6) (for adults, 30 mg.kg^–1 body weight.d^–1 for lysine and 15 mg.kg^–1 body weight.d^–1 for methionine + cysteine), estimated intakes in the French population are clearly higher. Indeed, there are obviously some limitations in the quality of data: the food table compiled by Paul et al. (5) lacks some basic food currently consumed in France and there are many uncertainties on recipes and values to be used for industrial ready-to-eat dishes. However, for adults, this estimated intake corresponds to a mean of 6.1 g.d^–1 for lysine and 2.1 g.d^–1 for methionine, which is close to that reported for Japanese people (7), for example, 5.27 and 1.92 g.d^–1, respectively. Expressed in mg.kg^–1 body weight.d^–1, intakes were higher in children than in adults; however, the ratios of intakes were the same (Fig. 2) and, moreover, these ratios (mean ± SD, 2.9 ± 0.2) were higher than that expected from the consideration of reference requirements (2.0). Despite the limitations of this study, the probability of inadequacy of intakes for indispensable amino acids seems to be very low in the French population. The same could be true for other industrialized countries, for which the intakes of good quality proteins (and thus indispensable amino acids) are largely above the values recommended by FAO/WHO/UNU (8).

View larger version (25K): [in this window] [in a new window]   FIGURE 1  Distribution of intakes of lysine and methionine in the French population. Results are expressed in milligrams of amino acid ingested per day and per kilogram of body weight, for adults (>15 y old) and children (3–15 y) and compared to estimated requirements. Unpublished data from the INCA study (7-d dietary record) (3).

View larger version (12K): [in this window] [in a new window]   FIGURE 2  Distribution of the ratio lysine/methionine in the French population for adults and children (defined as in Fig. 1). The ratio of requirements is deduced from the estimated requirements of Figure 1.

Management of functional foods ("health foods")

Compared to drugs, foods are freely chosen by consumers; ingested amounts are very different among people, and consumption can be performed on a very long-term basis. These characteristics lead to the fact that the use of amino acids, individually or in mixtures, as health-promoting ingredients or molecules to create functional foods, will be managed by regulatory bodies using specific procedures. These procedures are different among countries, depending on their historical, regulatory, nutritional, and cultural contexts. The U.S. clearly separated usual foods, regulated under the Nutrition Labeling Education Act, and dietary supplements, regulated under the Dietary Supplement and Health Education Act. In Japan, health foods were gathered in the groups of Foods for Specified Health Use. In Europe, the regulatory framework is not completely achieved (because Europe must reach agreement among 15, and soon 25, countries). However, like in other countries, and independent of the creation of various food categories, the two main topics concerning health foods are handled in two tightly interdependent ways:

1. The safety of foodstuffs is an absolute prerequisite in food regulations, to the extent where it is generally recognized that the analysis of the ratio benefit/risk is not pertinent for foods, contrary to drugs. The need for a sound safety evaluation could even be considered as more relevant, if possible, for products that are sold using health claims. The upper limit for intakes relies on the safety evaluation of the amino acid per se as analyzed in the previous lecture (10). For addition to foods, the complete specifications of the molecule are needed and assessed: knowledge of preparation processes at the industrial scale as well as types and frequencies of quality controls are mandatory for a complete assessment. The presence, nature, and amounts of possible contaminants must be checked, such as byproducts, solvent residues, heavy metals, microorganisms, etc. resulting from the chemical synthesis or the industrial process. In addition, the active amount of the ingredient must be present in the food or drink during the whole shelf-life of the product, so that time-dependent appearance of breakdown products and their characteristics should also be checked if necessary. In some instances for European countries, it cannot be excluded that the product assessment might be dependent on the European regulation of "Novel foods" (regulation #no. 258/97), because of the use of a new process (for example, production from genetically modified microorganisms) or unusual amounts. Scientists working in the industry are more familiar with such procedures than academic researchers.
   
