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Bioavailability of dietary minerals to humans: The stable isotope approach Judith R. Turnlund
a
a
USDA/ARS, Western Human Nutrition Research Center, P.O. Box 29997, Presidio of San Francisco, California Published online: 29 Sep 2009.
To cite this article: Judith R. Turnlund (1991): Bioavailability of dietary minerals to humans: The stable isotope approach, Critical Reviews in Food Science and Nutrition, 30:4, 387-396 To link to this article: http://dx.doi.org/10.1080/10408399109527549
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Critical Reviews in Food Science and Nutrition, 30(3):387—396 (1991)
Bioavailability of Dietary Minerals to Humans: The Stable Isotope Approach Judith R. Turnlund
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USDA/ARS Western Human Nutrition Research Center, P.O. Box 29997, Presidio of San Francisco, California
ABSTRACT: A number of minerals contained in foods are essential nutrients for humans, animals, and/or plants. While most vitamins are very well absorbed, most essential minerals are not. Usual absorption of minerals ranges from less than 1% to over 90%. The bioavailability of dietary minerals must be considered when determining whether the diet contains enough, too little, or too much. By using stable isotope tracers as labels, the metabolic fate of minerals in a specific day's diet, a specific meal, or a food can be distinguished from minerals from other sources and followed. A number of mass spectrometric methods have been used to measure stable isotopes. Magnetic sector, thermal ionization mass spectrometry (TIMS) is used routinely in our laboratory to study bioavailability of Zn, Cu, and Fe. Other mass spectrometric methods that are less precise, but useful for many applications requiring isotopic determinations include quadrupole TIMS, inductively coupled plasma mass spectrometry (ICP/MS), and fast atom bombardment mass spectrometry (FAB/MS). One of the major advantages of stable isotope studies is that multiple isotopes of the same mineral can be used simultaneously and multiple minerals can be studied simultaneously. The use of stable isotopes for studies of bioavailability of minerals in foods has gained widespread interest in recent years. The approach is expected to be applied to an increasing number of food science and nutrition problems in the future. KEY WORDS: bioavailability, minerals, stable isotope.
I. INTRODUCTION A number of minerals contained in foods are essential nutrients for humans. 1 If adequate amounts of these minerals are not included in the diet, nutritional status will be impaired and a variety of health problems can result. The essentiality of other minerals has not yet been established in humans, but they are required by one or more animal species. Still others have not yet been established to be essential to any animal species, but are required by plants. It is thought likely that some of these minerals required by animals and/or plants may also be required by humans. In addition to the above categories, some minerals in foods are important due to their toxicities. The minerals in all of these categories are of interest to food scientists and nutritionists.2 Those
known to be essential in the diets of humans are shown in Table 1, along with the current dietary recommendations for each. The minerals essential to one or more animal species and/or plants, but not yet known to be essential for humans, and those now known only for their toxicity or used therapeutically, are shown in Table 2. It is possible that some or all of those minerals essential to an animal or plant species may eventually be found to be essential to humans as well. All of the essential elements are toxic in sufficient quantities. It is possible that some of the minerals currently known only for their toxicity may someday be found to be essential in small amounts.
II. BIOAVAILABILITY Bioavailability of nutrients refers to the pro-
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TABLE 1 Elements Essential to Humans and Recommended Daily Dietary Intakes for Healthy Adults1
Element
RDA* mg/d
Element
ESADDI" mg/d
Calcium Phosphorus Magnesium Iron Zinc Iodine Selenium
800 800 300 (350)d 18(10) d 15 0.15 0.055 (0.07)d
Copper Manganese Fluoride Chromium Molybdenum
1.5—3.0 2.0—5.0 1.5—4.0 0.05—0.2 0.075—0.25
Element Sodium Potassium Chloride
EMR< mg/d 500 750 2000
a
Recommended dietary allowance. Estimated safe and adequate daily dietary intake. c Estimated minimum requirement. " Recommendations differ for women and men. The recommendation for women is followed by the recommendation for men in parentheses.
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b
portion in food that is absorbed and utilized by the body.3 Until a nutrient is absorbed from the gastrointestinal (GI) tract and enters the systemic circulation, it is not available for utilization. While most vitamins are very well absorbed, most essential minerals are not. Usual absorption of minerals ranges from less than 1% to over 90%. The bioavailability of dietary minerals must be considered when determining whether the diet contains enough, too little, or too much. The fraction of a specific mineral that is absorbed is dependent on a number of factors. A few elements, such as sodium and potassium, are very well absorbed under most conditions. Others are poorly absorbed and the fraction absorbed can vary greatly. The factors that influence absorption, some of which are listed in Table 3, include the amount in the diet, the oxidation state of the mineral, the chemical form and the presence of interfering or enhancing factors. Two examples of the variation in absorption of a mineral are found with iron and chromium. Only about 3 to 8% of the iron in plant foods is usually absorbed, while about 25% of heme iron, the form of iron contained in red meats, is absorbed.1 CrCl3 is not absorbed from the gastrointestinal tract, making it useful as a marker for intestinal transit; however, other inorganic Cr salts are better absorbed than the highly insoluble CrCl3. Cr in natural complexes is better absorbed
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than inorganic Cr salts, and hexavalent chromium is better absorbed than trivalent chromium.4
III. DETERMINING MINERAL BIOAVAILABILITY Determining the bioavailability or absorption of a mineral is complicated by the fact that once a food is consumed, it mixes in the GI tract with other foods that were consumed at about the same time. In addition, the dietary minerals in a meal or specific day's diet mix with minerals consumed in other meals and on other days that still remain in the GI tract. Varying fractions of a mineral consumed on a specific day and not absorbed are eliminated from the body via the GI tract over a period of several days. Complete elimination of an unabsorbed mineral usually takes from 6 to 12 d, and in a few instances, a shorter or longer period of time. The unabsorbed mineral will also mix with endogenous mineral that was in the body and was excreted via the bile or other secretions into the GI tract. Biliary excretion is the primary route of elimination from the body for a number of minerals. Therefore, one cannot determine the amount of unabsorbed mineral simply by measuring the amount eliminated in the feces. Once a mineral is absorbed into the body, it
TABLE 2 Other Elements of Interest to Nutritionists and Food Scientists2
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Elements suggested to be essential to one or more animal species Arsenic — known primarily for its toxicity Boron — essential to plants, recent evidence for essentiality in animals Bromine — pharmacological uses Cadmium — known primarily for its toxicity Cobalt — also essential to humans, but only as a part of vitamin B12. Lead — known primarily for its toxicity Lithium — pharmacological uses Nickel — better primarily toxicity Silicon Sulfur — also essential to humans, but only as a part of some amino acids Tin Vanadium Elements not yet suggested as essential to animals or plants, but of interest for other reasons Aluminum — limited toxicity Mercury — well known for toxicity Barium — medical uses
TABLE 3 Dietary Factors Influencing Mineral Absorption Chemical form Oxidation state Amount in the diet Other nutrients in the diet Minerals Carbohydrates Fats Proteins Vitamins Nonnutritive components of the diet Phytate Fiber
IV. ISOTOPIC TRACERS By using isotopic tracers as labels, the metabolic fate of minerals in a specific day's diet, a specific meal, or a food can be distinguished from minerals from other sources and followed. Isotopic tracers may be radioactive isotopes or stable isotopes. The research that demonstrated the difference in the bioavailability of heme and nonheme iron discussed above was done using radioisotopes as tracers. Stable isotopes were the first isotopic tracers used. Their use began in 1935. The first studies were done with 13C, followed by studies with stable isotopes of H, N, and O. Their use in biomedical research has been reviewed.5 The use of stable isotopes was followed and, for a number of years, replaced by use of radioisotopes of C andH. The first isotopic tracers of essential minerals were radioisotopes. Radioactive iron was used to study anemia in animals.6 This work was followed by human studies of iron metabolism in 1942.7 Radioisotopes were also used as tracers of other essential minerals, including copper, calcium, magnesium, and zinc.8 Radioisotopes offered the advantages of easy detection and little sample preparation prior to analysis. However, the disadvantages of radioisotopes, i.e., that they result in exposure to radiation and that some isotopes decay too rapidly to be useful for tracer experiments, have led to renewed interest in the use of stable isotopes. The stable isotopes of the minerals listed in Tables 1 and 2, and the natural abundance of each are listed in Table 4. Of the 30 minerals listed, 8 (fluorine, sodium, phosphorus, manganese, iodine, cobalt, aluminum, and arsenic) are monoisotopic, and stable isotopes cannot be used as tracers. The remainder have from 2 to 10 isotopes, and all can be used for stable isotope studies.
