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Zinc, through its structural and cofactor roles, affects a broad range of critical physiological functions, including growth, metabolism, immune and neurological functions. Zinc deficiency is widespread among populations around the world, and it may, therefore, underlie much of the global burden of malnutrition. Current zinc fortification strategies include biofortification and fortification with zinc salts with a primary focus on staple foods, such as wheat or rice and their products. However, zinc fortification presents unique challenges. Due to the influences of phytate and protein on zinc absorption, successful zinc fortification strategies should consider the impact on zinc bioavailability in the whole diet. When zinc is absorbed with food, shifts in plasma zinc concentrations are minor. However, co-absorbing zinc with food may preferentially direct zinc to cellular compartments where zinc-dependent metabolic processes primarily occur. Although the current lack of sensitive biomarkers of zinc nutritional status reduces the capacity to assess the impact of fortifying foods with zinc, new approaches for assessing zinc utilization are increasing.
- zinc
- nutrition
- fortification
- biofortification
- bioavailability
- global health
1. Introduction
Zinc, an essential trace element, has a broad range of critical biological functions that span all life stages and essential functions, including reproduction, growth, metabolism, neurological, and immune functions [1]. Zinc deficiency is widespread among populations around the world and, thus, underlies much of the global burden of malnutrition. Based on the prevalence of stunting, a symptom of zinc deficiency, among children under 5 years of age, or the prevalence of low plasma zinc or low zinc intakes, zinc deficiency is the most common nutritional problem worldwide [2]. Zinc deficiency is of particular concern among infants, children, and women of reproductive age, although it also occurs in adolescents and older adults. The prevalence of zinc deficiency is also higher in rural than urban areas, although it is present in both.
The intake of staples is also higher in rural over urban areas. Thus, zinc fortification strategies, i.e., fortification or biofortification of staple foods such as wheat, rice, or maize, will likely improve the zinc intakes of vulnerable populations worldwide. Although zinc fortification efforts have advanced recently, optimizing the amount of zinc absorbed and monitoring the health impacts due to fortification remain significant challenges. Both aspects are linked to the bioavailability of zinc, i.e., the proportion of zinc in food items that is released during the digestive processes, is absorbed, and is utilized for numerous biological functions [3].
2. Trends in Zinc Fortification Strategies
Fortification of staple grains post-harvest by the addition of inorganic zinc salts, typically zinc oxide or zinc sulfate, is the traditional approach to zinc fortification. Post-harvest fortification is often used in flours produced from staple grains. While the technique is well-established, it has several limitations. It requires sustaining well-controlled centralized processing to ensure homogenous distribution in the flours. This represents a major component of the post-harvest fortification expense (Table 1). In many settings where the risk of zinc deficiency is high, the availability of resources limits the implementation, coverage, and sustained use of post-harvest fortification strategies.
Table 1.
Comparison of recent zinc fortification strategies.
| Strategy | Advantages | Disadvantages |
|---|---|---|
| Post-harvest fortification of staples | Well-established for use in large-scale fortification of staples that are milled to flours, relatively simple to incorporate at milling | Requires capacity for centralized processing of staples, expensive to maintain coverage and sustained use within a target population, need to control zinc amount and maintain homogeneity, not practical for foods that are not milled into flours (e.g., rice, beans) |
| Biofortification | Applicable to large-scale fortification of staple crops, no need for special processing, no concern for excessive zinc, practical for crops that are not milled (e.g., rice, beans), low cost of sustained use after initial development | Time and expense of crop development, limitations to the amount of zinc that can be added |
| Fortification of manufactured food products | Well-established in fortification of population-specific products such as infant formulas or child nutrition biscuits | Production expense, challenges in coverage and sustained use within a target population, need to control zinc amount and maintain homogeneity |
| Home fortification packets | Readily produced, stored, and distributed, may improve coverage of lower income or otherwise hard to reach populations | Challenges in determining appropriate amount of zinc per packet, opportunity for overuse |
| Fortification of milk or milk products | High zinc bioavailability, may partially counter inhibitory effects of high phytate diets | Not applicable in populations that do not consume milk or milk products, need to control zinc amount and maintain homogeneity |
| Food-to-food fortification | Supports small scale implementation in low-resource settings lacking capacity for other modes of fortification | Phytate content of plant sources of zinc can be high, need to test acceptability of resulting flavor and other organoleptic properties |
Adverse effects may also occur if excessive zinc is inadvertently added to the target food, or pockets of high zinc levels exist due to uneven distribution during the fortification process. Unlike most other nutrients, there is a narrow window between zinc recommended intakes and the upper limit of intake before adverse effects are observed. While recommended daily intakes for adults typically range from 8 to 19 mg zinc per day, the upper limit is only 35 to 45 mg [4][15], i.e., a 2 to 4-fold increase. Zinc upper limits are based on reduced activity of the antioxidant protein, copper-zinc superoxide dismutase, in erythrocytes [5][67]. However, women supplemented with a modest 22 mg of zinc daily for 6 weeks, about half of the upper limit, had detectable increases in zinc protoporphyrin due to the incorporation of zinc in place of iron into hemoglobin during erythropoiesis [6][68].
