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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 55Fe that had been administered > or =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 menstruating 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: 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 < 0.0001) 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 confirmed human iron absorption results for maize meals but not for bean meals, and algorithm predictions were only qualitatively predictive.

Commercial elemental iron powders (electrolytic and reduced iron), as well as heme iron supplements, were tested for efficacy in improving the iron status of women. In a randomized, double-blind trial, 51 women with moderate to low iron stores received daily for 12 wk: 1) placebo, 2) 5 mg iron as heme iron or 50 mg iron as 3) electrolytic iron, 4) reduced iron, or 5) FeSO(4). Treatments were provided in 2 capsules (heme carrier) and 3 wheat rolls (other iron sources). Differences in iron status, food nonheme iron absorption, and fecal properties were evaluated. Body iron, assessed from the serum transferrin receptor:ferritin ratio, increased significantly more in subjects administered FeSO(4) (127 +/- 29 mg; mean +/- SEM) and electrolytic (115 +/- 37 mg), but not the reduced (74 +/- 32 mg) or heme (65 +/- 26 mg) iron forms, compared with those given placebo (2 +/- 19 mg). Based on body iron determinations, retention of the added iron was estimated as 3.0, 2.7, 1.8, and 15.5%, in the 4 iron-treated groups, respectively. Iron treatments did not affect food iron absorption. The 50 mg/d iron treatments increased fecal iron and free radical-generating capacity in vitro, but did not affect fecal water cytotoxicity. In subjects administered FeSO(4), fecal water content was increased slightly but significantly more than in the placebo group. In conclusion, electrolytic iron was approximately 86% as efficacious as FeSO(4) for improving body iron, but the power of this study was insufficient to detect any efficacy of the reduced or heme iron within 12 wk. With modification, this methodology of testing higher levels of food fortification for several weeks in healthy women with low iron stores has the potential for economically assessing the efficiency of iron compounds to improve iron status.

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.

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.

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 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.

Foods are fortified with elemental forms of iron to reduce iron deficiency. However, the nutritional efficacy of current, commercially produced elemental iron powders has not been verified. We determined the bioavailability of six commercial elemental iron powders and examined how physicochemistry influences bioavailability. Relative biological value (RBV) of the iron powders was determined using a hemoglobin repletion/slope ratio method, treating iron-deficient rats with repletion diets fortified with graded quantities of iron powders, bakery-grade ferrous sulfate or no added iron. Iron powders were assessed physicochemically by measuring iron solubility in hydrochloric acid at pH 1.0 and 1.7, surface area by nitrogen gas adsorption and surface microstructure by electron microscopy. Bioavailability from the iron powders, based on absolute iron intake, was significantly less than from FeSO4 (100%; P < 0.05) with the following rank order: Carbonyl (64%; Ferronyl, U.S.) > Electrolytic (54%; A-131, U.S.) > Electrolytic (46%; Electrolytic Iron, India) > H-Reduced (42%; AC-325, U.S.) > Reduced (24%; ATOMET 95SP, Canada) > CO-Reduced (21%; RSI-325, Sweden). Solubility testing of the iron powders resulted in different relative rankings and better RBV predictability with increasing time at pH 1.7 (R2 = 0.65 at 150 min). The prediction was improved with less time and lower pH (R2 = 0.82, pH 1.0 at 30 min). Surface area, ranging from 90 to 370 m2/kg, was also highly predictive of RBV (R2 = 0.80). Bioavailability of iron powders is less than bakery-grade ferrous sulfate and varies up to three times among different commercial forms. Solubility at pH 1.0 and surface area were predictive of iron bioavailability in rats.

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.

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.

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 <21 microg/L (n = 5), adapted to absorb less nonheme iron (3.2% at week 12 compared with 5.0% at week 0, P: < 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 microg/L). This higher ferritin concentration persisted for >/=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: < 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.