Oxalate
mixes with minerals from meals consumed relatively recently and from meals consumed weeks, months, or even years earlier. Thus the mineral excreted via feces, urine, and other miscellaneous routes is from a combination of recent dietary intake and earlier intake. Figure 1 depicts the metabolic fate of dietary minerals.
V. EARLY STABLE ISOTOPE STUDIES A stable isotope was first used as tracer of a mineral in 1963 by Lowman and Krivit, who used a stable isotope of iron (58Fe) to measure plasma clearance of iron.9 Neutron activation analysis (NAA) was used for this work, and stable isotope 389
ABSORPTION, DISTRIBUTION, AND EXCRETION OF DIETARY MINERALS DIETARY MINERALS MISCELLENEOUS LOSSES
GASTRO- j INTESTINALTRACT
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FECES
LIVER
URINE
FIGURE 1. Absorption, distribution, and elimination of dietary minerals. Solid lines through gastrointestinal tract represent unabsorbed minerals. Dotted lines represent endogenous minerals excreted into the gastrointestinal tract and eliminated with unabsorbed minerals. Miscellaneous losses include sweat, hair, integument, nails, seminal fluid, and menstrual blood.
studies of other essential minerals using the same analytical approach were suggested. The report influenced and may have slowed the progress of stable isotope research on the metabolism of essential minerals, since others interested in mineral nutrition and stable isotopes tracers geared research to NAA analysis and designed experiments with the limitations of NAA in mind. The precedent for using mass spectrometric analysis for stable isotope tracer studies had been established with the early studies of the elements carbon, nitrogen, oxygen, and hydrogen. Isotopic ratios of minerals had been measured routinely by mass spectrometry in the fields of geochemistry and nuclear chemistry, but mass spectrometry was not applied to the early mineral tracer studies reported.
VI. ANALYTICAL METHODS Few studies were conducted with stable isotopes of essential minerals prior to 1978, and all of these used NAA. This method has a number of limitations, however. For example, a nuclear reactor is required, severely limiting the availability of instrumentation; only isotopes that upon irradiation produce isotopes with suitable decay characteristics can be analyzed by NAA; a num-
390
ber of otherwise suitable isotopes of essential minerals, such as 67Zn, 57Fe, 42Ca, "Ca, and ^Mg, cannot be measured with NAA; and the precision and accuracy of NAA is not equivalent to highprecision mass spectrometry. Increasing awareness of the limitations of NAA for the determination of stable isotopes of minerals led to exploration of mass spectrometric techniques for studies of the metabolism of essential minerals in humans. A group who had used thermal ionization mass spectrometry extensively for precise isotopic measurements for geological dating applied the technique to elegant stable isotope tracer studies of the metabolism of lead, an element toxic to humans.10 The first application of mass spectrometry to a stable isotope study of metabolism of an essential mineral was reported in 197911, and mass spectrometry is now used for most stable isotope research. A number of mass spectrometric methods have been attempted with varying degrees of success. The method of choice depends upon the mineral being analyzed and the precision and sensitivity required. Magnetic sector, thermal ionization mass spectrometry (TIMS) is used routinely in our laboratory to study the bioavailability of Zn, Cu, and Fe. 12 Analytical precision of within 1% is easily achieved for all minerals amenable to TIMS
TABLE 4 Isotopic Composition of Elements of Interest to Food Scientists and Nutritionists 30 Elements essential to humans
Element Fluorine
19
100
Sodium
23
100
Magnesium
24 25 26 31
78.99 10.00 11.01 100
Chlorine
35 37
75.77 24.23
Potassium
39 40 41
93.26 0.0117 6.730
40 42 43 44 46 48
96.94 0.647 0.135 2.086 0.004 0.187
50 52 53 54 55 6
4.345 83.79 9.501 2.365 100 7.5
Phosphorus
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Isotopic Abundance weight (%)
Calcium
Chromium
Manganese Lithium
Element
Isotopic Abundance weight (%)
Iron
54 56 57 58
5.81 91.75 2.15 0.29
Copper
63 65 64 66 67 68 70
69.17 30.83 48.63 27.90 4.10 18.75 0.62
74 76 77 78 80 82
0.88 8.95 7.65 23.51 49.62 9.39
Zinc
Selenium
Molybdenum 92 94 95 96 97 98 100 127 Iodine 112 Tin
14.84 9.247 15.92 16.68 9.555 24.13 9.634 100 1.0
Other elements
Boron
7 10 11
92.5 19.9 80.1
Aluminum
27
Silicon
28 29 30
92.23 4.67 3.10
Sulfur
32 33 34 36
95.02 0.75 4.20 0.02
Vanadium
50 51
0.25 99.75
114 116 117 118 119 120 122 124
0.7 14.7 7.7 24.3 8.6 32.4 4.6 5.6
Barium
130 132 134 135 136 137 138
0.106 0.101 2.417 6.592 7.854 11.23 71.70
Mercury
196
0.15
100
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TABLE 4 (continued) Isotopic Composition of Elements of Interest to Food Scientists and Nutritionists30 Elements essential to humans
Element
Isotopic Abundance weight (%)
Cobalt
59
Nickel
58 60 61 62 64
Arsenic
75
Bromine
79 81 106 108 110 111 112 113 114 116
Element
100 68.27 26.10 1.13 3.59 0.91
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Lead
Cadmium
100 50.69 49.31 1.25 0.89 12.49 12.80 24.13 12.22 28.73 7.49
Isotopic Abundance weight (%) 198 199 200 201 202 204
10.1 17.0 23.1 13.2 29.65 6.8
204 206 207 208
1.4 24.1 22.1 52.4
From Holden, N. E., Pure Appl. Chem., 55, 1119, 1983. With permission.
