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Background: Iron excretion measured by isotope dilution has been a primary basis for the factorial derivation of recommendations for iron intake, but the results have been available for men only. Objective: The objective of this study was to confirm iron excretion measurements in healthy men and extend them to women. Design: The turnover rate of [sup.55]Fe that had been administered [greater than or equal to] 1 y earlier was determined from blood sampled semiannually for up to 3 y from 53 subjects in the community. Body iron was determined from hemoglobin, serum ferritin, and transferrin receptor. Complete menstrual collections were obtained from 13 women. Results: The total median (range) iron excretion was 1.18 (0.11-2.07) mg/d for 29 men, 1.58 (0.65-4.88) mg/d for 19 menstruating women, and 0.99 (0.86-1.57) for 5 postmenopausal women. When hormonal contraceptive users were omitted, the median for 15 menstruating women increased to 1.66 mg/d. The distribution of iron excretion was normal for the men and postmenopausal women and was highly skewed for the menstruating women; menstrual iron accounted for 90% of the variation. Iron excretion was not strongly related to body weight. Body iron in menstiuating women decreased somewhat (by 4.6%) in the men and tended to increase (by 1.5%) during the study. Conclusions: The results extend direct iron excretion measurements in men to include similar measurements in women. The results emphasize the wide range of iron excretion in humans, which results in a 40-fold range of requirements for absorbed iron. This trial was registered at clinicaltrials.gov as NCT00755105.

Background: The effect of meat protein on calcium retention at different calcium intakes is unresolved. Objective: The objective was to test the effect of dietary protein on calcium retention at low and high intakes of calcium. Design: In a randomized controlled feeding study with a 2 x 2 factorial crossover design, healthy postmenopausal women (n = 27) consumed either [approximately equal to]675 or [approximately equal to]1510 mg Ca/d, with both low and high protein (providing 10% and 20% energy) for 7 wk each, separated by a 3-wk washout period. After 3 wk, the entire diet was extrinsically labeled with [sup.47]Ca, and isotope retention was monitored by whole-body scintillation counting. Clinical markers of calcium and bone metabolism were measured. Results: High compared with low dietary protein significantly increased calcium retention from the low-calcium (29.5% compared with 26.0% absorbed) but not the high-calcium diet (18% absorbed). For the low-calcium diet, this effect nearly balanced a protein-related 0.5-mmol/d greater urinary calcium excretion. Protein-related calciuretic effects were independent of dietary calcium. Testing at 1, 2, 3, 5, and 7 wk showed no long-term adaptation in urinary acidity or urinary calcium excretion. High compared with low dietary protein decreased urinary deoxypyridinoline and increased serum insulin-like growth factor I without affecting parathyroid hormone, osteocalcin, bone-specific alkaline phosphatase, or tartrate-resistant acid phosphatase. Conclusions: In healthy postmenopausal women, a moderate increase in dietary protein, from 10% to 20% of energy, slightly improved calcium absorption from a low-calcium diet, nearly compensating for a slight increase in urinary calcium excretion. Under practical dietary conditions, increased dietary protein from animal sources was not detrimental to calcium balance or short-term indicators of bone health.

Background: Although calcium inhibits zinc bioavailability in rats, especially from high-phytate diets, the effect of calcium on zinc absorption by humans from practical diets remains unclear. Objective: The objective was to test the inhibitory effect of dietary calcium, in Western diets with high and low phytate content, on zinc absorption. Design: Using a 2 x 2 factorial design, zinc absorption was determined in 10 healthy women from 1-d diets with moderate and high calcium contents of [approximately equal to] 700 and 1800 mg/d and low and high phytate contents of [approximately equal to] 440 and 1800 mg/d. Absorption was measured by using extrinsically added [sup.65]Zn and subsequent whole-body scintillation counting. Results: Mean (+ or -]SE) fractional zinc absorption was 32.8 [+ or -] 2.3% from the moderate-calcium, low-phytate diet; 26.9 [+ or -] 2.4% from the moderate-calcium, high-phytate diet; 39.4 [+ or -] 2.4% from the high-calcium, low-phytate diet; and 26.2 [+ or -] 2.3% from the high-calcium, high-phytate diet. The respective values for absolute zinc absorption were 3.8 [+ or -] 0.3, 3.0 [+ or -] 0.3, 4.5 [+ or -] 0.3, and 3.2 [+ or -] 0.3 mg/d. Phytate significantly reduced fractional zinc absorption by [approximately equal to] 10 percentage points and reduced absolute zinc absorption by 25%, or [approximately equal to] 1 mg/d. Differences in dietary calcium did not affect zinc absorption, regardless of a high or low dietary phytate content. Conclusions: In healthy women consuming 1-d menus of ordinary foods (some fortified with calcium), dietary phytate reduces zinc absorption, but calcium does not impair zinc absorption, regardless of whether dietary phytate is low or high.

Background: An understanding of the relations among dietary zinc intake, bioavailability, and absorption is necessary for making dietary intake recommendations. Objectives: We aimed to assess adaptation in human zinc absorption to controlled differences in zinc and phytate intakes and to apply the results to predictive models. Design: In 3 experiments, radiotracers were used to assess zinc absorption by healthy adults (n = 109) from controlled diets, before and after 4 or 8 wk of dietary equi libration. Subjects consumed 4-29 mg Zn/d from 1 of 10 diets, 5 with molar ratios of phytate to zinc from 2 to 7 and 5 with ratios from 15 to 23. Results: Absorptive efficiency was inversely related to dietary zinc from both low- and high-phytate diets. In response to low zinc intakes (< 11 mg/d) for 4-8 wk, zinc absorption was up-regulated to as high as 92%, but only if the diets were low in phytate. The results help validate and refine a published saturable transport model that predicts zinc absorption from dietary zinc and phytate. Possible biomarkers of impaired zinc status, including erythrocyte osmotic fragility, in vitro erythrocyte [sup.65]Zn uptake, and leukocyte expression of the zinc transport proteins Zip1 and ZnT1, were unresponsive to dietary zinc content. Conclusions: Humans absorbed zinc more efficiently from low-zinc diets and adapted to further increase zinc absorption after consuming low-zinc, low-phytate diets for several weeks. Such adaptation did not occur with higher phytate diets. Zinc absorption can be predicted from dietary zinc and phytate after allowing for dietary equilibration.

