EURRECA-Estimating selenium requirements for deriving dietary reference values.

Current reference values for selenium, an essential micronutrient, are based on the intake of selenium that is required to achieve maximal glutathione peroxidase activity in plasma or erythrocytes. In order to assess the evidence of relevance to setting dietary reference values for selenium, the EURRECA Network of Excellence focused on systematic searches, review, and evaluation of (i) selenium status biomarkers and evidence for relationships between intake and status biomarkers, (ii) selenium and health (including the effect of intake and/or status biomarkers on cancer risk, immune function, HIV, cognition, and fertility), (iii) bioavailability of selenium from the diet, and (iv) impact of genotype/single nucleotide polymorphisms on status or health outcomes associated with selenium. The main research outputs for selenium and future research priorities are discussed further in this review.

EURRECA-Estimating iron requirements for deriving dietary reference values.

Currently, a factorial approach is used to derive reference values for iron. Calculations include the use of a bioavailability factor to convert the physiological requirement, derived from obligatory losses and requirements for growth and development, into a dietary intake value. A series of systematic reviews undertaken by the EURRECA Network of Excellence aimed to identify data that may increase the accuracy of factorial calculations across all population groups. The selection of robust data was guided by the use of standardized review methodology and the evidence-based selection of status biomarkers and dietary intake assessment techniques. Results corroborated the dearth of relevant factorial data, including whole-diet bioavailability data, and confirmed the need to continue extrapolating physiological requirements across population groups. Data were also unavailable that would allow reference values to be based on selected health outcomes associated with iron intake or status. Ideally, a series of observational and randomized controlled trial (RCT) studies need to be undertaken across all population groups and life stages to generate robust data for setting dietary reference values for iron. It will also be essential to include information on polymorphisms that potentially influence iron absorption and status in the derivation process.

EURRECA-Evidence-based methodology for deriving micronutrient recommendations.

The EURopean micronutrient RECommendations Aligned (EURRECA) Network of Excellence explored the process of setting micronutrient recommendations to address the variance in recommendations across Europe. Work centered upon the transparent assessment of nutritional requirements via a series of systematic literature reviews and meta-analyses. In addition, the necessity of assessing nutritional requirements and the policy context of setting micronutrient recommendations was investigated. Findings have been presented in a framework that covers nine activities clustered into four stages: stage one "Defining the problem" describes Activities 1 and 2: "Identifying the nutrition-related health problem" and "Defining the process"; stage two "Monitoring and evaluating" describes Activities 3 and 7: "Establishing appropriate methods," and "Nutrient intake and status of population groups"; stage three "Deriving dietary reference values" describes Activities 4, 5, and 6: "Collating sources of evidence," "Appraisal of the evidence," and "Integrating the evidence"; stage four "Using dietary reference values in policy making" describes Activities 8 and 9: "Identifying policy options," and "Evaluating policy implementation." These activities provide guidance on how to resolve various issues when deriving micronutrient requirements and address the methodological and policy decisions, which may explain the current variation in recommendations across Europe. [Supplementary materials are available for this article. Go to the publisher's online edition of Critical Reviews in Food Science and Nutrition for the following free supplemental files: Additional text, tables, and figures.].

EURRECA-Estimating zinc requirements for deriving dietary reference values.

Zinc was selected as a priority micronutrient for EURRECA, because there is significant heterogeneity in the Dietary Reference Values (DRVs) across Europe. In addition, the prevalence of inadequate zinc intakes was thought to be high among all population groups worldwide, and the public health concern is considerable. In accordance with the EURRECA consortium principles and protocols, a series of literature reviews were undertaken in order to develop best practice guidelines for assessing dietary zinc intake and zinc status. These were incorporated into subsequent literature search strategies and protocols for studies investigating the relationships between zinc intake, status and health, as well as studies relating to the factorial approach (including bioavailability) for setting dietary recommendations. EMBASE (Ovid), Cochrane Library CENTRAL, and MEDLINE (Ovid) databases were searched for studies published up to February 2010 and collated into a series of Endnote databases that are available for the use of future DRV panels. Meta-analyses of data extracted from these publications were performed where possible in order to address specific questions relating to factors affecting dietary recommendations. This review has highlighted the need for more high quality studies to address gaps in current knowledge, in particular the continued search for a reliable biomarker of zinc status and the influence of genetic polymorphisms on individual dietary requirements. In addition, there is a need to further develop models of the effect of dietary inhibitors of zinc absorption and their impact on population dietary zinc requirements.