analysis, precision of within 0.1% is routine for most isotopes and minerals, and precision of within 0.02% can often be achieved. The newer, automated, computer-controlled instruments minimize the limitations of early TIMS instruments, i.e., slow sample throughput. Other mass spectrometric methods that are less precise but useful for many applications requiring isotopic determinations include quadrupole TTMS,13 inductively coupled plasma mass spectrometry (ICP/ MS),14 and fast-atom-bombardment mass spectrometry (FAB/MS).15 The advantages and disadvantages of each of these methods have been reviewed.16
VII. METHODS USED TO DETERMINE BIOAVAILABILITY To determine the bioavailability of minerals in the diet or specific foods, stable isotopes of
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the minerals under investigation are added to the foods or diets of interest. Absorption is currently most often determined by fecal monitoring.17 When fecal monitoring is used, complete fecal collections are made for a sufficient time to collect all isotope fed and not absorbed. Absorption is calculated by subtracting the amount recovered in the feces from the amount fed. The amount recovered in the feces can be calculated by isotope dilution, feeding one isotope and adding a second isotopic diluent to the sample, and measuring the ratio of each to a reference isotope. When a mineral has only two isotopes, such as Cu, the isotopic diluent can be added to one replicate sample and isotopic ratios of each determined.17 Other methods that have been used to a limited extent to determine bioavailability include the use of two different isotopes of the same mineral (one given orally and one injected), followed by the measurement of isotopic enrichment in the plasma or urine.13 Iron absorption can be
determined by measuring isotopic enrichment of erythrocytes about 2 weeks following the feeding of isotopically enriched iron.18 When radioisotopic tracers are used, absorption can also be determined from whole-body counting after a sufficient period of time has elapsed to eliminate all unabsorbed isotopes.
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VIII. DESIGNING AND CONDUCTING HUMAN STUDIES Research using stable isotopes to study mineral bioavailability in humans requires that the research team include individuals with expertise in stable isotope analysis, experimental design, human nutrition, and mineral metabolism. Careful control of all experimental conditions and sufficient enrichment of tissues to be analyzed are essential if reliable data are to be obtained. When the required conditions are met, data can be obtained with stable isotopes that cannot be obtained in any other way in human subjects. Most of the studies done by my colleagues and myself have been conducted in metabolic research units, with compliance to experimental diets and conditions by subjects and with complete sample collection.
IX. HUMAN STUDIES One of the major advantages of stable isotope studies is that multiple isotopes of the same mineral can be used simultaneously, and multiple minerals can be studied simultaneously. For example, we have fed isotopes of three minerals — Zn, Cu, and Fe — simultaneously and infused isotopes of five minerals —Zn, Cu, Fe, Ca, and Mg — simultaneously. We have conducted numerous studies with Zn, Cu, and Fe; done a limited amount of work with Ca and Mg; and are beginning a major effort to study Mo metabolism. In one set of studies of mineral absorption by young and elderly men, we demonstrated that Zn absorption from the diet is much less efficient in elderly men than in young men,19 but Cu and Fe absorption are similar between age groups.20
Marked differences in iron absorption were observed among individuals. Data from these studies are summarized in Table 5. A study conducted in pregnant women and nonpregnant women could not have been done without stable isotopes, due to ethical considerations. As shown in Table 6, this study demonstrated that absorption of dietary Zn did not differ significantly between pregnant and nonpregnant women.21 Absorption of dietary Cu was different between pregnant and nonpregnant women from a primarily vegetable protein diet, but not from a primarily animal protein diet.22 Another study demonstrated that Zn absorption is inhibited when phytate, a substance present in much larger amounts in whole-grain products than in refined products, is added to the diet.23 The reduction in Zn absorption was accompanied by an increased loss of endogenous Zn based on stable isotope data. Alpha cellulose, one form of dietary fiber, did not impair Zn absorption. Cu and Fe absorption appeared to be unaffected by either phytate or alpha cellulose.12-24 These results are summarized in Table 7. Based on a number of studies conducted over a period of years, we hypothesized that absorption of Cu from the diet was dependent on the dietary Cu intake, a fact that had not been considered previously when estimating the dietary Cu requirement. A study of Cu absorption and retention demonstrated that our hypothesis was correct,25 with marked and highly significant differences in Cu absorption, depending upon the dietary Cu intake (Figure 2). The results of this research should have an impact on future dietary Cu recommendations for humans. Other studies we conducted demonstrated that Zn absorption is also influenced by the level of dietary intake,26 but that within the range of normal intake, the level of dietary Zn does not influence Cu absorption.27 Some studies have used intrinsic stable isotope labels to study mineral bioavailability. Plants were grown in media containing stable isotopes; animals, including chickens and cows, were fed stable isotopes of minerals. The labeled foods were then fed to participants in bioavailability experiments.28 These studies were conducted be-
393
TABLE 5 Zinc, Copper, and Iron Absorption by Young and Elderly Men After 9 Weeks of Adaptation to a Constant Diet
Young men Elderly men a b
Zinc absorption*
Copper absorption
Iron absorption
33 ± 2 18 ± 4b
26 ± 1
8 ±3 9 ±4
28 ± 1
Mean ± SEM. Significantly lower in elderly men.
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From Turnlund, J. R. et al., J. Nutr., 116, 1239, 1986 and Turnlund, J. R. et a\.,Nutr. Res., 8,333,1988. With permission.
TABLE 6 Zinc and Copper Absorption in Pregnant and Nonpregnant Women from Animal and Plant Protein Diets Zinc Copper absorption* absorption Nonpregnant women Animal protein diet Plant protein diet Pregnant women Animal protein diet Plant protein diet •
X. FUTURE OF BIOAVAILABILITY STUDIES 23.8 ± 2.0 25.4 ± 1.7
41.2 ± 1.3 33.8 ± 0.8
24.2 ± 2.2 26.6 ± 3.6
42.2 ± 2.5 40.7 ± 3.0
Mean ± SEM.