Background: An in vitro digestion and Caco-2 cell model may predict iron bioavailability to humans; however, direct comparisons are lacking. Objective: The objective was to test the differences in iron bioavailability between 2 maize varieties and 2 bean varieties (white beans and colored beans) by comparing human, Caco-2, and algorithm results. Design: Two randomized, 2 X 2 factorial experiments compared women's iron absorption from 2 maize varieties (ACR and TZB; n = 26) and 2 bean varieties (great northern and pinto; n = 13), each fed with and without ascorbic acid (AA) from orange juice. Nonheme iron bioavailability was determined from 2-wk retention of extrinsic radioiron tracers and was compared with Caco-2 cell and algorithm results from identical meals. Results: Without AA supplementation, women absorbed only about 2% of the iron from the maize or bean meals. The results were unaffected by the variety of either maize or beans. Adding AA (15-20 molar ratios of AA:iron) roughly tripled the iron absorption (P < 0.0001) from all test meals. Although the Caco-2 model predicted a slightly improved bioavailability of iron from ACR maize than from TZB maize (P < 0.05), it accurately predicted relative iron absorption from the maize meals. However, the Caco-2 model inaccurately predicted both a considerable difference between bean varieties (P < 0.000l) and a strong interaction between bean varieties and enhancement by AA (P < 0.0001). The algorithm method was more qualitatively than quantitatively useful and requires further development to accurately predict the influence of polyphenols on iron absorption. Conclusions: Caco-2 predictions continued human iron absorption results for maize meals but not for bean meals, and algorithm predictions were only qualitatively predictive. Am J Clin Nutr 2007;86:388-96. KEY WORDS Iron absorption, bioavailability, Caco-2 cells, ascorbic acid, phytic acid, polyphenols, tannins

Background: Although hepcidin is proposed as a regulator of iron absorption, this has not been assessed in humans. Objective: Our objective was to assess the relation between serum or urinary prohepcidin and iron absorption in healthy premenopausal women. Design: The subjects were 28 healthy women aged 22-51 y with normal hemoglobin concentrations (120-152 g/L). Absorption of 0.5 mg Fe with 0.2 [micro]Ci [sup.59]Fe tracer, both as FeS[O.sub.4], was measured by whole-body scintillation counting 13 d after oral administration. Fasting blood and urine samples were collected the day of and 16 wk after the absorption measurement. Serum and urinary prohepcidin concentrations were measured by an enzyme-linked immunosorbent assay by using an antibody against amino acid residues 28-47 of the proregion. Results: Mean ([+ or -] SD) iron absorption was 36 [+ or -] 19% (range: 4-81%), and serum ferritin (geometric [??]) was 27 [micro]g/L (range: 4-122 [micro]g/L), as commonly observed in healthy premenopausal women. Serum prohepcidin was 196 [micro] g/L (range: 99-376 [micro] g/L) and, in contrast with urinary prohepcidin, was relatively consistent for the women between 0 and 16 wk. Serum prohepcidin correlated directly with serum ferritin ([R.sup.2] = 0.28, P < 0.01) but was unrelated to [sup.59]Fe absorption, in contrast to serum ferritin ([R.sup.2] = 0.33, P < 0.01). Conclusions: Serum prohepcidin concentrations were relatively stable within subjects and correlated with serum ferritin. However, unlike serum ferritin, neither serum nor urinary prohepcidin concentrations were related to iron absorption in healthy women. Am J Clin Nutr 2006;84:150-5. KEY WORDS Iron absorption, hepcidin, prohepcidin, iron status, serum ferritin, postmenopausal women

Background: Calcium is the only reported dietary inhibitor of both heme- and nonheme-iron absorption. It has been proposed that the 2 forms of iron enter a common pool in the enterocyte and that calcium inhibits the serosal transfer of iron into blood. Objectives: We aimed to ascertain whether the inhibitory effect of calcium occurs during initial mucosal uptake or during serosal transfer and to compare the serosal transfer of heme and nonheme iron, which should not differ if the 2 forms have entered a common mucosal iron pool. Design: Whole-gut lavage and whole-body counting were used to measure the initial uptake (8 h) and retention (2 wk) of heme and nonheme iron with and without a calcium supplement (450 mg). Two experiments tested basal meals with low iron bioavailability and 360 mg Ca (n = 15) or with high iron bioavailability and 60 mg Ca (n = 12). Results: Added calcium reduced the initial uptake of heme iron by 20%, from 49% to [approximately equal to] 40% from both meals (P = 0.02), and reduced the total iron absorbed from the low- and high-bioavailability meals by [approximately equal to] 25% [from 0.033 to 0.025 mg (P = 0.06) and from 0.55 to 0.40 mg (P < 0.01), respectively]. Calcium did not affect the serosal transfer of either form of iron. Conclusions: Calcium supplementation reduced heme and total iron without significantly affecting nonheme-iron absorption, regardless of meal bioavailability. Calcium inhibited the initial mucosal uptake rather than the serosal transfer of heme iron. Differences in serosal transfer indicate that heme and nonheme iron did not enter a common absorptive pool within 8 h after a meal. KEY WORDS Heme iron, nonheme iron, whole-body counting, whole-gut lavage, mucosal uptake, absorption, retention, serosal transfer, humans, calcium, bioavailability