EURRECA's approach for estimating micronutrient requirements.

In Europe, micronutrient dietary reference values have been established by (inter)national committees of experts and are used by public health policy decision-makers to monitor and assess the adequacy of diets within population groups. The approaches used to derive dietary reference values (including average requirements) vary considerably across countries, and so far no evidence-based reason has been identified for this variation. Nutrient requirements are traditionally based on the minimum amount of a nutrient needed by an individual to avoid deficiency, and is defined by the body's physiological needs. Alternatively the requirement can be defined as the intake at which health is optimal, including the prevention of chronic diet-related diseases. Both approaches are confronted with many challenges (e. g., bioavailability, inter and intra-individual variability). EURRECA has derived a transparent approach for the quantitative integration of evidence on Intake-Status-Health associations and/or Factorial approach (including bioavailability) estimates. To facilitate the derivation of dietary reference values, EURopean micronutrient RECommendations Aligned (EURRECA) is developing a process flow chart to guide nutrient requirement-setting bodies through the process of setting dietary reference values, which aims to facilitate the scientific alignment of deriving these values.

Increasing fish consumption does not affect genotoxicity markers in the colon in an intervention study.

Observational studies suggest that fish consumption is associated with a decreased colorectal cancer (CRC) risk. A possible mechanism by which fish could reduce CRC risk is by decreasing colonic genotoxicity. However, concerns have also been raised over the levels of toxic compounds found in mainly oil-rich fish, which could increase genotoxicity. Therefore, the objective was to investigate the effects of fish on genotoxicity markers in the colon in a randomized controlled parallel intervention study. For a period of 6 months, subjects were randomly allocated to receive two extra weekly portions of (i) oil-rich fish (salmon), (ii) lean fish (cod) or (iii) just dietary advice (DA). The Comet Assay was used to measure the DNA damage-inducing potential of fecal water (n = 89) and DNA damage in colonocytes (n = 70) collected pre- and post-intervention as markers of genotoxicity. Genotoxicity of fecal water was not markedly changed after fish consumption: 1.0% increase in tail intensity (TI) [95% confidence interval (CI) -5.1; 7.0] in the salmon group and 0.4% increase in TI (95% CI -5.3; 6.1) in the cod group compared with the DA group. DNA damage in colonocytes was also not significantly changed after fish consumption, in either the salmon group (-0.5% TI, 95% CI -6.9; 6.0) or cod group (-3.3% TI, 95% CI -10.8; 4.3) compared with the DA group. Measurements of genotoxicity of fecal water and DNA damage in colonocytes did not correlate (r = 0.06, n = 34). In conclusion, increasing consumption of either oil-rich or lean fish did not affect genotoxicity markers in the colon.

Increased consumption of fatty and lean fish reduces serum C-reactive protein concentrations but not inflammation markers in feces and in colonic biopsies.