From Turnlund, J. R. et al., J. Nutr., 113, 2346, 1983 and Turnlund, J. R. et al., Biol. Trace Elem. Res., 17, 31, 1988. With permission.
cause of a concern that stable isotopes added to foods may differ in bioavailability from the mineral naturally in the food. With the exception of selenium, research to date has generally demonstrated that the intrinsic labels are of the same or nearly the same bioa-
394
vailability as extrinsic labels added to foods, validating the extrinsic label approach to stable isotope studies. Methods and applications of intrinsic labels for bioavailability studies have been reviewed.29
The use of stable isotopes for studies of bioavailability of minerals in foods has gained widespread interest in recent years. This approach is expected to be applied to an increasing number of food science and nutrition problems in the future. Currently, the number of laboratories equipped to conduct stable isotope studies limits the use of the methodology. Unfortunately, many more investigators are interested in using stable isotopes than have access to the expertise, facilities, and equipment necessary to conduct such work. However, the number of applications has expanded greatly in the last decade and can be expected to continue to expand as the availability of instrumentation, facilities, and experience with stable isotope research increases.
TABLE 7 Zinc, Copper, and Iron Absorption from Diets Containing Phytate and Fiber
Diet only Diet ± phytate Diet ± acellulose •
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b
Zinc absorption*
Copper absorption
Iron absorption
34.0 ± 3.5" 17.5 ± 3.5"
35.0 ± 2.4 31.4 ± 2.4
8.9 ± 7.4 4.8 ± 1.9
33.8 ± 3.5
34.1 ± 2.4
3.5 ± 1.9
Mean ± SEM. Significantly lower with phytate added to the diet.
From Turnlund, J. R.Biol. Trace Elem. Res., 12,247,1987; Turnlund, J. R. et al.,J. Nutr., 115,1345,1985; and Turnlund, J. R. et a\.,Am. J. Clin. Nutr., 42,18,1985. With permission.
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50-
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E
40-
-6
a. O 30
a.
CO
m < 2010-1
o-\ 1 2
3
4
5
6
7
CU INTAKE (mg/d) FIGURE 2. Copper absorption % (+ (-) and mg/d (•—•) with dietary Cu intake between 0.785 and 7.53 mg/d.
1. National Research Council, Recommended Dietary Allowances, 10th ed., National Academy of Sciences, Washington, D.C., 1989. 2. Mertz, W., Trace Elements in Human and Animal Nutrition, Vols 1 and 2., 5th ed., Academic Press, San Diego, 1987. 3. O'Dell, B. L., Bioavailability of trace elements, Nutr. Rev., 42, 301, 1984. 4. Anderson, R. A., Chromium, in Trace Elements in Human and Animal Nutrition, Vol. 1., Mertz W., Ed., Academic Press, San Diego, 1987, 225. 5. Klein, P. D., Hachey, D. L., Kreek, M. J., and Schoeller, D. A., Stable isotopes: essential tools in biological and medical research, in Stable Isotopes. Applications in Pharmacology, Toxicology, and Clinical Research, Baillie T. A., Ed., University Park Press, Baltimore, 1978, 3. 6. Hahn, P. F., Bale, W. F., Lawrence, E. O., and Whipple, G. H., Radioactive iron and its metabolism in anemia. Its absorption, transportation, and utilization, J. Exp. Med., 69, 739, 1939. 7. Balfour, W. M., Hahn, P. F., Bale, W. F., Pommerenke, W. T., and Whipple, G. H., Radioactive iron absorption in clinical conditions: normal, pregnancy, anemia, and hemochromatosis, J. Exp. Med., 76, 15, 1942.
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8. Turnlund, J. R., The use of stable isotopes in mineral nutrition research, J. Nutr., 119, 7, 1989. 9. Lowman, J. T. and Krivit, W., New in vivo tracer method with the use of nonradioactive isotopes and activation analysis, J. Lab. Clin. Med., 61, 1042, 1963. 10. Rabinowitz, M. B., Wetherill, G. W., and Kopple, J. D., Lead metabolism in the normal human: stable isotope studies, Science, 182, 725, 1973. 11. Schwartz, R. and Giesecke, C. C., Mass spectrometry of a volatile Mg chelate in the measurement of stable 26Mg when used as a tracer, Clin. Chem. Acta, 97, 1, 1979. 12. Turnlund, J. R., Zinc, copper, and iron nutrition studied with enriched stable isotopes, Biol. Trace Elem. Res., 12, 247, 1987. 13. Schwartz, R., Spencer, H., and Wentworth, R. A., Measurement of magnesium absorption in man using stable 28Mg as a tracer, Clin. Chem. Acta, 97, 1, 1978. 14. Serfass, R. E., Thompson, J. J., and Houk, R. S., Isotope ratio determinations by inductively coupled plasma mass spectrometry for zinc bioavailability studies, Anal. Chim. Acta, 188, 73, 1986. 15. Rajagopalan, K. V., Molybdenum — An essential trace element, Nutrit. Rev., 45, 321, 1987. 16. Hachey, D. L., Wong, W. W., Boutton, T. W., and Klein, P. D., Isotope ratio measurement in nutrition and biomedical research, Mass Sped. Rev., 6, 289, 1987. 17. Turnlund, J. R., Trace element utilization in humans studied with enriched stable isotopes and thermal ionization mass spectrometry, in Stable Isotopes in Nutrition, Turnlund, J. R. and Johnson, P. E., Eds., American Chemical Society, Washington, D.C., 1984, 41. 18. Fomon, S. J., Janghorbani, M., and Ting, B. T. G. et al., Erythrocyte incorporation of ingested 58-iron by infants, Pediatr. Res., 24, 20, 1988. 19. Turnlund, J. R., Costa, F., Durkin, N., and Margen, S., Stable isotope studies of zinc absorption and retention in young and elderly men, J. Nutr., 116, 1239, 1986.
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20. Turnlund, J. R., Reager, R., and Costa, F., Iron and copper absorption in young and elderly men, Nutr. Res., 8, 333, 1988. 21. Swanson, C. A., Turnlund, J. R., and King, J. C., Effect of dietary zinc sources and pregnancy on zinc utilization in adult women fed controlled diets, J. Nutr., 113, 2557, 1983. 22. Turnlund, J. R., Swanson, C. A., and King, J. C., Copper absorption and retention in pregnant women fed diets based on animal and plant proteins, J. Nutr., 113, 2346, 1983. 23. Turnlund, J. R., King, J. C., Keyes, W. R., Gong, B., and Michel, M. C., A stable isotope study of zinc absorption in young men: effects of phytate and alpha cellulose, Am. J. Clin Nutr., 40, 1071, 1984. 24. Turnlund, J. R., King, J. C . , Gong, B., Keyes, W. R., and Michel, M. C., A stable isotope study of copper absorption in young men: effect of phytate and alpha-cellulose, Am. J. Clin.Nutr., 42, 18, 1985. 25. Turnlund, J. R., Keyes, W. R., Anderson, H. L., and Acord, L. L., Copper absorption and retention in young men at three levels of dietary copper using the stable isotope 65Cu, Am. J. Clin. Nutr., 49, 870, 1989. 26. Wada, L., Turnlund, J. R., and King, J. C., Zinc utilization in young men fed adequate and low zinc intakes, J. Nutr., 115, 1345, 1985. 27. Turnlund, J. R., Wada, L., King, J. C., Keyes, W. R., and Acord, L. L., Copper absorption in young men fed adequate and low zinc diets, Biol. Trace Elem. Res., 17, 31, 1988. 28. Swanson, C. A., Reamer, D. C., Veillon, C., and Levander, O. A., Intrinsic labeling of chicken products with a stable isotope of selenium (76Se), J. Nutr., 113, 793, 1983. 29. Weaver, C., Isotopic tracer methodology: potential in mineral nutrition, in Trace Minerals in Foods, Smith, K., Ed., Marcel Dekker, New York, 1988, 429. 30. Holden, N. E., Martin, R. L., and Barnes, I. L., Isotopic compositions of the elements 1981, Pure Appl. Chem., 55, 1119, 1983.