Background: Research conducted before genotyping was possible suggested that subjects heterozygous for the genetic mutation associated with hemochromatosis absorbed nonheme iron more efficiently than did control subjects when tested with a fortified meal. Heme-iron absorption in these subjects has not been reported. Objective: We compared the absorption of heme and nonheme iron from minimally or highly fortified test meals between HFE C282Y-heterozygous and wild-type control subjects. Design: After prospective genotyping of 256 healthy volunteers, 11 C282Y-heterozygous and 12 wild-type control subjects were recruited, and their iron absorption was compared by using a hamburger test meal with or without added iron and ascorbic acid. After retrospective genotyping of 103 participants in previous iron-absorption studies, 5 C282Y-heterozygous subjects were compared with 72 wild-type control subjects. Results: HFE C282Y-heterozygous subjects did not differ significantly from wild-type control subjects in their absorption of either heme or nonheme iron from minimally or highly fortified test meals. No differences were detected in blood indexes of iron status (including serum ferritin, transferrin saturation, and non-transferrin-bound iron) or in blood lipids or transaminases, but heterozygotes had significantly greater, although normal, fasting glucose concentrations than did wild-type control subjects. Compound heterozygotes (those who had both HFE C282Y and H63D mutations) absorbed more nonheme (but not heme) iron from meals with high (but not low) iron bioavailability. Conclusions: HFE C282Y-heterozygous subjects did not absorb dietary iron more efficiently, even when foods were highly fortified with iron from ferrous sulfate and ascorbic acid, than did control subjects. Iron fortification of foods should not pose an additional health risk to HFE C282Y heterozygotes. KEY WORDS Nutrient-gene interactions, nonheme-iron absorption, heme-iron absorption, diet, iron bioavailability, iron fortification, hemochromatosis, serum ferritin, non-transferrin-bound iron, glucose

Background: Adaptation of iron absorption in response to dietary iron bioavailability is less likely in premenopausal women, who generally have lower iron stores, than in men. Objective: The objective of the study was to ascertain whether iron absorption in women adapts to dietary iron bioavailability and whether adaptation reflects altered absorptive efficiency or adjustment to specific inhibitors or enhancers of absorption. Design: Heme- and nonheme-iron absorption from either high- or low-bioavailability diets was measured at 0 and 10 wk in premenopausal women as they consumed one of the diets for 12 wk (randomized 2 x 2 factorial design). The high- and low-bioavailability diets contained similar amounts of total iron, as 13.1 and 14.8 mg/d nonheme and 2.0 and 0.3 mg/d heme iron, respectively, and they differed in contents of meat, ascorbate, whole grains, legumes, and tea. Results: In premenopausal women, the efficiency of nonheme-iron absorption (P = 0.06, two-tailed test), but not of heme-iron absorption, tended to adapt in response to a 12-wk difference in dietary iron bioavailability, whether absorption was tested with high- or low-bioavailability menus. Bioavailability, but not adaptation, substantially influenced total iron absorption ([approximately equal to] 6-fold). In contrast with iron absorption from the low-bioavailability diet, that from the high-bioavailability diet consistently was inversely associated with serum ferritin. Conclusion: Only the high-bioavailability diet enabled women to absorb more iron in relation to their low iron stores. Women consuming the high-bioavailability diet absorbed up to 4.5 mg (30-35%) dietary iron with minimal influence of the diet consumed during the previous 10 wk. KEY WORDS Gastrointestinal adaptation, nonheme iron, heme iron, iron absorption, dietary bioavailability, iron requirements, serum ferritin, fecal ferritin, ascorbic acid, meat, phytic acid, tea

Iron and zinc are currently the trace minerals of greatest concern when considering the nutritional value of vegetarian diets. With elimination of meat and increased intake of phytate-containing legumes and whole grains, the absorption of both iron and zinc is lower with vegetarian than with nonvegetarian, diets. The health consequences of lower iron and zinc bioavailability are not clear, especially in industrialized countries with abundant, varied food supplies, where nutrition and health research has generally supported recommendations to reduce meat and increase legume and whole-grain consumption. Although it is clear that vegetarians have lower iron stores, adverse health effects from lower iron and zinc absorption have not been demonstrated with varied vegetarian diets in developed countries, and moderately lower iron stores have even been hypothesized to reduce the risk of chronic diseases. Premenopausal women cannot easily achieve recommended iron intakes, as modified for vegetarians, with foods alone; however, the benefit of routine iron supplementation has not been demonstrated. It may be prudent to monitor the hemoglobin of vegetarian children and women of childbearing age. Improved assessment methods are required to determine whether vegetarians are at risk of zinc deficiency. In contrast with iron and zinc, elements such as copper appear to be adequately provided by vegetarian diets. Although the iron and zinc deficiencies commonly associated with plant-based diets in impoverished nations are not associated with vegetarian diets in wealthier countries, these nutrients warrant attention as nutritional assessment methods become more sensitive and plant-based diets receive greater emphasis. KEY WORDS Iron, zinc, copper, vegetarian, bioavailability, trace elements, minerals