2. More relevant to the topic of the workshop is the addition of a very specific nutrient, in amounts generally not found in usual diets or, even, that could not be reached using current foods without seriously unbalancing the diet. It is supposed that this amount has been demonstrated to induce a specific biological or physiological effect, linked to a well-established health benefit (11). Marketing of such a product is invariably accompanied by health claims. In the first Codex Alimentarius Commission norm adopted in 1979, a claim is defined as any statement that affirms, suggests, or implies that a food or a constituent of food has a specific property, whatever this property may be—in this case, in relation to health. International consensus on the scientific support for such claims is currently under elaboration at supranational levels. Guidelines for the scientific basis in the development of functional foods were published by the European Council in July, 2001; the Codex Committee on Nutrition and Foods for Specific Dietary Uses (CCNFSDU) adopted a working document on the issue in June, 2000 and a draft of "Recommendations for the scientific justification of health claims," prepared by France and the U.S. with the help of some other countries (Japan, Canada, Brazil, etc.), was submitted to commentaries for discussion at the Codex Committee meeting held in Bonn, Germany in November, 2003.
   

These documents recommend that the scientific justification relies on the totality of the evidence available in the scientific literature. Ideally, the proofs should be obtained by human studies, performed with sound methodologies, on a sufficient number of subjects and during a sufficient period of time, adapted to the issue under study. It is frequently suggested that results of at least two independent studies should be provided. There should be a significant scientific consensus on the fact that the markers used in these studies (biological, physiological, clinical, or epidemiological markers) are relevant for a health benefit. The modification of the biomarker should be biologically relevant and not simply statistically significant. These modifications must be obtained in the context of the usual diet of the targeted population, consuming "reasonable" amounts of the health ingredient. The meaning of the word "reasonable" may lead to endless discussions; however, at least, it means that the intake is below the upper safety limit. In addition, data on the possible underlying mechanism of the functional effect must be provided: this ensures that possible modification of the product does not affect its health effect and can be used by regulatory bodies in control procedures. For example, in the case of amino acids, if an effect only depends on the ratio of some specific acids, moderate modifications of absolute amounts will be without significance; in other situations, the effect could depend on absolute and relative amounts of specific acids, which will thus be the values to be controlled.

Monte Carlo simulations

In addition to these usual experimental, clinical, and epidemiological data, it is useful to highlight the power and usefulness of computerized methodologies, just quoted in the previous workshop (12), namely Monte Carlo simulations, using Bayesian statistics. These techniques can fill a gap in the translation of basic research into operational foods, by producing valuable data, in line with the concerns of public authorities, regarding consumer protection, fair trade, and truthful communication, which are the three central dogmas of food laws. These techniques are frequently used in risk analysis for the assessment of consumers' exposure to toxic contaminants and can also be used in the nutrition area (13,14). Their results especially support proposals for: i) the amount of the health ingredient incorporated in one or several food(s) or food categories, ii) the choice of food or food category to which the ingredient will be added, iii) the pertinence of the claim at the population level in nonexperimental conditions, and iv) the probable absence of deleterious side effects in the proposed conditions.

The application of Monte Carlo simulations requires that consumption data, if possible obtained from representative dietary surveys of the targeted population, are available. Crossing the distribution of food intakes and the distribution of other studied parameters, on a random and repetitive basis, it is possible to produce a stable and reliable statistical distribution of the amount of the added amino acids that could be ingested at the population level, taking into account spontaneous ingestion from other foods (Fig. 3). This distribution is compared to otherwise scientifically established values: in the best scenario, the distribution indicates that a substantial part of the targeted population ingests amounts above the threshold required to obtain a beneficial health effect (efficacy threshold), whereas no one is located above the upper safety limit. Such computer simulations can easily and routinely be performed to test various hypotheses, alone or in multiple combinations, such as the nature of vehicle foods, incorporated amounts, eating occasion, estimated market shares, etc.

View larger version (28K): [in this window] [in a new window]   FIGURE 3  Schematic principle of a Monte Carlo simulation.

Despite extensive premarket assessment, it is clear that the insertion of a new product in the complex actual dietary environment could lead to nonpredictable interactions. Therefore, the development of functional foods raises largely unsolved questions for health authorities: would it be necessary in the near future to develop postmarketing surveys (the issue is clearly studied for genetically modified organisms in Europe)? With which methodologies? Who must pay for that? etc. At least, it could seem reasonable that claims should be periodically reevaluated, including trying to verify that the hypotheses tested during Monte Carlo simulations and eventually in quantitative risk (benefit) analyses, which constituted one basis of the authorization, are those that have become effective in the population.