Critical Reviews in Food Science and Nutrition Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/bfsn20
Bioavailability of dietary minerals to humans: The stable isotope approach Judith R. Turnlund
a
a
USDA/ARS, Western Human Nutrition Research Center, P.O. Box 29997, Presidio of San Francisco, California Published online: 29 Sep 2009.
To cite this article: Judith R. Turnlund (1991): Bioavailability of dietary minerals to humans: The stable isotope approach, Critical Reviews in Food Science and Nutrition, 30:4, 387-396 To link to this article: http://dx.doi.org/10.1080/10408399109527549
PLEASE SCROLL DOWN FOR ARTICLE Full terms and conditions of use: http://www.tandfonline.com/page/terms-and-conditions This article may be used for research, teaching, and private study purposes. Any substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any form to anyone is expressly forbidden. The publisher does not give any warranty express or implied or make any representation that the contents will be complete or accurate or up to date. The accuracy of any instructions, formulae, and drug doses should be independently verified with primary sources. The publisher shall not be liable for any loss, actions, claims, proceedings, demand, or costs or damages whatsoever or howsoever caused arising directly or indirectly in connection with or arising out of the use of this material.
Critical Reviews in Food Science and Nutrition, 30(3):387—396 (1991)
Bioavailability of Dietary Minerals to Humans: The Stable Isotope Approach Judith R. Turnlund
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USDA/ARS Western Human Nutrition Research Center, P.O. Box 29997, Presidio of San Francisco, California
ABSTRACT: A number of minerals contained in foods are essential nutrients for humans, animals, and/or plants. While most vitamins are very well absorbed, most essential minerals are not. Usual absorption of minerals ranges from less than 1% to over 90%. The bioavailability of dietary minerals must be considered when determining whether the diet contains enough, too little, or too much. By using stable isotope tracers as labels, the metabolic fate of minerals in a specific day's diet, a specific meal, or a food can be distinguished from minerals from other sources and followed. A number of mass spectrometric methods have been used to measure stable isotopes. Magnetic sector, thermal ionization mass spectrometry (TIMS) is used routinely in our laboratory to study bioavailability of Zn, Cu, and Fe. Other mass spectrometric methods that are less precise, but useful for many applications requiring isotopic determinations include quadrupole TIMS, inductively coupled plasma mass spectrometry (ICP/MS), and fast atom bombardment mass spectrometry (FAB/MS). One of the major advantages of stable isotope studies is that multiple isotopes of the same mineral can be used simultaneously and multiple minerals can be studied simultaneously. The use of stable isotopes for studies of bioavailability of minerals in foods has gained widespread interest in recent years. The approach is expected to be applied to an increasing number of food science and nutrition problems in the future. KEY WORDS: bioavailability, minerals, stable isotope.
I. INTRODUCTION A number of minerals contained in foods are essential nutrients for humans. 1 If adequate amounts of these minerals are not included in the diet, nutritional status will be impaired and a variety of health problems can result. The essentiality of other minerals has not yet been established in humans, but they are required by one or more animal species. Still others have not yet been established to be essential to any animal species, but are required by plants. It is thought likely that some of these minerals required by animals and/or plants may also be required by humans. In addition to the above categories, some minerals in foods are important due to their toxicities. The minerals in all of these categories are of interest to food scientists and nutritionists.2 Those
known to be essential in the diets of humans are shown in Table 1, along with the current dietary recommendations for each. The minerals essential to one or more animal species and/or plants, but not yet known to be essential for humans, and those now known only for their toxicity or used therapeutically, are shown in Table 2. It is possible that some or all of those minerals essential to an animal or plant species may eventually be found to be essential to humans as well. All of the essential elements are toxic in sufficient quantities. It is possible that some of the minerals currently known only for their toxicity may someday be found to be essential in small amounts.
II. BIOAVAILABILITY Bioavailability of nutrients refers to the pro-
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TABLE 1 Elements Essential to Humans and Recommended Daily Dietary Intakes for Healthy Adults1
Element
RDA* mg/d
Element
ESADDI" mg/d
Calcium Phosphorus Magnesium Iron Zinc Iodine Selenium
800 800 300 (350)d 18(10) d 15 0.15 0.055 (0.07)d
Copper Manganese Fluoride Chromium Molybdenum
1.5—3.0 2.0—5.0 1.5—4.0 0.05—0.2 0.075—0.25
Element Sodium Potassium Chloride
EMR< mg/d 500 750 2000
a
Recommended dietary allowance. Estimated safe and adequate daily dietary intake. c Estimated minimum requirement. " Recommendations differ for women and men. The recommendation for women is followed by the recommendation for men in parentheses.