Background: Quantitative data on the mucosal uptake and serosal transfer of nonheme-iron absorption in humans and the effects of calcium on these components are limited. Objective: Our objective was to measure the initial mucosal uptake and the subsequent serosal transfer of nonheme iron and to determine the effects of adding calcium to a meal on both heme-and nonheme-iron retention. Design: Whole-gut lavage and whole-body scintillation counting methods were applied to determine the 8-h uptake of nonheme iron and the 2-wk retention (absorption) of heme and nonheme iron in healthy adults (n = 17) after the consumption of meals of radiolabeled food. Results: The initial uptake and absorption of nonheme iron were 11% and 7%, respectively, and the absorption of heme iron was 15%. Two-thirds of the nonheme iron taken up by the mucosa within 8 h was retained by the body after 2 wk (serosal transfer index: 0.63). Serum ferritin correlated inversely with the initial uptake and absorption of nonheme iron, but not with the nonheme serosal transfer index or the absorption of heme iron. Adding calcium (127 mg in cheese) to the meal did not affect absorption. Conclusions: On the basis of its association with serum ferritin, the initial mucosal uptake was the primary control point for nonheme-iron absorption. An apparent reduction in heme-iron absorption associated with the lavage procedure suggested that uptake of heme iron may take longer and proceed further through the intestine than that of nonheme iron. The absorption of both forms of iron was unaffected by the addition of cheese to this meal with high iron bioavailability. KEY WORDS Heme iron, nonheme iron, whole-body counting, whole-gut lavage, mucosal uptake, absorption, retention, serosal transfer, humans, calcium, erythrocyte incorporation

Background: Vegetarian diets often contain more copper than do nonvegetarian diets, but observations of decreased plasma copper associated with vegetarian diets suggest that these diets have lower copper bioavailability than do nonvegetarian diets. Objective: Our objective was to determine apparent copper absorption from controlled lactoovovegetarian and nonvegetarian diets. Design: Eighteen women aged 20-43 y consumed lactoovovegetarian and nonvegetarian weighed diets for 8 wk each in a randomized, crossover design. The lactoovovegetarian and nonvegetarian diets provided 1.45 and 0.94 mg Cu, 38 and 16 g dietary fiber; and 1584 and 518 mg phytic acid, respectively, per 9.2 MJ (2200 kcal). After the women had been consuming each diet for 4 wk, their apparent copper absorption was determined by measuring the fecal excretion of the [sup.65]Cu stable isotope, extrinsically added to the entire menu as [sup.65]Cu[Cl.sub.2]. Results: Plasma copper and ceruloplasmin were not affected by diet. The efficiency of apparent copper absorption from the lactoovovegetarian diet was less (33%) than that from the nonvegetarian diet (42%) (pooled SD: 9%; P < 0.05). However, because the lactoovovegetarian diet contained [approximately equal to] 50% more copper, the total apparent copper absorption from the lactoovovegetarian diet (0.48 mg/d) was greater than that from the nonvegetarian diet (0.40 mg/d) (pooled SD: 0.09 mg; P < 0.05). Conclusion: Although copper was less efficiently absorbed from a vegetarian diet than from a nonvegetarian diet, total apparent copper absorption was greater from the vegetarian diet because of its greater copper content. Am J Clin Nutr 2001;74:803-7. KEY WORDS Apparent copper absorption, bioavailability, ceruloplasmin, vegetarian diets, meat, phytic acid, hormonal contraceptives, women

Zinc absorption, mineral balance, and blood lipid concentrations were measured in 21 women aged 33 [+ or -] 7 y (range: 20-42 y) consuming controlled lactoovovegetarian and nonvegetarian diets for 8 wk each in a crossover design. The lactoovovegetarian and nonvegetarian diets, respectively, provided (by analysis) 973 and 995 mg Ca, 1.8 and 1.3 mg Cu, 367 and 260 mg Mg, 5.9 and 2.5 mg Mn, 1457 and 1667 mg P, 9.1 and 11.1 mg Zn, and (by calculation) 40 and 16 g dietary fiber, 2.5 and 0.8 mmol phytic acid, molar ratios of phytate to Zn of 14 and 5, and millimolar ratios of (phytate X Ca) to Zn of 344 and 111. Dietary zinc absorption was measured by extrinsic isotopic labeling and whole-body counting. Plasma cholesterol, cholesterol fractions, and lipoproteins were reduced 7-12% with the lactoovovegetarian diet, consistent with predictions based on dietary cholesterol and fat. Blood pressure was unaffected. Calcium, copper, magnesium, and phosphorus balances were not different between diets; manganese balance tended to be greater with the lactoovovegetarian diet (P [is less than] 0.07). The lactoovovegetarian diet was associated with a 21% reduction in absorptive efficiency that, together with a 14% reduction in dietary zinc, reduced the amount of zinc absorbed by 35% (2.4 compared with 3.7 mg/d) and reduced plasma zinc by 5% within the normal range. Zinc balance was maintained with both diets. Although there is a greater risk of zinc deficiency in persons consuming lactoovovegetarian compared with omnivorous diets, with inclusion of whole grains and legumes zinc requirements can be met and zinc balance maintained. Am J Clin Nutr 1998;67:421-30.

The effects of three diet - high meat (HM), low meat (LM), or low meat with mineral supplements (LS) - on zinc absorption, elemental balance, and related clinical indexes were investigated in a metabolic study of 14 women aged 51-70 y. The women ate each of the three diets for 7 wk in random order. Lean beef, chicken, ham, and tuna in the HM diet replaced foods with a low mineral content in the LM diet. The LS diet was similar to the HM diet in K, P, Fe, Mg, and Zn contents. Compared with the other diets, the HM diet increased zinc absorption and retention, and slightly increased urinary zinc. Nitrogen and calcium balances and urinary calcium were not different for the HM and LM diets. Iron balance was not different for the HM and LS diets with similar iron content, but the HM diet was unexpectedly associated with lower iron status higher iron-binding capacity and lower ferritin than LM and LS diet. These results indicate that 0.8 g protein/kg body wt meets protein requirements in older women, and that high meat consumption increases zinc retention without compromising calcium status and may reduce indexes of iron status, in contrast with iron absorption results from studies with radiolabeled test meals.