Furthermore, due to the low solubility of zinc oxide at a neutral pH [7][9], variability in stomach acidity may determine how well the zinc is solubilized and absorbed. Zinc from porridges fortified with zinc oxide has a lower fractional absorption than zinc sulfate [8][21]. Zinc oxide, when given as a supplement, also has a lower fractional absorption than zinc gluconate or zinc citrate [9][69]. Recent studies in animals further showed negative effects on gut health, including increased oxidative stress and a shift in the microbiome towards a genetic profile consistent with increased antibiotic resistance, when zinc sulfate or zinc oxide fortifying salts were compared with zinc with amino acids complexes [10][11][70,71].
Soluble complexes of zinc with amino acids or zinc-chelating peptides from protein hydrolysates, are an alternative to inorganic zinc salts. These zinc complexes appear to enhance zinc uptake into cultured cells, and zinc absorption in animal models [12][13][14][15][17,72,73,74]. In humans, the response in serum zinc concentration over a six-hour period following a dose of 20 mg zinc as a zinc histidine complex was greater than the same amount as zinc sulfate [16][75]. Similarly, the serum response over the course of 8 h following a 15 mg dose of zinc as zinc bisglycinate was greater than the same amount as zinc gluconate [17][76]. Further study is indicated to evaluate the potential of zinc amino acid complexes for zinc delivery in food fortification.
Biofortification, accomplished through selective breeding, transgenic crops, and/or agronomic fortification by adding zinc to the soil or to growing crops, increases the intrinsic zinc content of staple foods [18][77]. There is an increasing trend towards zinc biofortification as a more cost-effective and sustainable option for increasing zinc intakes. Biofortification has several advantages. Crops that are not typically eaten as flours, such as rice or beans, are more readily fortified using biofortification because zinc is incorporated into the edible portion of the plant [19][78]. Compared with post-harvest fortification, the lack of a need for special processing reduces the cost of biofortification after the initial crop development. Recent crops targeted for zinc biofortification include wheat [20][21][22][36,79,80], rice [23][24][25][60,81,82], maize [26][27][27,83], pearl millet [28][29][25,84], beans [30][31][43,85], and bananas [32][86].
Biofortification targets proposed for use in Africa could potentially reduce the risk of zinc deficiency 10-fold [33][38]. Although there are physiological limits to the amount of zinc that may be incorporated into crops through biofortification [34][87], excessive or uneven distribution of zinc within the crop is unlikely. Furthermore, zinc from biofortified crops is well-absorbed. Fractional zinc absorption did not differ between biofortified vs. post-harvest fortified wheat, maize or rice [26][35][36][22,23,27].
Several fortification strategies are more appropriately applied on a small scale, or take advantage of non-staple foods commonly consumed in a subpopulation at particularly high risk for zinc deficiency. Although the fortification of infant formulas and ready-to-eat breakfast cereals to prevent zinc deficiency in infants and young children is not new, these strategies require that zinc is added in the factories where the foods are produced. As with other types of post-harvest fortification, the development of systems for adding and maintaining the appropriate amounts of zinc in the finished food products increases the production cost. Coverage may also be limited by market forces or poor distribution within a population. Alternatively, home fortification packets that are readily produced, stored, and distributed, may easily be added to complementary foods at home. Consequently, recent zinc fortification strategies targeting infants have included the home fortification of complementary foods with zinc [37][38][39][40][41][26,50,88,89,90].