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b
portion in food that is absorbed and utilized by the body.3 Until a nutrient is absorbed from the gastrointestinal (GI) tract and enters the systemic circulation, it is not available for utilization. While most vitamins are very well absorbed, most essential minerals are not. Usual absorption of minerals ranges from less than 1% to over 90%. The bioavailability of dietary minerals must be considered when determining whether the diet contains enough, too little, or too much. The fraction of a specific mineral that is absorbed is dependent on a number of factors. A few elements, such as sodium and potassium, are very well absorbed under most conditions. Others are poorly absorbed and the fraction absorbed can vary greatly. The factors that influence absorption, some of which are listed in Table 3, include the amount in the diet, the oxidation state of the mineral, the chemical form and the presence of interfering or enhancing factors. Two examples of the variation in absorption of a mineral are found with iron and chromium. Only about 3 to 8% of the iron in plant foods is usually absorbed, while about 25% of heme iron, the form of iron contained in red meats, is absorbed.1 CrCl3 is not absorbed from the gastrointestinal tract, making it useful as a marker for intestinal transit; however, other inorganic Cr salts are better absorbed than the highly insoluble CrCl3. Cr in natural complexes is better absorbed
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than inorganic Cr salts, and hexavalent chromium is better absorbed than trivalent chromium.4
III. DETERMINING MINERAL BIOAVAILABILITY Determining the bioavailability or absorption of a mineral is complicated by the fact that once a food is consumed, it mixes in the GI tract with other foods that were consumed at about the same time. In addition, the dietary minerals in a meal or specific day's diet mix with minerals consumed in other meals and on other days that still remain in the GI tract. Varying fractions of a mineral consumed on a specific day and not absorbed are eliminated from the body via the GI tract over a period of several days. Complete elimination of an unabsorbed mineral usually takes from 6 to 12 d, and in a few instances, a shorter or longer period of time. The unabsorbed mineral will also mix with endogenous mineral that was in the body and was excreted via the bile or other secretions into the GI tract. Biliary excretion is the primary route of elimination from the body for a number of minerals. Therefore, one cannot determine the amount of unabsorbed mineral simply by measuring the amount eliminated in the feces. Once a mineral is absorbed into the body, it
TABLE 2 Other Elements of Interest to Nutritionists and Food Scientists2
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Elements suggested to be essential to one or more animal species Arsenic — known primarily for its toxicity Boron — essential to plants, recent evidence for essentiality in animals Bromine — pharmacological uses Cadmium — known primarily for its toxicity Cobalt — also essential to humans, but only as a part of vitamin B12. Lead — known primarily for its toxicity Lithium — pharmacological uses Nickel — better primarily toxicity Silicon Sulfur — also essential to humans, but only as a part of some amino acids Tin Vanadium Elements not yet suggested as essential to animals or plants, but of interest for other reasons Aluminum — limited toxicity Mercury — well known for toxicity Barium — medical uses
TABLE 3 Dietary Factors Influencing Mineral Absorption Chemical form Oxidation state Amount in the diet Other nutrients in the diet Minerals Carbohydrates Fats Proteins Vitamins Nonnutritive components of the diet Phytate Fiber
IV. ISOTOPIC TRACERS By using isotopic tracers as labels, the metabolic fate of minerals in a specific day's diet, a specific meal, or a food can be distinguished from minerals from other sources and followed. Isotopic tracers may be radioactive isotopes or stable isotopes. The research that demonstrated the difference in the bioavailability of heme and nonheme iron discussed above was done using radioisotopes as tracers. Stable isotopes were the first isotopic tracers used. Their use began in 1935. The first studies were done with 13C, followed by studies with stable isotopes of H, N, and O. Their use in biomedical research has been reviewed.5 The use of stable isotopes was followed and, for a number of years, replaced by use of radioisotopes of C andH. The first isotopic tracers of essential minerals were radioisotopes. Radioactive iron was used to study anemia in animals.6 This work was followed by human studies of iron metabolism in 1942.7 Radioisotopes were also used as tracers of other essential minerals, including copper, calcium, magnesium, and zinc.8 Radioisotopes offered the advantages of easy detection and little sample preparation prior to analysis. However, the disadvantages of radioisotopes, i.e., that they result in exposure to radiation and that some isotopes decay too rapidly to be useful for tracer experiments, have led to renewed interest in the use of stable isotopes. The stable isotopes of the minerals listed in Tables 1 and 2, and the natural abundance of each are listed in Table 4. Of the 30 minerals listed, 8 (fluorine, sodium, phosphorus, manganese, iodine, cobalt, aluminum, and arsenic) are monoisotopic, and stable isotopes cannot be used as tracers. The remainder have from 2 to 10 isotopes, and all can be used for stable isotope studies.
Oxalate
mixes with minerals from meals consumed relatively recently and from meals consumed weeks, months, or even years earlier. Thus the mineral excreted via feces, urine, and other miscellaneous routes is from a combination of recent dietary intake and earlier intake. Figure 1 depicts the metabolic fate of dietary minerals.
V. EARLY STABLE ISOTOPE STUDIES A stable isotope was first used as tracer of a mineral in 1963 by Lowman and Krivit, who used a stable isotope of iron (58Fe) to measure plasma clearance of iron.9 Neutron activation analysis (NAA) was used for this work, and stable isotope 389
ABSORPTION, DISTRIBUTION, AND EXCRETION OF DIETARY MINERALS DIETARY MINERALS MISCELLENEOUS LOSSES
GASTRO- j INTESTINALTRACT
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FECES
LIVER
URINE
FIGURE 1. Absorption, distribution, and elimination of dietary minerals. Solid lines through gastrointestinal tract represent unabsorbed minerals. Dotted lines represent endogenous minerals excreted into the gastrointestinal tract and eliminated with unabsorbed minerals. Miscellaneous losses include sweat, hair, integument, nails, seminal fluid, and menstrual blood.
studies of other essential minerals using the same analytical approach were suggested. The report influenced and may have slowed the progress of stable isotope research on the metabolism of essential minerals, since others interested in mineral nutrition and stable isotopes tracers geared research to NAA analysis and designed experiments with the limitations of NAA in mind. The precedent for using mass spectrometric analysis for stable isotope tracer studies had been established with the early studies of the elements carbon, nitrogen, oxygen, and hydrogen. Isotopic ratios of minerals had been measured routinely by mass spectrometry in the fields of geochemistry and nuclear chemistry, but mass spectrometry was not applied to the early mineral tracer studies reported.