The effect of ascorbic acid supplementation on apparent iron absorption was tested in women with low iron stores. For 10 wk, 25 healthy nonpregnant women, aged 20-45 y with low serum ferritin (3.5 - 17.7 [micro]/L), consumed either a diet with predicted poorly bioavailable iron or a typical Western diet, classified according to dietary meat and ascorbic acid contents. Meals were supplemented with ascorbic acid (500 mg, three times a day) for 5 of the 10 wk, in a double-blind, crossover design. Ascorbic acid did not affect most biochemical indexes of iron status, the biological half-life of [Fe.sup.59], or apparent iron absorption diet - feces) from either diet, but slightly increased serum ferritin (11.9 vs 10.7 [micro]g/L, P < 0.06) when data from both diets were combined. These results support other evidence that ascorbic acid has less effect on iron bioavailability than has been predicted from tests with single meals. 1994;59:1381-5

The influence of dietary iron on spontaneous activity was investigated in growing rats. Male rats weighing 97 [+ or -] 10 g fed diets containing 4.6 (deficient), 19.9 (marginal), and 108.4 (adequate) mg Fe/kg diet for 8 wks had hemoglobin values of 52 [+ or -] 6, 152 t 4, and 159 [+ or -] 6 g/l, and liver nonheme iron concentrations of 0.79 [+ or -] 0.24, 1.36 [+ or -] 0.39, and 4.58 [+ or -] 0.62 [mu]mol/g, respectively. Body weights were affected only at the lowest iron intake. Diurnal activity was not reversed by iron status; all animals were more active during the dark cycle than the light cycle. Iron deficiency resulted in less time and frequency of horizontal, vertical, and stereotypic movements; less distance moved; and less frequent rotations. Movement speed of iron-deficient rats was faster during early iron deficiency. In the light, rats with marginal iron nutriture were generally more active than were iron-deficient or iron-adequate animals. In the dark, activity generally decreased with each reduction in dietary iron.

Iron absorption is enhanced by consuming vitamin C at the same meal. More specifically, iron in foods other than meats, also called nonheme iron, is better absorbed in the presence of vitamin C, while heme iron, found in meats, is not affected in this way. It is particularly important to improve iron absorption in young, premenopausal women because it is difficult for them to meet their daily iron needs from diet alone without an iron supplement. Because women generally do not eat as much food as men, and often consume less meat, they obtain less iron from the diet. However, due to menstrual blood loss and the iron requirements of pregnancy and lactation, the iron needs of young women are significantly greater than those of men. A study was performed to investigate the effects of vitamin C on iron absorption in 11 premenopausal women. The iron stores of the women were first depleted by following a low iron diet for two to three months and by taking blood samples, which removed iron from the body. The women then consumed a diet supplying 13.7 milligrams (mg) of iron in 2,000 calories per day for 5.5 weeks; this is less than the Recommended Dietary Allowance for women. Subjects also took either an inert placebo or a 500 mg vitamin C tablet at each meal (1,500 mg daily). Iron absorption was greater in the vitamin C-supplemented group, who absorbed an average of 38 percent of the iron consumed, than in the placebo group, who absorbed 27 percent of the iron ingested. Thus, in iron-depleted premenopausal women, vitamin C supplementation improved iron absorption. (Consumer Summary produced by Reliance Medical Information, Inc.)

Background: Results of cross-sectional studies suggest that in healthy people, iron absorption adapts to meet physiologic needs and stabilize iron stores, but this has not been adequately tested in longitudinal studies. Objective: We tested whether heme- and nonheme-iron absorption decrease in response to increased iron intake and whether iron stores reach a steady state. Design: In a randomized, placebo-controlled trial, heme- and nonheme-iron absorption by healthy men and women (n = 57) were measured before and after 12 wk of supplementation with 50 mg Fe/d as ferrous sulfate. Serum and fecal ferritin were measured during supplementation and for 6 mo thereafter. Results: Initially, both heme- and nonheme-iron absorption were inversely associated with serum ferritin concentration. Volunteers who took iron supplements, even those with serum ferritin [is less than] 21 [micro]g/L (n = 5), adapted to absorb less nonheme iron (3.2% at week 12 compared with 5.0% at week 0, P [is less than] 0.001) but not less heme iron from a beef-based meal. Serum ferritin concentration was slightly but significantly higher after iron supplementation than after placebo (difference = 13 [micro]g/L). This higher ferritin concentration persisted for [is greater than or equal to] 6 mo after supplementation, except in subjects with low iron stores, whose serum ferritin returned to baseline within 3 mo. Fecal ferritin excretion increased 2.5-fold (P [is less than] 0.05) during supplementation. Conclusions: Healthy individuals, even those with low iron stores, had reduced nonheme-iron absorption from food in response to iron supplementation. Despite this partial adaptation, iron stores were greater after iron supplementation than after placebo and this difference was sustained, except in individuals with the lowest iron stores. Am J Clin Nutr 2000;72:982-9. KEY WORDS Iron supplementation, heme iron, nonheme iron, iron absorption, fecal ferritin, serum ferritin, adaptation, meat, erythrocyte incorporation, humans, anemia, iron deficiency, hemoglobin, hematocrit