Conclusions

In the present time, there is not yet worldwide consensus concerning labeling rules for the use of claims, in contrast with the growing consensus on the nature and quality of scientific proofs supporting claims. Scientists must be aware of these rules and their evolution, because they can have a profound impact on the way they will perform research on health-promoting molecules. At least, they must know that the results of their research will be used in a regulatory framework, which is more and more precise and imposes more and more constraints.

	FOOTNOTES

 
¹ Presented at the conference "The Third Workshop on the Assessment of Adequate Intake of Dietary Amino Acids" held October 23–24, 2003 in Nice, France. The conference was sponsored by the International Council on Amino Acid Science. The Workshop Organizing Committee included Vernon R. Young, Yuzo Hayashi, Luc Cynober, and Motoni Kadowaki. Conference proceedings were published as a supplement to The Journal of Nutrition. Guest editors for the supplement publication were Vernon R. Young, Dennis M. Bier, Luc Cynober, Yuzo Hayashi, and Motoni Kadowaki.

	LITERATURE CITED

TOP ABSTRACT LITERATURE CITED

 

1. Food and Nutrition Board, Institute of Medicine (2003) Dietary Reference Intakes (2000–2003). National Academy Press, Washington, DC.

2. Martin, A., coordinator. (2001) French Nutritional Recommendations. Sci. Alim. 21: 309–458.

3. Volatier, J. L., Maffre, J. & Couvreur, A. (2000) Enquête individuelle et nationale sur les consommations alimentaires (INCA). Tec & Doc Lavoisier, Paris, France.

4. Hercberg, S., Preziosi, P. & Briançon, S. (1998) A primary prevention trial using nutritional doses of antioxidant vitamins and minerals in cardiovascular disease and cancers in a general population: the SU.VI.MAX study—designs, methods and participant characteristics. Contr. Clin. Trials 19: 336–351.

5. Paul, A. A., Southgate, D. A. T. & Russell, J. (1987) First Supplement to McCance and Widdowson's The Composition of Foods: Amino Acids, Fatty Acids. Ministry of Agriculture, Fisheries and Food, Her Majesty's Stationery Office, London, UK.

6. Young, V. R. (1998) Human amino acid requirements: counterpoint to Millward and the importance of tentative revised estimates. J. Nutr. 128: 1570–1573.[Free Full Text]

7. Hayashi, Y. (2003) Application of the concepts of risk assessment to the study of amino acid supplements. J. Nutr. 133: 2021S–2024S.[Abstract/Free Full Text]

8. Food and Agriculture Organization/World Health Organization/United Nations University (1986) Energy and Protein Requirements. Report of a Joint Expert Consultation, no. 724. Geneva, Switzerland.

9. Anonymous. (2003) Amino acid health drinks becoming increasingly popular in Japan. Nutraceut. Int. 7: 15.

10. Renwick, A. G. (2004) Establishing the upper end of the range of adequate and safe intakes for amino acids—a toxicologist's viewpoint. J. Nutr. 134: 1617S–1624S.[Abstract/Free Full Text]

11. Diplock, A. T., Aggett, P. J., Ashwell, M., Bornet, F., Fern, E. B. & Roberfroid, M. B. (1999) Scientific concepts of functional foods in Europe: consensus document. Br. J. Nutr. 81 (Suppl. 1): S1–S27.

12. Roderick, J. V. (2003) Approaches to risk assessment for macronutrients and amino acids. J. Nutr. 133: 2025S–2030S.[Abstract/Free Full Text]

13. Covello, V. T. & Merkhofer, M. W. (1993) Risk Assessment Methods. Approaches for Assessing Health and Environmental Risks. Plenum Press, New York, NY.

14. Vose, D. (2000) Risk Analysis. A Quantitative Guide, 2nd ed. Wiley & Sons, Chichester, UK.

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