In a study of Kenyan infants, the provision of 5 mg zinc per day increased zinc absorption enough to meet the physiological requirement, and it increased the EZP compared with control [41][90]. However, in Cameroon, the provision of 6 mg zinc/day in young children failed to alter plasma zinc concentrations [38][50]. Higher amounts of zinc for longer periods of time may be needed to change zinc biomarkers. For example, home-fortified complementary foods providing an additional 10 mg zinc per day did not increase the EZP after 3 months, although extension of the program to 9 months did [37][26]. Similar goals may also be achieved through biofortification. Increasing the zinc intakes by 2.7 mg/d from biofortified maize in young Zambian children met their physiological requirements for absorbed zinc [26][27].
These studies further demonstrate that the amounts needed to meet physiological requirements vary. What is adequate for one population may approach the upper limits for another. Daily use of a micronutrient powder that provided 4.1 mg of zinc per packet increased the simulated prevalence of an excessive zinc intake from zero to 50% among young Ethiopian children [39][88]. Without biomarkers responsive to small changes in zinc intake, it is tempting to further increase zinc intakes in pursuit of changes in zinc biomarkers to support claims of efficacy. However, depending on the needs of the population, this could risk excessive zinc intakes. The challenge is further compounded by limited data regarding the adverse effects of excessive zinc intake in children [42][91]. Due to the limited knowledge of the safety and efficacy of supplemental zinc in pediatric populations, biomarkers related to adverse effects of excessive zinc intake should be monitored in zinc fortification where current upper limits for zinc are likely to be exceeded.
Recently, there has also been a trend to fortify milk and milk products with zinc for populations other than infants, i.e., toddlers [43][92], pre-school [44][93] and school-age children [45][46][47][28,94,95], non-pregnant [48][96] and pregnant women [49][97], and the elderly [50][62]. These studies included the fortification of milk or milk-based beverages [43][44][45][46][50][28,62,92,93,94], and yogurt [47][51][95,98].
In adolescents, zinc fortified milk providing 6 mg zinc per day increased zinc absorption from 1.1 mg per day to 3.1 mg per day [45][28]. The researchers used stable isotopic tracers to measure the zinc absorption from the milk and from the rest of the diet at the same time. Interestingly, about 15% of the 2.0 mg per day increase in absorbed zinc was due to the effect of the milk on zinc absorption from the rest of the diet, while 85% of the increase was accounted for by zinc absorption from the milk. These data are consistent with other observations of the effects of milk or milk products on zinc bioavailability from the rest of the diet [52][99]. The potential of milk or milk products, and dietary protein in general, to increase zinc absorption and retention from the rest of the meal, makes these foods intriguing targets for zinc fortification.
Another recent trend in fortification, food-to-food fortification, is defined as a fortification approach that uses locally available foods containing usefully high quantities of a micronutrient or micronutrients of interest, to fortify another food [53][100]. Since the flavor and consistency of the fortified foods are altered, food-to-food fortification requires recipe development and acceptability testing. While examples are limited, the strategy appears to have good potential for increasing the zinc content of the target foods. For example, gari or tapioca made from cassava may be fortified with soy [54][101]. This increased the zinc content of tapioca from 0.3 to 1.5 mg zinc per 100 g, and of gari from 0.8 to 1.4 mg zinc per 100 g. Since plant sources of zinc are typically high in phytate, the phytate content should be measured. Concurrent strategies to reduce phytate, (e.g., malting, fermentation, soaking, or germination) should also be developed where feasible.
In contrast, the addition of some foods may partially neutralize the negative effects of phytate on zinc absorption. For example, milk added to a high phytate rice meal increased zinc absorption from the whole meal [48][96]. The addition of milk or yogurt to a meal of corn tortillas and black beans increased zinc absorption by more than 70%, even though they only increased the zinc content of the meal by 20% [55][102]. While the addition of dairy products to enhance zinc absorption does not fall precisely within the above definition of food-to-food fortification, these approaches may provide similar or greater benefit increasing zinc absorption.