Background: Short-term measurements of iron absorption are substantially influenced by dietary bioavailability of iron, yet bioavailability negligibly affects serum ferritin in longer, controlled trials. Objective: Our objective was to test the hypothesis that in men fed diets with high or low iron bioavailability, iron absorption adapts to homeostatically maintain body iron stores. Design: Heme- and nonheme-iron absorption from whole diets were measured in 31 healthy men at 0 and 10 wk while the men consumed weighed, 2-d repeating diets with either high or low iron bioavailability for 12 wk. The diets with high and low iron bioavailability contained, respectively, 14.4 and 15.3 mg nonheme Fe/d and 1.8 and 0.1 mg heme Fe/d and had different contents of meat, ascorbic acid, whole grains, legumes, and tea. Results: Adaptation occurred with nonheme- but not with heme-iron absorption. Total iron absorption decreased from 0.96 to 0.69 mg/d (P [is less than] 0.05) and increased from 0.12 to 0.17 mg/d (P [is less than] 0.05) after 10 wk of the high- and low-bioavailability diets, respectively. This partial adaptation reduced the difference in iron bioavailability between the diets from 8- to 4-fold. Serum ferritin was insensitive to diet but fecal ferritin was substantially lower with the low- than the high-bioavailability diet. Erythrocyte incorporation of absorbed iron was inversely associated with serum ferritin. Conclusions: Iron-replete men partially adapted to dietary iron bioavailability and iron absorption from a high-bioavailability diet was reduced to [approximately equals] 0.7 mg Fe/d. Short-term measurements of absorption overestimate differences in iron bioavailability between diets. Am J Clin Nutr 2000;71:94-102. KEY WORDS Gastrointestinal adaptation, nonheme-iron absorption, heme-iron absorption, dietary bioavailability, iron requirements, serum ferritin, fecal ferritin, ascorbic acid, meat, phytic acid, tea, men

The current use of serum retinol concentrations as a measurement of subclinical vitamin A deficiency is unsatisfactory for many reasons. The best technique available for vitamin A status assessment in humans is the measurement of total body pool size. Pool size is measured by the administration of retinol labelled with stable isotopes of carbon or hydrogen that are safe for human subjects, with subsequent measurement of the dilution of the labelled retinol within the body pool. However, the isotope techniques are time-consuming, technically challenging, and relatively expensive. There is also a need to assess different types of tracers and doses, and to establish clear guidelines for the use and interpretation of this method in different populations. Field-friendly improvements are desirable to encourage the application of this technique in developing countries where the need is greatest for monitoring the risk of vitamin A deficiency, the effectiveness of public health interventions, and the potential of hypervitaminosis due to combined supplement and fortification programs. These techniques should be applied to validate other less technical methods of assessing vitamin A deficiency. Another area of public health relevance for this technique is to understand the bioconversion of β-carotene to vitamin A, and its relation to existing vitamin A status, for future dietary diversification programs.

Inadequate vitamin A (VA) nutrition continues to be a major problem worldwide, and many interventions being implemented to improve VA status in various populations need to be evaluated. The interpretation of results after an intervention depends greatly on the method selected to assess VA status. To evaluate the effect of an intervention on VA status, researchers in Cameroon, India, Indonesia, Mexico, Senegal and Zambia have used serum retinol as an indicator, and have not always found improvement in response to supplementation. One problem is that homeostatic control of serum retinol may mask positive effects of treatment in that changes in concentration are observed only when status is either moderately to severely depleted or excessive. Because VA is stored mainly in the liver, measurements of hepatic VA stores are the “gold standard” for assessing VA status. Dose response tests such as the relative dose response (RDR) and the modified relative dose response (MRDR), allow a qualitative assessment of VA liver stores. On the other hand, the use of the vitamin A-labeled isotope dilution (VALID) technique, (using 13C or 2H-labeled retinyl acetate) serves as an indirect method to quantitatively estimate total body and liver VA stores. Countries including Cameroon, China, Ghana, Mexico, Thailand and Zambia are now applying the VALID method to sensitively assess changes in VA status during interventions, or to estimate a population’s dietary requirement for VA. Transition to the use of more sensitive biochemical indicators of VA status such as the VALID technique is needed to effectively assess interventions in populations where mild to moderate VA deficiency is more prevalent than severe deficiency.

Background: The characteristics of vegetarian diets suggest that these diets would have lower dietary iron bioavailability than nonvegetarian diets, but there is no evidence of iron deficiency in vegetarians. Objective: We evaluated the responsiveness of serum and fecal ferritin to differences in iron absorption from controlled lactoovovegetarian and nonvegetarian diets. Design: Twenty-one women aged 20-42 y with serum ferritin concentrations from 6 to 149 [micro]g/L consumed lactoovovegetarian and nonvegetarian weighed diets for 8 wk each (crossover design). The diets differed substantially in meat and phytic acid contents. Nonheme-iron absorption was measured from the whole diets after 4 wk by using extrinsic [sup.59]Fe and whole-body counting. Ferritin in extracts of fecal composites and in serum was measured by enzyme-linked immunosorbent assay the last 2 wk of each diet. Results: Nonheme-iron absorption was less from the lactoovovegetarian diet than from the nonvegetarian diet (1.1% compared with 3.8%; P [is less than] 0.01; n = 10). Diet did not affect hemoglobin, transferrin saturation, erythrocyte protoporphyrin, or serum ferritin. Substantially less fecal ferritin was excreted with the lactoovovegetarian diet than with the nonvegetarian diet (1.1 compared with 6.0 [micro]g/d, respectively; P [is less than] 0.01; n = 21). Conclusions: This research indicates 1) 70% lower nonheme-iron absorption from a lactoovovegetarian diet than from a nonvegetarian diet; 2) an associated decrease in fecal ferritin excretion, suggesting partial physiologic adaptation to increase the efficiency of iron absorption; and 3) an insensitivity of blood iron indexes, including serum ferritin, to substantial differences in dietary iron absorption for 8 wk. Am J Clin Nutr 1999;69:944-52.