Fish consumption is associated with a reduced colorectal cancer risk. A possible mechanism by which fish consumption could decrease colorectal cancer risk is by reducing inflammation. However, thus far, intervention studies investigating both systemic and local gut inflammation markers are lacking. Our objective in this study was to investigate the effects of fatty and lean fish consumption on inflammation markers in serum, feces, and gut. In an intervention study, participants were randomly allocated to receive dietary advice (DA) plus either 300 g of fatty fish (salmon) or 300 g of lean fish (cod) per week for 6 mo, or only DA. Serum C-reactive protein (CRP) concentrations were measured pre- and postintervention (n = 161). In a subgroup (n = 52), we explored the effects of the fish intervention on fecal calprotectin and a wide range of cytokines and chemokines in fecal water and in colonic biopsies. Serum CRP concentrations were lower in the salmon (-0.5 mg/L; 95% CI -0.9, -0.2) and cod (-0.4 mg/L; 95% CI -0.7, 0.0) groups compared with the DA group. None of the inflammation markers in fecal water and colonic biopsies differed between the DA group and the groups that consumed extra fish. In conclusion, increasing salmon or cod consumption for 6 mo resulted in lower concentrations of the systemic inflammation marker CRP. However, exploratory analysis of local markers of inflammation in the colon or feces did not reveal an effect of fish consumption.

Does ageing affect zinc homeostasis and dietary requirements?

Dietary intakes of zinc are lower in the elderly because of reduced energy requirements, and it is not clear whether ageing impacts on adaptive homeostatic mechanisms, namely absorptive efficiency and endogenous losses in the GI tract. Physiological requirements for zinc are unlikely to change significantly, but there are several attributes of ageing that may affect aspects of zinc metabolism (e.g. changes in gut structure and function, disease states, chronic inflammation, epigenetic changes in genes that express zinc-related proteins and drug regimens) that are worthy of further investigation. There is, as yet, no information on the effects of ageing on zinc transporters, and there are no sensitive and specific measures of zinc status, therefore dietary recommendations for zinc have been derived from factorial calculations using information on zinc absorption and loss, and estimates of dietary bioavailability.

Biomarkers of copper status: a brief update.

The essentiality of copper (Cu) in humans is demonstrated by various clinical features associated with deficiency, such as anaemia, hypercholesterolaemia and bone malformations. Despite significant effort over several decades a sensitive and specific Cu status biomarker has yet to be identified. The present article updates a comprehensive review recently published by the authors which assesses the reliability and robustness of current biomarkers and outlines the on-going search for novel indicators of status(1). The essential features of this earlier review are reiterated whilst considering whether there are other approaches, not yet tested, which may provide valuable information in the quest for an appropriate measure of copper status. Current biomarkers include a range of cuproenzymes such as the acute phase protein caeruloplasmin and Cu-Zn-superoxide dismutase all of which are influenced by a range of other dietary and environmental factors. A recent development is the identification of the Cu chaperone, CCS as a potential biomarker; although its reliability has yet to be established. This appears to be the most promising potential biomarker, responding to both Cu deficiency and excess. The potential for identifying a 'suite' of biomarkers using high-throughput technologies such as transcriptomics and proteomics is only now being examined. A combination of these technologies in conjunction with a range of innovative metal detection techniques is essential if the search for robust copper biomarkers is to be successful.

Comparing Diet and Exercise Monitoring Using Smartphone App and Paper Diary: A Two-Phase Intervention Study.

BACKGROUND: There is increasing recognition that personalized approaches may be more effective in helping people establish healthier eating patterns and exercise more, and that this approach may be particularly effective in adolescents. OBJECTIVE: The objective of this study was to investigate the use of a smartphone app (FoodWiz2) in supporting healthy lifestyle choices in adolescence. METHODS: Participants (N=34: 11 male, 23 female) aged 16-19 years in full- or part-time education were recruited from sixth form colleges, schools, and other further education establishments in Norfolk and Suffolk, United Kingdom, between February and May 2015. Participants recorded food intake and exercise using a paper diary for 4-5 weeks and then used the app for the same duration. Initial nutrition education and general support were provided during the paper diary use, but the app included personalized messages sent in response to app activity. At the end of each study phase, participants completed an online questionnaire to describe their experience of using the paper diary and app. RESULTS: Record completion declined throughout the study, possibly affected by examination pressure. Food intake data showed increased fruit consumption and significantly reduced consumption of chocolate snacks (P=.01) and fizzy drinks (P=.002) among participants using the app. Questionnaire responses indicated that the app was generally preferred to the paper diary, in particular, the app was seen as less boring to use (P=.03) and more acceptable in social settings (P<.001). CONCLUSIONS: This app-based approach has shown the potential for a more effective approach to improving adolescent diet and exercise levels.