VI. ANALYTICAL METHODS Few studies were conducted with stable isotopes of essential minerals prior to 1978, and all of these used NAA. This method has a number of limitations, however. For example, a nuclear reactor is required, severely limiting the availability of instrumentation; only isotopes that upon irradiation produce isotopes with suitable decay characteristics can be analyzed by NAA; a num-
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ber of otherwise suitable isotopes of essential minerals, such as 67Zn, 57Fe, 42Ca, "Ca, and ^Mg, cannot be measured with NAA; and the precision and accuracy of NAA is not equivalent to highprecision mass spectrometry. Increasing awareness of the limitations of NAA for the determination of stable isotopes of minerals led to exploration of mass spectrometric techniques for studies of the metabolism of essential minerals in humans. A group who had used thermal ionization mass spectrometry extensively for precise isotopic measurements for geological dating applied the technique to elegant stable isotope tracer studies of the metabolism of lead, an element toxic to humans.10 The first application of mass spectrometry to a stable isotope study of metabolism of an essential mineral was reported in 197911, and mass spectrometry is now used for most stable isotope research. A number of mass spectrometric methods have been attempted with varying degrees of success. The method of choice depends upon the mineral being analyzed and the precision and sensitivity required. Magnetic sector, thermal ionization mass spectrometry (TIMS) is used routinely in our laboratory to study the bioavailability of Zn, Cu, and Fe. 12 Analytical precision of within 1% is easily achieved for all minerals amenable to TIMS
TABLE 4 Isotopic Composition of Elements of Interest to Food Scientists and Nutritionists 30 Elements essential to humans
Element Fluorine
19
100
Sodium
23
100
Magnesium
24 25 26 31
78.99 10.00 11.01 100
Chlorine
35 37
75.77 24.23
Potassium
39 40 41
93.26 0.0117 6.730
40 42 43 44 46 48
96.94 0.647 0.135 2.086 0.004 0.187
50 52 53 54 55 6
4.345 83.79 9.501 2.365 100 7.5
Phosphorus
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Isotopic Abundance weight (%)
Calcium
Chromium
Manganese Lithium
Element
Isotopic Abundance weight (%)
Iron
54 56 57 58
5.81 91.75 2.15 0.29
Copper
63 65 64 66 67 68 70
69.17 30.83 48.63 27.90 4.10 18.75 0.62
74 76 77 78 80 82
0.88 8.95 7.65 23.51 49.62 9.39
Zinc
Selenium
Molybdenum 92 94 95 96 97 98 100 127 Iodine 112 Tin
14.84 9.247 15.92 16.68 9.555 24.13 9.634 100 1.0
Other elements
Boron
7 10 11
92.5 19.9 80.1
Aluminum
27
Silicon
28 29 30
92.23 4.67 3.10
Sulfur
32 33 34 36
95.02 0.75 4.20 0.02
Vanadium
50 51
0.25 99.75
114 116 117 118 119 120 122 124
0.7 14.7 7.7 24.3 8.6 32.4 4.6 5.6
Barium
130 132 134 135 136 137 138
0.106 0.101 2.417 6.592 7.854 11.23 71.70
Mercury
196
0.15
100
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TABLE 4 (continued) Isotopic Composition of Elements of Interest to Food Scientists and Nutritionists30 Elements essential to humans
Element
Isotopic Abundance weight (%)
Cobalt
59
Nickel
58 60 61 62 64
Arsenic
75
Bromine
79 81 106 108 110 111 112 113 114 116
Element
100 68.27 26.10 1.13 3.59 0.91
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Lead
Cadmium
100 50.69 49.31 1.25 0.89 12.49 12.80 24.13 12.22 28.73 7.49
Isotopic Abundance weight (%) 198 199 200 201 202 204
10.1 17.0 23.1 13.2 29.65 6.8
204 206 207 208
1.4 24.1 22.1 52.4
From Holden, N. E., Pure Appl. Chem., 55, 1119, 1983. With permission.
analysis, precision of within 0.1% is routine for most isotopes and minerals, and precision of within 0.02% can often be achieved. The newer, automated, computer-controlled instruments minimize the limitations of early TIMS instruments, i.e., slow sample throughput. Other mass spectrometric methods that are less precise but useful for many applications requiring isotopic determinations include quadrupole TTMS,13 inductively coupled plasma mass spectrometry (ICP/ MS),14 and fast-atom-bombardment mass spectrometry (FAB/MS).15 The advantages and disadvantages of each of these methods have been reviewed.16
VII. METHODS USED TO DETERMINE BIOAVAILABILITY To determine the bioavailability of minerals in the diet or specific foods, stable isotopes of
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the minerals under investigation are added to the foods or diets of interest. Absorption is currently most often determined by fecal monitoring.17 When fecal monitoring is used, complete fecal collections are made for a sufficient time to collect all isotope fed and not absorbed. Absorption is calculated by subtracting the amount recovered in the feces from the amount fed. The amount recovered in the feces can be calculated by isotope dilution, feeding one isotope and adding a second isotopic diluent to the sample, and measuring the ratio of each to a reference isotope. When a mineral has only two isotopes, such as Cu, the isotopic diluent can be added to one replicate sample and isotopic ratios of each determined.17 Other methods that have been used to a limited extent to determine bioavailability include the use of two different isotopes of the same mineral (one given orally and one injected), followed by the measurement of isotopic enrichment in the plasma or urine.13 Iron absorption can be
determined by measuring isotopic enrichment of erythrocytes about 2 weeks following the feeding of isotopically enriched iron.18 When radioisotopic tracers are used, absorption can also be determined from whole-body counting after a sufficient period of time has elapsed to eliminate all unabsorbed isotopes.
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VIII. DESIGNING AND CONDUCTING HUMAN STUDIES Research using stable isotopes to study mineral bioavailability in humans requires that the research team include individuals with expertise in stable isotope analysis, experimental design, human nutrition, and mineral metabolism. Careful control of all experimental conditions and sufficient enrichment of tissues to be analyzed are essential if reliable data are to be obtained. When the required conditions are met, data can be obtained with stable isotopes that cannot be obtained in any other way in human subjects. Most of the studies done by my colleagues and myself have been conducted in metabolic research units, with compliance to experimental diets and conditions by subjects and with complete sample collection.
IX. HUMAN STUDIES One of the major advantages of stable isotope studies is that multiple isotopes of the same mineral can be used simultaneously, and multiple minerals can be studied simultaneously. For example, we have fed isotopes of three minerals — Zn, Cu, and Fe — simultaneously and infused isotopes of five minerals —Zn, Cu, Fe, Ca, and Mg — simultaneously. We have conducted numerous studies with Zn, Cu, and Fe; done a limited amount of work with Ca and Mg; and are beginning a major effort to study Mo metabolism. In one set of studies of mineral absorption by young and elderly men, we demonstrated that Zn absorption from the diet is much less efficient in elderly men than in young men,19 but Cu and Fe absorption are similar between age groups.20
Marked differences in iron absorption were observed among individuals. Data from these studies are summarized in Table 5. A study conducted in pregnant women and nonpregnant women could not have been done without stable isotopes, due to ethical considerations. As shown in Table 6, this study demonstrated that absorption of dietary Zn did not differ significantly between pregnant and nonpregnant women.21 Absorption of dietary Cu was different between pregnant and nonpregnant women from a primarily vegetable protein diet, but not from a primarily animal protein diet.22 Another study demonstrated that Zn absorption is inhibited when phytate, a substance present in much larger amounts in whole-grain products than in refined products, is added to the diet.23 The reduction in Zn absorption was accompanied by an increased loss of endogenous Zn based on stable isotope data. Alpha cellulose, one form of dietary fiber, did not impair Zn absorption. Cu and Fe absorption appeared to be unaffected by either phytate or alpha cellulose.12-24 These results are summarized in Table 7. Based on a number of studies conducted over a period of years, we hypothesized that absorption of Cu from the diet was dependent on the dietary Cu intake, a fact that had not been considered previously when estimating the dietary Cu requirement. A study of Cu absorption and retention demonstrated that our hypothesis was correct,25 with marked and highly significant differences in Cu absorption, depending upon the dietary Cu intake (Figure 2). The results of this research should have an impact on future dietary Cu recommendations for humans. Other studies we conducted demonstrated that Zn absorption is also influenced by the level of dietary intake,26 but that within the range of normal intake, the level of dietary Zn does not influence Cu absorption.27 Some studies have used intrinsic stable isotope labels to study mineral bioavailability. Plants were grown in media containing stable isotopes; animals, including chickens and cows, were fed stable isotopes of minerals. The labeled foods were then fed to participants in bioavailability experiments.28 These studies were conducted be-
393
TABLE 5 Zinc, Copper, and Iron Absorption by Young and Elderly Men After 9 Weeks of Adaptation to a Constant Diet
Young men Elderly men a b
Zinc absorption*
Copper absorption
Iron absorption
33 ± 2 18 ± 4b
26 ± 1
8 ±3 9 ±4
28 ± 1
Mean ± SEM. Significantly lower in elderly men.
