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Symposium: Plant Breeding: A New Tool for Fighting Micronutrient Malnutrition

Evaluating the Impact of Plant Biofortification on Human Nutrition¹

U. S. Department of Agriculture/Agricultural Research Service, Western Human Nutrition Research Center, University of California, Davis, CA 95616

²To whom correspondence should be addressed. E-mail: jking{at}whnrc.usda.gov

	ABSTRACT

TOP ABSTRACT INTRODUCTION Step one: assess nutrient... Step two: assess efficacy... Step three: assessment of... LITERATURE CITED

 
An evaluation of the efficacy of biofortified foods for improving human nutrition and health requires both laboratory- and community-based trials. A three-step process is proposed. First, tests of nutrient bioavailability should be conducted in the laboratory. Various genotypes of modified foods may be screened for bioavailability using in vitro cell-culture systems or experimental animals before testing in humans. Second, comprehensive feeding trials are conducted to test the efficacy of the biofortified food for improving the nutrition and health of target populations. These trials are generally done for several weeks or months, and they involve measuring a comprehensive set of endpoints. If efficacy is demonstrated in the feeding trial, the third step, a community-based trial, is planned. This final trial involves evaluating the nutritional, health, agricultural, societal, environmental and economic effects of the biofortified food in the community. A multidisciplinary team including consumers, policymakers, health leaders, as well as scientists is required for successful completion of the community trial.

KEY WORDS: • bioavailability • human nutrition • efficacy trials • nutrition interventions

	INTRODUCTION

TOP ABSTRACT INTRODUCTION Step one: assess nutrient... Step two: assess efficacy... Step three: assessment of... LITERATURE CITED

 
As described in the previous articles in this symposium, plant-breeding strategies, or biofortification, are an effective means of improving dietary quality. By using either conventional plant-breeding strategies (e.g., cross-breeding) or genetic engineering techniques, the amount and bioavailability of selected nutrients in a staple food item can be enhanced. Before these new food items can be introduced into the general food supply, the efficacy of these foods for improving human nutrition needs to be evaluated in both laboratory- and community-based trials. The purpose of this article is to describe a model for evaluating the efficacy of these modified foods in improving human nutrition. Because biofortification efforts have focused primarily on ß-carotene and iron, examples related to those nutrients will be used throughout the article.

	Step one: assess nutrient bioavailability

TOP ABSTRACT INTRODUCTION Step one: assess nutrient... Step two: assess efficacy... Step three: assessment of... LITERATURE CITED

 
Bioavailability is defined in this article as the fraction of the ingested nutrient that is utilized for normal physiological functions or storage (1 ). One of the major determinants of bioavailability is the proportion that is absorbed from the gastrointestinal tract. However, tissue utilization (or lack thereof) of the absorbed nutrient also influences bioavailability. This is particularly true for some vitamins and minerals, such as selenium. Gastrointestinal absorption is the primary determinant of iron and zinc bioavailability.

The bioavailability of nutrients from a food item may be influenced by a number of factors unrelated to the characteristics of the foodstuff, i.e., the previous intake of the nutrient, the body status of the nutrient, gut transit time, and gastrointestinal function.

The various methods used to assess bioavailability in humans are summarized in Table 1 . In selecting a method, one needs to consider how tissue nutrient homeostasis is maintained, access to isotopic tracer techniques, and the population to be studied. For example, because circulating iron is readily taken up by the tissues after it is absorbed, measuring the plasma response to a specific food source does not provide a valid estimate of iron bioavailability; measuring erythrocyte incorporation of an iron isotopic tracer would be more valid. Also, because intestinal mucosal cells readily absorb selenium, measuring intestinal absorption is not a valid estimate of selenium bioavailability. Changes in a physiological marker, such as serum glutathione peroxidase, are more valid.

Rat and poultry have been used to assess the bioavailability of nutrients, but the results obtained may not be applicable to humans due to differences in gastrointestinal function. The mini-pig model is more acceptable because the gastrointestinal function of the pig closely parallels that of humans. However, use of the pig is relatively expensive and, therefore, has limited value for screening large numbers of plant staples for bioavailability. Currently, efforts to screen promising nutrient-dense staple foods for nutrient bioavailability are done by the in vitro Caco-2 cell model or by feeding trials in experimental animals, usually the rat.

After a screening process has identified the most promising genotypes of plant staples, the bioavailability of the target nutrient needs to be measured in humans using an appropriate method (Table 1) . The following issues need to be addressed in developing the experimental design for the human study: 1) If an isotopic tracer is used, should it be added intrinsically or extrinsically to the test meals?; 2) Should the test food be evaluated alone in or a test meal as it is typically consumed?; and 3) Should the nutritional status of the test subjects be low or marginal?