Effect of high-dose iron supplements on fractional zinc absorption and status in pregnant women.

BACKGROUND: Women have an increased risk of iron deficiency during pregnancy because of the demands of the developing fetus. Iron supplements are commonly advocated as a prophylactic treatment and are generally taken with meals to reduce side effects, but iron can interfere with the absorption of zinc. OBJECTIVE: The aim was to determine the effect of consuming an iron supplement (100 mg Fe/d as ferrous gluconate) with meals from 16 wk gestation to term on zinc status and absorption. DESIGN: Stable-isotope techniques were used to measure zinc status (exchangeable zinc pool, EZP) and fractional zinc absorption (FZA) in early and late pregnancy from a meal consumed at a different time from that of iron supplement or placebo consumption in 6 women given iron supplements and 7 given a placebo. RESULTS: FZA increased during pregnancy, independent of iron supplementation. FZA was significantly higher (P < 0.001) at week 34 than at weeks 16 and 24, and urinary zinc excretion was higher at week 34 than at week 16 (P = 0.02). The size of the EZP remained unchanged throughout pregnancy and was unaffected by iron supplementation. The iron status of iron-supplemented women was higher than that of the placebo group. CONCLUSIONS: In iron-replete pregnant women who consumed a Western diet, no detectable adverse effects on zinc metabolism were observed after ingestion of 100 mg Fe/d. An increase in the efficiency of zinc absorption was observed during late pregnancy.

Stable isotope pilot study of exchangeable copper kinetics in human blood plasma.

To develop further our understanding of initial dietary copper metabolism, a method has been developed to separate plasma copper that is bound to albumin, from that bound to ceruloplasmin. This method has been tested using plasma samples from a pilot study involving six human volunteers who consumed 3mg oral doses of the stable isotope (65)Cu and gave blood samples at timed intervals up to 7 days. The results suggest that this method can be used to monitor dynamic fluctuations in newly absorbed copper over a short time frame.

Modeling tool for calculating dietary iron bioavailability in iron-sufficient adults.

Background: Values for dietary iron bioavailability are required for setting dietary reference values. These are estimated from predictive algorithms, nonheme iron absorption from meals, and models of iron intake, serum ferritin concentration, and iron requirements.Objective: We developed a new interactive tool to predict dietary iron bioavailability.Design: Iron intake and serum ferritin, a quantitative marker of body iron stores, from 2 nationally representative studies of adults in the United Kingdom and Ireland and a trial in elderly people in Norfolk, United Kingdom, were used to develop a model to predict dietary iron absorption at different serum ferritin concentrations. Individuals who had raised inflammatory markers or were taking iron-containing supplements were excluded.Results: Mean iron intakes were 13.6, 10.3, and 10.9 mg/d and mean serum ferritin concentrations were 140.7, 49.4, and 96.7 mg/L in men, premenopausal women, and postmenopausal women, respectively. The model predicted that at serum ferritin concentrations of 15, 30, and 60 mg/L, mean dietary iron absorption would be 22.3%, 16.3%, and 11.6%, respectively, in men; 27.2%, 17.2%, and 10.6%, respectively, in premenopausal women; and 18.4%, 12.7%, and 10.5%, respectively, in postmenopausal women.Conclusions: An interactive program for calculating dietary iron absorption at any concentration of serum ferritin is presented. Differences in iron status are partly explained by age but also by diet, with meat being a key determinant. The effect of the diet is more marked at lower serum ferritin concentrations. The model can be applied to any adult population in whom representative, good-quality data on iron intake and iron status have been collected. Values for dietary iron bioavailability can be derived for any target concentration of serum ferritin, thereby giving risk managers and public health professionals a flexible and transparent basis on which to base their dietary recommendations. This trial was registered at clinicaltrials.gov as NCT01754012.