Several bioavailability algorithms have been proposed for iron and zinc, confirming the need for these tools while emphasizing the challenge of deriving algorithms with accepted accuracy. This manuscript briefly reviews current evidence on the accuracy of proposed algorithms. Iron absorption is strongly influenced by both body iron status and dietary availability, and most evidence suggests that these do not interact. There is considerable evidence of a logarithmic relationship between percent iron absorption and serum ferritin that allows a simple and accurate computation of how human iron status affects absorption (in the absence of inflammation). Computing the effect of dietary variation on nonheme iron absorption has been challenging because of multiple influential dietary factors and incomplete knowledge of their chemical characteristics, food composition, interactions, and dose-response relationships. At present there is no fully validated algorithm for dietary iron bioavailability. Predicting zinc absorption is less complex. Fractional zinc absorption is substantially influenced by the amount of zinc consumed, and this factor, together with ingested phytic acid, account for a considerable degree of the variance. A multivariate saturation model based on these two variables has been derived using data from multiple studies and independently validated with a single large data set.

Objective:To determine if human Zn absorption adapts to chronic high Zn intakes.Methods:Zn absorption was measured at 0, 8, and 16 wk in healthy postmenopausal women who consumed controlled diets with ∼5 mg Zn from food, supplemented to 14 (n = 6), 32 (n = 3), or 47 (n = 3) mg Zn/d for 22 wk. Zn absorption for 1 day was determined by 65Zn-labeling of meals and whole body scintillation counting.Results:At wk 0, less Zn was absorbed from diets with 14, compared with 32 or 47 mg/d (4.6, 8.7, and 10.3 mg/d, respectively; pooled SE = 0.9; p < 0.05). These differences were not apparent at wk 8 (5.4, 5.8, 6.4; NS) and became negligible by wk 16 (5.0, 5.0, 5.1; NS). Plasma Zn concentrations were unaffected. The results are consistent with a saturation response model of Zn absorption.Conclusion:Within several weeks, postmenopausal women biologically adapted to absorb a relatively uniform amount of 5 mg Zn/d when controlled, Zn-supplemented diets supplied consistent Zn intakes between 14 and 47 mg/d.

Iron deficiency, a global health problem, impairs reproductive performance, cognitive development, and work capacity. One proposed strategy to address this problem is the improvement of dietary iron bioavailability. Knowledge of the molecular mechanisms of iron absorption is growing rapidly, with identification of mucosal iron transport and regulatory proteins. Both body iron status and dietary characteristics substantially influence iron absorption, with minimal interaction between these two factors. Iron availability can be regarded mainly as a characteristic of the diet, but comparisons between human studies of iron availability for absorption require normalization for the iron status of the subjects. The dietary characteristics that enhance or inhibit iron absorption from foods have been sensitively and quantitatively determined in human studies employing iron isotopes. People with low iron status can substantially increase their iron absorption from diets with moderate to high availability. But while iron supplementation and fortification trials can effectively increase blood indices of iron status, improvements in dietary availability alone have had minimal influence on such indices within several weeks or months. Plentiful, varied diets are the ultimate resolution to iron deficiency. Without these, more modest food-based approaches to human iron deficiency likely will need to be augmented by dietary iron fortification.

A study was done to examine the effects of aluminum, magnesium, and boron on major mineral metabolism in postmenopausal women. This communication describes some of the effects of dietary boron on 12 women between the ages of 48 and 82 housed in a metabolic unit. A boron supplement of 3 mg/day markedly affected several indices of mineral metabolism of seven women consuming a low‐magnesium diet and five women consuming a diet adequate in magnesium; the women had consumed a conventional diet supplying about 0.25 mg boron/day for 119 days. Boron supplementation markedly reduced the urinary excretion of calcium and magnesium; the depression seemed more marked when dietary magnesium was low. Boron supplementation depressed the urinary excretion of phosphorus by the low‐magnesium, but not by the adequate‐magnesium, women. Boron supplementation markedly elevated the serum concentrations of 17β‐estradiol and testosterone; the elevation seemed more marked when dietary magnesium was low. Neither high dietary aluminum (1000 mg/day) nor an interaction between boron and aluminum affected the variables presented. The findings suggest that supplementation of a low‐boron diet with an amount of boron commonly found in diets high in fruits and vegetables induces changes in postmenopausal women consistent with the prevention of calcium loss and bone demineralization.— Nielsen, F. H.; Hunt, C. D.; Mullen, L. M.; Hunt, J. R. Effect of dietary boron on mineral, estrogen, and testosterone metabolism in postmenopausal women. FASEB J.1: 394‐397; 1987.

Zinc availability from a series of foods was determined using 65Zn-labeled test meals fed to rats. Zinc availability relative to zinc chloride depended on the amount of the zinc source in the test meal. Zinc availability from several foods was similar to that from zinc chloride when tested in smaller amounts, but enhanced when fed in larger amounts. The range of zinc availability was similar for foods of plant and animal origin. Rats retained significantly more zinc from pork, chicken, peanut butter, egg or milk than from rice, beef, soybean flour or navy beans. Foods with intermediate zinc availability were sweet corn, whole wheat bread, cheese and oysters. Several food characteristics were examined for possible relationships with zinc availability, including the solubility or molecular size of zinc compounds after an in vitro enzymatic digestion and the contents of phytic acid, minerals, amino acids, carbohydrate and fatty acids relative to the zinc content of the food. Protein and several amino acids predicted about half of the variance in zinc availability. Following in vitro enzymatic digestion, neither zinc solubility nor the partitioning of zinc between low and high molecular weight substances was a strong predictor of zinc availability.