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From Turnlund, J. R. et al., J. Nutr., 116, 1239, 1986 and Turnlund, J. R. et a\.,Nutr. Res., 8,333,1988. With permission.
TABLE 6 Zinc and Copper Absorption in Pregnant and Nonpregnant Women from Animal and Plant Protein Diets Zinc Copper absorption* absorption Nonpregnant women Animal protein diet Plant protein diet Pregnant women Animal protein diet Plant protein diet •
X. FUTURE OF BIOAVAILABILITY STUDIES 23.8 ± 2.0 25.4 ± 1.7
41.2 ± 1.3 33.8 ± 0.8
24.2 ± 2.2 26.6 ± 3.6
42.2 ± 2.5 40.7 ± 3.0
Mean ± SEM.
From Turnlund, J. R. et al., J. Nutr., 113, 2346, 1983 and Turnlund, J. R. et al., Biol. Trace Elem. Res., 17, 31, 1988. With permission.
cause of a concern that stable isotopes added to foods may differ in bioavailability from the mineral naturally in the food. With the exception of selenium, research to date has generally demonstrated that the intrinsic labels are of the same or nearly the same bioa-
394
vailability as extrinsic labels added to foods, validating the extrinsic label approach to stable isotope studies. Methods and applications of intrinsic labels for bioavailability studies have been reviewed.29
The use of stable isotopes for studies of bioavailability of minerals in foods has gained widespread interest in recent years. This approach is expected to be applied to an increasing number of food science and nutrition problems in the future. Currently, the number of laboratories equipped to conduct stable isotope studies limits the use of the methodology. Unfortunately, many more investigators are interested in using stable isotopes than have access to the expertise, facilities, and equipment necessary to conduct such work. However, the number of applications has expanded greatly in the last decade and can be expected to continue to expand as the availability of instrumentation, facilities, and experience with stable isotope research increases.
TABLE 7 Zinc, Copper, and Iron Absorption from Diets Containing Phytate and Fiber
Diet only Diet ± phytate Diet ± acellulose •
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b
Zinc absorption*
Copper absorption
Iron absorption
34.0 ± 3.5" 17.5 ± 3.5"
35.0 ± 2.4 31.4 ± 2.4
8.9 ± 7.4 4.8 ± 1.9
33.8 ± 3.5
34.1 ± 2.4
3.5 ± 1.9
Mean ± SEM. Significantly lower with phytate added to the diet.
From Turnlund, J. R.Biol. Trace Elem. Res., 12,247,1987; Turnlund, J. R. et al.,J. Nutr., 115,1345,1985; and Turnlund, J. R. et a\.,Am. J. Clin. Nutr., 42,18,1985. With permission.
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5
6
7
CU INTAKE (mg/d) FIGURE 2. Copper absorption % (+ (-) and mg/d (•—•) with dietary Cu intake between 0.785 and 7.53 mg/d.
1. National Research Council, Recommended Dietary Allowances, 10th ed., National Academy of Sciences, Washington, D.C., 1989. 2. Mertz, W., Trace Elements in Human and Animal Nutrition, Vols 1 and 2., 5th ed., Academic Press, San Diego, 1987. 3. O'Dell, B. L., Bioavailability of trace elements, Nutr. Rev., 42, 301, 1984. 4. Anderson, R. A., Chromium, in Trace Elements in Human and Animal Nutrition, Vol. 1., Mertz W., Ed., Academic Press, San Diego, 1987, 225. 5. Klein, P. D., Hachey, D. L., Kreek, M. J., and Schoeller, D. A., Stable isotopes: essential tools in biological and medical research, in Stable Isotopes. Applications in Pharmacology, Toxicology, and Clinical Research, Baillie T. A., Ed., University Park Press, Baltimore, 1978, 3. 6. Hahn, P. F., Bale, W. F., Lawrence, E. O., and Whipple, G. H., Radioactive iron and its metabolism in anemia. Its absorption, transportation, and utilization, J. Exp. Med., 69, 739, 1939. 7. Balfour, W. M., Hahn, P. F., Bale, W. F., Pommerenke, W. T., and Whipple, G. H., Radioactive iron absorption in clinical conditions: normal, pregnancy, anemia, and hemochromatosis, J. Exp. Med., 76, 15, 1942.
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20. Turnlund, J. R., Reager, R., and Costa, F., Iron and copper absorption in young and elderly men, Nutr. Res., 8, 333, 1988. 21. Swanson, C. A., Turnlund, J. R., and King, J. C., Effect of dietary zinc sources and pregnancy on zinc utilization in adult women fed controlled diets, J. Nutr., 113, 2557, 1983. 22. Turnlund, J. R., Swanson, C. A., and King, J. C., Copper absorption and retention in pregnant women fed diets based on animal and plant proteins, J. Nutr., 113, 2346, 1983. 23. Turnlund, J. R., King, J. C., Keyes, W. R., Gong, B., and Michel, M. C., A stable isotope study of zinc absorption in young men: effects of phytate and alpha cellulose, Am. J. Clin Nutr., 40, 1071, 1984. 24. Turnlund, J. R., King, J. C . , Gong, B., Keyes, W. R., and Michel, M. C., A stable isotope study of copper absorption in young men: effect of phytate and alpha-cellulose, Am. J. Clin.Nutr., 42, 18, 1985. 25. Turnlund, J. R., Keyes, W. R., Anderson, H. L., and Acord, L. L., Copper absorption and retention in young men at three levels of dietary copper using the stable isotope 65Cu, Am. J. Clin. Nutr., 49, 870, 1989. 26. Wada, L., Turnlund, J. R., and King, J. C., Zinc utilization in young men fed adequate and low zinc intakes, J. Nutr., 115, 1345, 1985. 27. Turnlund, J. R., Wada, L., King, J. C., Keyes, W. R., and Acord, L. L., Copper absorption in young men fed adequate and low zinc diets, Biol. Trace Elem. Res., 17, 31, 1988. 28. Swanson, C. A., Reamer, D. C., Veillon, C., and Levander, O. A., Intrinsic labeling of chicken products with a stable isotope of selenium (76Se), J. Nutr., 113, 793, 1983. 29. Weaver, C., Isotopic tracer methodology: potential in mineral nutrition, in Trace Minerals in Foods, Smith, K., Ed., Marcel Dekker, New York, 1988, 429. 30. Holden, N. E., Martin, R. L., and Barnes, I. L., Isotopic compositions of the elements 1981, Pure Appl. Chem., 55, 1119, 1983.