Use of mathematical modeling to study copper metabolism in humans.

BACKGROUND: An improved understanding of copper metabolism is needed to derive more precise estimates of dietary requirements. OBJECTIVES: The objectives were to validate a method for estimating endogenous losses of copper, test whether a simple model can predict true absorption from the plasma appearance of labeled copper, and develop a compartmental model for copper metabolism by using stable isotopes. DESIGN: A stable isotope of copper was intravenously administered to 6 men, and fecal samples were collected for 14 d. Four weeks later the study was repeated, but with an oral dose, and blood samples were collected for 7 d and fecal samples for 14 d. RESULTS: There was no significant difference (P = 0.48) in the estimated endogenous loss of copper calculated by using either the excreted intravenous dose (x +/- SD: 32 +/- 5%) or the absorbed and excreted oral dose (35 +/- 2%). A simple mathematical model fitted to plasma isotope appearance data estimated true absorption to be 8 +/- 2% compared with 48-49% measured by fecal monitoring. A more complicated compartmental model predicted that, when newly absorbed copper first enters the blood, 74% is removed by the liver and 99% is bound to ceruloplasmin in the plasma. The exchangeable pool of copper was estimated to be 43 +/- 30 mg. Daily endogenous losses were predicted to be 2.4 mg. CONCLUSIONS: The results showed that fecal monitoring is the only method that can reliably measure labeled copper absorption, and it is not necessary to administer an intravenous dose of copper to estimate endogenous losses. The compartmental model provides new insights into human copper metabolism.

Estimation of dietary iron bioavailability from food iron intake and iron status.

Currently there are no satisfactory methods for estimating dietary iron absorption (bioavailability) at a population level, but this is essential for deriving dietary reference values using the factorial approach. The aim of this work was to develop a novel approach for estimating dietary iron absorption using a population sample from a sub-section of the UK National Diet and Nutrition Survey (NDNS). Data were analyzed in 873 subjects from the 2000-2001 adult cohort of the NDNS, for whom both dietary intake data and hematological measures (hemoglobin and serum ferritin (SF) concentrations) were available. There were 495 men aged 19-64 y (mean age 42.7±12.1 y) and 378 pre-menopausal women (mean age 35.7±8.2 y). Individual dietary iron requirements were estimated using the Institute of Medicine calculations. A full probability approach was then applied to estimate the prevalence of dietary intakes that were insufficient to meet the needs of the men and women separately, based on their estimated daily iron intake and a series of absorption values ranging from 1-40%. The prevalence of SF concentrations below selected cut-off values (indicating that absorption was not high enough to maintain iron stores) was derived from individual SF concentrations. An estimate of dietary iron absorption required to maintain specified SF values was then calculated by matching the observed prevalence of insufficiency with the prevalence predicted for the series of absorption estimates. Mean daily dietary iron intakes were 13.5 mg for men and 9.8 mg for women. Mean calculated dietary absorption was 8% in men (50th percentile for SF 85 µg/L) and 17% in women (50th percentile for SF 38 µg/L). At a ferritin level of 45 µg/L estimated absorption was similar in men (14%) and women (13%). This new method can be used to calculate dietary iron absorption at a population level using data describing total iron intake and SF concentration.

Alginate inhibits iron absorption from ferrous gluconate in a randomized controlled trial and reduces iron uptake into Caco-2 cells.