Effects of previous dietary Zn (or body Zn stores) and current dietary Zn intake on absorption and endogenous excretion of Zn were studied by using radioisotope dilution. Rats were fed diets containing 1.5, 12.6 or 50.3 mg Zn/kg for 19 d (dietary period I). Total body Zn in the three groups was 1870 ± 340, 3953 ± 698 and 4126 ± 844 µg Zn/rat. Each group was divided into four subgroups fed 3.6, 12.6, 20.5 or 50.3 mg Zn/kg diet for 3 wk (dietary period II). Rats were injected intramuscularly with 65Zn after 7 d of dietary period II. True absorption and endogenous excretion were calculated by isotope dilution. Zinc intake, urinary and fecal excretion, balance and percent Zn absorption were significantly affected only by dietary Zn in dietary period II (P< 0.01). Endogenous excretion was affected by both past dietary Zn deficiency (body Zn stores) and by dietary Zn in dietary period II (P= 0.0001). Total body Zn at the end of the experiment was significantly affected by both periods of dietary treatment (P< 0.001), but total body Zn concentration was affected only by the final dietary treatment (P< 0.05). These results show that Zn absorption is affected by the current diet, but that turnover of Zn (endogenous excretion) is regulated by both curent Zn intake and past Zn intake, probably through an effect on body Zn stores.

Absorption of stable 65Cu incorporated intrinsically or extrinsically into foods was studied in women fed a diet marginal in Cu content. Isotopic enrichment was 73.1 ± 1.0 atom percent 65Cu in goose breast meat, 74.9 ± 0.5 atom percent in goose liver, and 55–69.5 atom percent in two crops of peanuts. Seven women were fed a basal diet containing 1.25 mg Cu/d. At 4-wk intervals, they were fed test meals over a 3-d period; each set of meals contained one of the labeled test foods in amounts with similar copper content. Absorption of 65Cu from intrinsically labeled liver was (mean ± SD) 65 ± 4%; extrinsic liver, 65 ± 10%; E/I = 1.00 ± 0.16. 65Cu absorption from intrinsically labeled goose breast meat was 54 ± 6%; extrinsic meat, 52 ± 10%; E/I = 0.97 ± 0.18. 65Cu absorption from intrinsically labeled peanut butter was 58 ± 15%; extrinsic peanut butter, 54 ± 10%; E/I = 0.93 ± 0.11. 65Cu absorption from extrinsically labeled sunflower butter was 50 ± 2%. There were no differences in absorption of intrinsic and extrinsic Cu from these foods. Absorption of Cu was significantly higher from goose liver than from goose meat or sunflower butter (P< 0.05). With a dietary intake of 1.25 ± 0.20 mg Cu/d, Cu balance, exclusive of surface losses, was essentially zero (0.01 ± 0.13 mg/d) in the seven subjects.

The effect of dietary protein concentration on zinc bioavailability, requirements and incorporation into bones was investigated in growing rats. Zinc requirements were determined by the broken-line method. Protein did not affect either absorption or biological half-life of 65Zn added to the diet. Zinc requirements based on weight gain or tibia zinc were generally greater when rats were fed 30% rather than 15% egg white. When fed 30% rather than 15% egg white, zinc-deficient rats gained less weight and tended to incorporate less zinc into bone, whereas zinc-adequate rats gained weight similarly and incorporated more zinc into bone. Dietary protein concentration apparently elevated the maximum amount of zinc incorporated into bones of rats fed adequate zinc. When dietary zinc was adequate (25 mg/kg diet), tibia zinc concentrations increased linearly with dietary concentrations of 15, 25, 35 and 45% egg white. When dietary zinc was adequate, higher protein diets resulted in lower tibia nitrogen, and higher tibia zinc, without substantial changes in tibia size or calcium concentration. These results indicate that high protein diets increase zinc requirements and bone zinc deposition, the latter being a consequence of altered bone zinc metabolism, rather than improved zinc bioavailability.

The influences of zinc in a meal and usual zinc intake on zinc retention and turnover were investigated in 7-wk-old male rats fed diets containing 12–151 mg Zn/kg for 3 wk before and after consuming a 65Zn-labeled meal containing ZnCl2. Retention corrected to zero time and turnover rate were determined by whole-body counting. Percent zinc retention was inversely proportional to the natural logarithm of the meal zinc, between 0.09 and 26 µmol. In comparison to lower doses, higher doses resulted in lower percent retention but greater amounts of zinc retained. Although the latter relationship was slightly curvilinear, there was no indication of a limited capacity for zinc retention with high doses. However, doses above 4 µmol resulted in higher turnover rates in rats accustomed to lower zinc intakes. Percent retention and the reciprocal of the turnover rate were proportional to the reciprocal of the dietary zinc concentration. The greatest differences in retention and turnover occurred between 12 and 26 mg Zn/kg diet. The zinc dose in a meal and the usual dietary zinc separately influenced percent zinc retention. These factors also interacted, such that greater dose effects were observed at lower zinc intakes and greater dietary zinc effects were observed at lower doses.

Focuses on the study to determine whether a partial adaptation to modify the influence of dietary iron availability occurs in premenopausal women in the U.S. Factors that influence iron availability; Responsiveness of body iron stores to changes in dietary iron bioavailability; Importance of diets with high iron bioavailability for premenopausal women.

Studies the adequacy of zinc content of vegetarian diets from the report of the United States Department of Agriculture Grand Forks Human Nutrition Research Center in North Dakota. Comparison between lacto-ovo-vegetarian and non-vegetarian diets; Findings on the true zinc content of the diets; Indications of results of the study.