Extrinsic labeling (i.e., adding the isotopic tracer to the test meal) is frequently used for bioavailability studies because it is more rapid and less expensive than producing intrinsically labeled plant foods (i.e., growing test plants in isotopically labeled nutrient solutions (3 ). Numerous validity studies comparing extrinsic with intrinsic tracers of iron or zinc have been done (4 –9 ). The studies suggest that the validity of extrinsic tracers for measuring iron or zinc bioavailability varies with the test food. Complete equilibration between extrinsic and intrinsic tags in the gastrointestinal tract is dependent on gut transit time and on the mineral-binding ligands present in the food. To be certain that an extrinsic tag is a valid tracer for bioavailability studies, the two types of tags should be compared before an extrinsic tag is used. In general, extrinsic labeling for nonheme-iron bioavailability seems to be valid for most foods; milk may be an exception due to the more rapid transit of the liquid food (10 ). Zinc extrinsic tags, however, do not seem to exchange fully with endogenous zinc in many foods (6 ).

In determining whether the test food should be given alone or in a typical meal, one must decide how important it is to evaluate the potential impact of inhibitor and promoter substances. Plant foods, especially seeds and grains, contain various antinutrients, such as phytic acid, tannins, polyphenolics, and oxalic acid, which reduce nutrient bioavailability. Promoter substances include certain organic acids, e.g., ascorbic acid, amino acids, and hemoglobin. If the inhibitor or promoter content of the staple food has been modified as well as the amount of nutrient by plant-breeding strategies, assessment of the test food alone is more appropriate. However, if there are no changes in the inhibitor and promoter substances and the test food is normally consumed with other foods that could alter nutrient bioavailability, then a test meal approach should be used.

The bioavailability of micronutrients in plant foods can be affected by food preparation techniques (11 ,12 ). Fermentation, germination or soaking cereal grains before cooking improve the bioavailability of iron and zinc. The food preparation methods used for evaluating bioavailability should mimic typical food preparation methods by the target population.

The nutritional status of the subjects used for the bioavailability studies will affect the amount of the nutrient absorbed and retained. Individuals who have a low or marginal status will absorb and retain more than those in good status because the cellular processes involved in nutrient absorption and transfer to body pools and stores are up-regulated. Individuals in marginal status are preferred for studies of bioavailability to maximize the capacity to measure the response to the meal. For example, iron absorption fluctuates directly with differences in iron status; individuals in good status may absorb 3–5% of nonheme iron from most food sources, whereas those in poor or marginal status may absorb two times as much. In general, the greater the capacity for absorbing iron, the greater the ability to differentiate the bioavailability of various food iron sources.

	Step two: assess efficacy for improving human nutritional status

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Studies of the bioavailability of a nutrient from a stable food describe the potential of that food for improving the nutritional status of a population. Efficacy trials are needed, however, to determine the actual capacity for correcting nutritional deficits in a target population. These efficacy trials should be done using a vulnerable group within a target population. Ideally, a randomized, double-blinded controlled design is used in which the modified test food is fed as a part of the total diet in a manner similar to the way that food item is normally prepared and consumed long enough to detect the response of a comprehensive set of molecular, biochemical and functional endpoints.

Efficacy trials are much more expensive and difficult to conduct than are assessments of bioavailability. The studies need to be designed with care to ensure that they provide valid results. Selection bias, or the lack of random assignments of the subjects to the intervention and control groups, is a common problem. Also, because these studies are so expensive, they frequently suffer from an insufficient sample or power to detect significant differences. It is also important to ensure that intake of the test food item is the only difference between the intervention and control group. For example, consumption of a food biofortified with zinc may increase appetite and overall food intake in the intervention group. This could lead to a general improvement in the overall diet quality that would confound the study evaluation. Finally, it is important to control the factors other than the nutrient studied that influence the endpoints. The presence of disease is a common confounding factor among vulnerable groups in developing countries. Malaria, for example, could confound the interpretation of an efficacy trial of iron or zinc. This problem may be avoided by providing treatment or preventive therapies to all of the participants before starting the efficacy trial.

	Step three: assessment of the biofortified food at the community level

TOP ABSTRACT INTRODUCTION Step one: assess nutrient... Step two: assess efficacy... Step three: assessment of... LITERATURE CITED

 
A community assessment is the final step in evaluating the efficacy of a new biofortified plant food. This should only be done after completing all agricultural studies (e.g., evaluations of yield, disease resistance) and assessments of bioavailability and efficacy.