UNLABELLED: Previous in vitro results indicated that alginate beads might be a useful vehicle for food iron fortification. A human study was undertaken to test the hypothesis that alginate enhances iron absorption. A randomised, single blinded, cross-over trial was carried out in which iron absorption was measured from serum iron appearance after a test meal. Overnight-fasted volunteers (n = 15) were given a test meal of 200 g cola-flavoured jelly plus 21 mg iron as ferrous gluconate, either in alginate beads mixed into the jelly or in a capsule. Iron absorption was lower from the alginate beads than from ferrous gluconate (8.5% and 12.6% respectively, p = 0.003). Sub-group B (n = 9) consumed the test meals together with 600 mg calcium to determine whether alginate modified the inhibitory effect of calcium. Calcium reduced iron absorption from ferrous gluconate by 51%, from 11.5% to 5.6% (p = 0.014), and from alginate beads by 37%, from 8.3% to 5.2% (p = 0.009). In vitro studies using Caco-2 cells were designed to explore the reasons for the difference between the previous in vitro findings and the human study; confirmed the inhibitory effect of alginate. Beads similar to those used in the human study were subjected to simulated gastrointestinal digestion, with and without cola jelly, and the digestate applied to Caco-2 cells. Both alginate and cola jelly significantly reduced iron uptake into the cells, by 34% (p = 0.009) and 35% (p = 0.003) respectively. The combination of cola jelly and calcium produced a very low ferritin response, 16.5% (p < 0.001) of that observed with ferrous gluconate alone. The results of these studies demonstrate that alginate beads are not a useful delivery system for soluble salts of iron for the purpose of food fortification. TRIAL REGISTRATION: ClinicalTrials.gov NCT01528644.

The absorption of iron from whole diets: a systematic review.

BACKGROUND: Absorption factors are required to convert physiologic requirements for iron into Dietary Reference Values, but the absorption from single meals cannot be used to estimate dietary iron absorption. OBJECTIVE: The objective was to conduct a systematic review of iron absorption from whole diets. DESIGN: A structured search was completed by using the Medline, EMBASE, and Cochrane CENTRAL databases from inception to November 2011. Formal inclusion and exclusion criteria were applied, and data extraction, validity assessment, and meta-analyses were undertaken. RESULTS: Nineteen studies from the United States, Europe, and Mexico were included. Absorption from diets was higher with an enhancer (standard mean difference: 0.53; 95% CI: 0.21, 0.85; P = 0.001) and was also higher when compared with low-bioavailability diets (standard mean difference: 0.96; 95% CI: 0.51, 1.41; P < 0.0001); however, single inhibitors did not reduce absorption (possibly because of the limited number of studies and participants and their heterogeneity). A regression equation to calculate iron absorption was derived by pooling data for iron status (serum and plasma ferritin) and dietary enhancers and inhibitors from 58 individuals (all from US studies): log[nonheme-iron absorption, %] = -0.73 log[ferritin, µg/L] + 0.11 [modifier] + 1.82. In individuals with serum ferritin concentrations from 6 to 80 µg/L, predicted absorption ranged from 2.1% to 23.0%. CONCLUSIONS: Large variations were observed in mean nonheme-iron absorption (0.7-22.9%) between studies, which depended on iron status (diet had a greater effect at low serum and plasma ferritin concentrations) and dietary enhancers and inhibitors. Iron absorption was predicted from serum ferritin concentrations and dietary modifiers by using a regression equation. Extrapolation of these findings to developing countries and to men and women of different ages will require additional high-quality controlled trials.