This study was designed to examine the interactions among dietary iron (Fe), copper (Cu), and zinc (Zn) and their effects on Fe status and oxidative stress in female rats. In a three-factor central composite response surface design, rats were assigned to 15 groups and fed modified AIN-93G basal diets with varying amounts of Fe and Zn (7.0, 15.5, 45.8, 135.6, or 300 micrograms/g diet) and Cu (0.5, 1.1, 3.2, 9.2, or 20 micrograms/g diet) for 6 wk. Variations in hemoglobin, hematocrit, and serum ferritin were mainly related to dietary Fe. Liver nonheme Fe was directly affected by dietary Fe and was slightly attenuated by interactions between Cu and Zn, and Zn and Fe. Serum ceruloplasmin activity was primarily determined by an interaction between Cu and Zn with substantial moderation by the quadratic effect of dietary Cu. Liver and heart total superoxide dismutase (SOD) and Cu/Zn SOD activities were directly affected by dietary Cu. Dietary Fe was the only significant, yet weak, predictor of liver thiobarbituric acid reactive substances (TBARS) and vitamin E content and serum triacylglycerols. Variability in serum Cu was mostly determined by the interaction between Cu and Fe, with modification from the quadratic effect of dietary Cu. Serum Zn varied with dietary Zn with a small negative influence from the interaction between Cu and Fe. In summary, Fe status was minimally influenced by dietary Zn or Cu, and Fe intakes 10-fold greater than required did not induce overt oxidative stress in female rats. In addition, measures of antioxidant capacity were primarily influenced by dietary Cu and were optimal at moderate intakes of this micronutrient.

To test the hypothesis that low iron status or other nutritional deficiencies are associated with symptoms of depression in premenopausal women, the authors related blood indices of iron status to scores on the Minnesota Multiphasic Personality Inventory (MMPI) and responses to a mood adjective checklist. Participants recruited locally provided fasting blood samples and completed the MMPI during the follicular phase of the menstrual cycle. Of 365 apparently healthy participants, 4% had hemoglobin < 120 g/L, 6% had transferrin saturation < 16%, 20% had ferritin < 12 micrograms/L, and 8% had clinically elevated scores (T > or = 70) on the Depression scale of the MMPI. The frequency of elevated MMPI Depression scores was unrelated to the frequency of low hemoglobin, transferrin saturation, or ferritin. The results do not support the hypothesis that low iron status contributes to symptoms of depression in women.

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 microg/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 59Fe 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 < 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 microg/d, respectively; P < 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.

In addition to determining the amounts of isolated nutrients required for physiological function and homeostatic control, setting Recommended Dietary Allowances requires a consideration of nutrient bioavailability from foods in common diets. Bioavailability algorithms, or mathematical models to estimate nutrient bioavailability from different diets, have great appeal to help establish recommended intakes and identify beneficial dietary modifications. Accurate algorithms are difficult to develop because of the chemical complexity of the food supply and the numerous interactions that affect the bioavailability of mineral elements. A combination of reductionist and holistic approaches is necessary to identify the effects of isolated dietary components, and then to evaluate these effects in the complicated matrix of a whole diet. The most extensive development of bioavailability algorithms for mineral nutrients has been for iron, and understanding the strengths and weaknesses of the iron algorithms may help in development of algorithms for other inorganic nutrients such as zinc. Examples are provided to indicate the possible revision of iron bioavailability algorithms, the difficulty of verifying the iron bioavailability algorithms with iron status indices, and the possible development of zinc bioavailability algorithms. Bioavailability must be considered in the context of the biological control of mineral absorption, utilization and excretion, which may outweigh the importance of mineral bioavailability from diets in affluent countries with a varied and abundant food supply. While bioavailability algorithms may be helpful in estimating the effects of dietary changes or recommendations, and in improving diets of populations with a high incidence of deficiency of the mineral, they are not as yet sufficiently developed and validated for setting quantitative recommendations for "bioavailable" mineral intake.

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 micrograms/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 59Fe, or apparent iron absorption (diet-feces) from either diet, but slightly increased serum ferritin (11.9 vs 10.7 micrograms/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.

The influence of dietary iron on spontaneous activity was investigated in growing rats. Male rats weighing 97 +/- 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 +/- 6, 152 +/- 4, and 159 +/- 6 g/L, and liver nonheme iron concentrations of 0.79 +/- 0.24, 1.36 +/- 0.39, and 4.58 +/- 0.62 mumol/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.

The effect of ascorbic acid on iron retention from a diet with predicted low iron bioavailability (containing minimal meat and ascorbic acid) was investigated in iron-depleted premenopausal women. Eleven women were depleted of storage iron (indicated by serum ferritin) through a combination of diet (5.0 mg Fe/2000 kcal for 67-88 d) and phlebotomy. They then consumed a diet containing 13.7 mg Fe/2000 kcal, supplemented with placebo or ascorbic acid three times daily (1500 mg total) with meals for 5.5 wk. Ascorbic acid improved apparent iron absorption (balance method) [38 +/- 2% (means +/- SEM) vs 27 +/- 2%]. Ascorbic acid also improved hemoglobin, erythrocyte protoporphyrins, and serum iron but not hematocrit, serum ferritin, iron-binding capacity, or transferrin saturation. In iron-depleted women consuming a diet with predicted poor iron availability, ascorbic acid supplementation enhanced body iron retention for 5.5 wk.