A comprehensive system for evaluating societal, environmental, regulatory, agricultural and health issues needs to be part of the community trial. An example of some of the issues that need to be studied follows. What is the impact of the biofortified food on the nutrition and health of the community? How does it affect direct (e.g., plasma concentrations) as well as indirect (e.g., work performance, reproduction and learning capacity) indicators? Do all segments of the community accept the taste and appearance of the biofortified food? How does the cost compare with traditional foods? Does it require more or less time for preparation? Does its shelf-life differ? Does it produce more or less waste than the traditional food? How does it affect the environment? Should the product be labeled? If so, how? What additional regulatory systems need to be established? Will those regulations impair the overall acceptance of the food item?

A community trial can only be conducted through the coordinated efforts of the entire community involving policymakers, agricultural scientists, nutritionists, sociologists and economists. Involvement of the consumers in all aspects of the community intervention is the primary key to success. This should include being part of the initial decision to conduct the trial, assisting with the intervention design and conduct, receiving the results, and formulating a plan for future implementation of the food item based on those findings.

	FOOTNOTES

 
¹ Presented as part of the symposium "Plant Breeding: A New Tool for Fighting Micronutrient Malnutrition" given at the Experimental Biology 2001 meeting, Orlando, Florida, on April 1, 2001. This symposium was sponsored by the American Society for Nutritional Sciences. Guest editor for the symposium publication was Howarth E. Bouis, International Food Policy Research Institute, Washington, DC.

	LITERATURE CITED

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1. Jackson, M. J. (1997) The assessment of bioavailability of micronutrients: introduction. Eur. J. Clin. Nutr. 51:S1-S2.

2. Glahn, R. P., Wien, E. M., Van Campen, D. R. & Miller, D. D. (1996) Caco-2 cell iron uptake from meat and casein digests parallels in vivo studies: use of a novel in vitro method for rapid estimation of iron bioavailability. J. Nutr. 126:332-339.

3. House, W. A. (1999) Trace element bioavailability as exemplified by iron and zinc. Field Crops Res 60:115-141.

4. Johnson, P. E. & Lykken, G. I. (1988) Copper-65 absorption by men fed intrinsically and extrinsically labeled whole wheat bread. J. Agric. Food Chem. 36:537-540.

5. Egan, C. B., Smith, F. G., Houk, R. S. & Serfass, R. E. (1991) Zinc absorption in women: comparison of intrinsic and extrinsic stable-isotope labels. Am. J. Clin. Nutr. 53:547-553.[Abstract/Free Full Text]

6. Fairweather-Tait, S. J., Fox, T. E., Wharf, S. B., Eagles, J., Crews, H. M. & Massey, R. (1991) Apparent zinc absorption by rats from foods labelled intrinsically and extrinsically with ⁶⁷Zn. Br. J. Nutr. 66:65-71.[Medline]

7. Gallaher, D. D., Johnson, P. E., Hunt, J. R., Lykken, G. I. & Marchello, M. J. (1988) Bioavailability in humans of zinc from beef: intrinsic vs extrinsic labels. Am. J. Clin. Nutr. 48:350-354.[Abstract/Free Full Text]

8. Meyer, N. R., Stuart, M. A. & Weaver, C. M. (1982) Bioavailability of zinc from defatted soy flour, soy hulls and whole eggs as determined by intrinsic and extrinsic labeling techniques. J. Nutr. 113:1255-1264.

9. Janghorbani, M., Istfan, N. W., Pagounes, J. O., Steinke, F. H. & Young, V. R. (1982) Absorption of dietary zinc in man: comparison of intrinsic and extrinsic labels using a triple stable isotope method. Am. J. Clin. Nutr. 36:537-545.[Abstract/Free Full Text]

10. Gislason, J., Jones, B., Lonnerdal, B. & Hambraeus, L. (1992) Iron absorption differs in piglets fed extrinsically and intrinscially 59Fe-labeled sow’s milk. J. Nutr. 122:1287-1292.

11. Gibson, R. S. & Hotz, C. (2001) Dietary diversification/modification strategies to enhance micronutrient content and bioavailability of diets in developing countries. Br. J. Nutr. 85:159-166.

12. Hotz, C., Gibson, R. S. & Temple, L. (2001) A home-based method to reduce phytate content and increase zinc bioavailability in maize-based complementary diets. Int. J. Food Sci. Nutr. 52:133-142.[Medline]

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