Effect of iron intake on iron status: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: The response of status biomarkers to an increase in iron supply depends on several physiologic and environmental factors, which make it difficult to predict the outcome of an intervention. OBJECTIVE: We assessed effects of baseline iron status, sex, menopausal status, duration of intervention, iron form, and daily dose on the change in iron status in response to iron supplementation. DESIGN: A systematic review of randomized controlled trials (RCTs) of iron-supplementation and -fortification trials that assessed effects on hemoglobin, serum ferritin (SF), soluble transferrin receptor, or body iron was conducted. Subgrouping and straight-line and curved metaregression were used to describe the magnitude and dose-responsiveness of effect modifiers with respect to changes in status. RESULTS: Forty-one RCTs were included; none of the RCTs were judged at low risk of bias. Random-effects meta-analyses showed that iron supplementation significantly improved iron status but with high levels of heterogeneity. Metaregression explained approximately one-quarter of between-study variance in effect size. There were clear effects on SF with study duration (increase in SF concentration/wk: 0.51 µg/L; 95% CI: 0.02, 1.00 µg/L; P = 0.04) and dose (increase in SF concentration/g Fe: 0.10 µg/L; 95% CI: 0.01, 0.20 µg/L; P = 0.036) and on hemoglobin concentrations with baseline iron status [-0.08 g/dL (95% CI: 0.15, 0.00 g/dL) per 10-µg/L increase in baseline SF concentration; P = 0.02]. Insufficient data were available to assess effects on body iron, sex, or menopausal status. CONCLUSION: Quantitative relations between baseline iron status, study duration, and iron dose on changes in iron-status biomarkers, which were generated from the meta-analyses, can be used to predict effects of trials of iron supplementation and fortification and to design iron-intervention programs.

Selenium and prostate cancer: systematic review and meta-analysis.

BACKGROUND: Prostate cancer is a growing public health problem. Several human studies have shown a potentially protective effect of selenium, but the conclusions from published reports are inconsistent. OBJECTIVE: The objective was to examine the evidence for relations between selenium intake, selenium status, and prostate cancer risk. DESIGN: This was a systematic review and meta-analysis of randomized controlled trials, case-control studies, and prospective cohort studies. The World Cancer Research Fund/American Institute for Cancer Research Continuous Update Project database was searched up to September 2010. The studies included reported measurements of selenium intake or status (plasma, serum, or toenail selenium), assessments of prostate cancer cases (number of events), and the RR in the adult population. Meta-analyses were performed, and study quality, heterogeneity, and small study effects were assessed. Dose-response meta-analyses were used, with restricted cubic splines and fractional polynomials for nonlinear trends, to investigate the association between selenium status and prostate cancer risk. RESULTS: Twelve studies with a total of 13,254 participants and 5007 cases of prostate cancer were included. The relation between plasma/serum selenium and prostate cancer in a nonlinear dose-response meta-analysis showed that the risk decreased with increasing plasma/serum selenium up to 170 ng/mL. Three high-quality studies included in the meta-analysis of toenail selenium and cancer risk indicated a reduction in prostate cancer risk (estimated RR: 0.29; 95% CI: 0.14, 0.61) with a toenail selenium concentration between 0.85 and 0.94 µg/g. CONCLUSION: The relation between selenium status and decreased prostate cancer risk was examined over a relatively narrow range of selenium status; further studies in low-selenium populations are required.

Risk-benefit analysis of mineral intakes: case studies on copper and iron.

Dietary reference values for essential trace elements are designed to meet requirements with minimal risk of deficiency and toxicity. Risk-benefit analysis requires data on habitual dietary intakes, an estimate of variation and effects of deficiency and excess on health. For some nutrients, the range between the upper and lower limits may be extremely narrow and even overlap, which creates difficulties when setting safety margins. A new approach for estimating optimal intakes, taking into account several health biomarkers, has been developed and applied to selenium, but at present there are insufficient data to extend this technique to other micronutrients. The existing methods for deriving reference values for Cu and Fe are described. For Cu, there are no sensitive biomarkers of status or health relating to marginal deficiency or toxicity, despite the well-characterised genetic disorders of Menkes and Wilson's disease which, if untreated, lead to lethal deficiency and overload, respectively. For Fe, the wide variation in bioavailability confounds the relationship between intake and status and complicates risk-benefit analysis. As with Cu, health effects associated with deficiency or toxicity are not easy to quantify, therefore status is the most accessible variable for risk-benefit analysis. Serum ferritin reflects Fe stores but is affected by infection/inflammation, and therefore additional biomarkers are generally employed to measure and assess Fe status. Characterising the relationship between health and dietary intake is problematic for both these trace elements due to the confounding effects of bioavailability, inadequate biomarkers of status and a lack of sensitive and specific biomarkers for health outcomes.