Lead Review Article December 2002: 391–406

TheUsefulness of Elemental Iron for Cereal Flour FortiŽ cation: ASUSTAIN TaskForce Report RichardHurrell, Ph.D.,Thomas Bothwell, M.D., James D. Cook,M.D., Omar Dary,Ph.D., Lena Davidsson,Dr. Med.Sc., Susan Fairweather-Tait, Ph.D.,Leif Hallberg,M.D., SeanLynch, M.D., Jorge Rosado, Ph.D., Tomas Walter, M.D., and Paul Whittaker,Ph.D.

FortiŽcation of cereal ours may bea useful public Introduction health strategy to combat iron deŽciency. Cereal IrondeŽ ciency is a majorpublic health problem in ours that areused shortly afterproduction (e.g., baking our)can be fortiŽ ed with soluble iron com- developingcountries that affects up to 50% of infants, pounds,such as ferrous sulfate, whereasthe ma- children,and women of childbearingage in poorer pop- jority of ours stored for longer periodsis usually ulationsof Africa, Asia,and Latin America. Approxi- fortiŽed with elemental iron powdersto avoid un- matelyone-half of these people suffers from themost acceptablesensory changes. Elemental iron pow- severeform ofiron deŽ ciency, iron deŽ ciency anemia dersare less well absorbedthan soluble iron com- (IDA). IDA isanimportantcause of cognitivedeŽ cits in poundsand they varywidely in their absorption infantsand young children; 1 itcan cause premature dependingon manufacturing method andphysico- birth2 andincreased maternal 3 andperinatal mortality. 4 chemical characteristics. Costs vary with powder IDA alsohas a profoundeffect on workperformance and type, but elemental iron powdersare generally less productivity. 5,6 Ithas important negative economic con- expensive than ferrous sulfate. This review evalu- sequencesin countries where it is a majorhealth prob- ates the usefulness of the different elemental iron lem.7 For healthand economic reasons, therefore, many powdersbased on results from in vitro studies, rat developingcountries are evaluating strategies to combat assays, human bioavailability studies, andefŽ cacy irondeŽ ciency. Whereas food fortiŽ cation is usually studies monitoring iron status in human subjects. It consideredthe most cost-effective long-term approach to concludes that, at the presenttime, only electrolytic combatnutrient deŽ ciencies, 8 itshould form partof a iron powdercan be recommended as aniron forti- multiple-strategyapproach that includes iron supplemen- Žcant. Becauseit is only approximately half as well tationand dietary modiŽ cation. FortiŽ cation of wheat absorbedas ferrous sulfate, it should beadded to ourwith iron and vitamins has been used in theUnited providedouble the amount of iron. Statesand some European countries for morethan 50 Key Words: elemental iron, iron bioavailability, years.Although wheat  ourfortiŽ cation was suggested cerealfortiŽ cation, wheat our fortiŽcation asthe main reason for theimproved iron status of ©2002International Life Sciences Institute Swedishwomen, 9 itsefŽ cacy has never been properly evaluated10 andits usefulness has been questioned. To understandthe issues that underlie the current debate, it Drs. Hurrell and Davidsson are with the Swiss Fed- ishelpful to consider the factors that in uence the bio- eral Institute of Technology, Zu¨rich, Switzerland. Dr. availabilityof fortiŽ cation iron. CORE Bothwell is withMetadata, citation the and similar papers University at core.ac.uk of Witwatersrand, Johan- Provided by RERO DOC Digital Library nesburg, SouthAfrica. Dr.Cook is with the Kansas University Medical Center, Kansas City, Kansas, USA. Factors Affecting theBioavailability of Dr.Dary is with MOST,the Micronutrient USAIDPro- FortiŽcation Iron gram,Arlington, VA, USA.Dr. Fairweather-Tait is with the Institute of FoodResearch, Norwich, UK.Dr. Hallberg is Theamount of fortiŽcation iron absorbed from apartic- with the University of Go¨teborg,Go ¨teborg,Sweden. Dr. ulardiet depends on three factors. These include the Lynch is with the Eastern Virginia Medical School,Nor- compositionof the diet, the iron status of individuals folk, Virginia, USA.Dr. Rosado is with the Institute of consumingthe diet, and the relative bioavailability of the Medical Sciences and Nutrition, MexicoCity, Mexico. 11 Dr.Walter is with the Institute of Nutrition and Food ironfortiŽ cant. Thereare two types of iron in the diet, Technology, Santiago,Chile. Dr.Whittaker is with the US hemeiron (derived from hemoglobinand myoglobin) Foodand DrugAdministration, Washington DC,USA. andnonheme iron (derived mainly from cereals,vegeta-

NutritionReviews ,Vol. 60,No. 12 391 bles,and fruit). Most forms ofnonhemeiron in a meal, CurrentUse of IronForti Žcants whateverthe origin, enter a commonpool during diges- In1941, the United States was the Ž rst countryto enrich tionand are thus equally susceptible to a numberof low-extractionwheat  ourwith iron and vitamins; by promotersand inhibitors of ironabsorption. 12 The major 1965,virtually all white wheat  ourand wheat bread promotersof iron absorption are meat and ascorbic andmost corn meal (86 –94%),grits, and macaroni acid,12 whereasthe major inhibitors are phytates and 13 productswere forti Ž edwith iron, as were alargepro- polyphenols. 17 portionof other cereal products. By1979, most of Solubleiron forti Ž cants,such as ferrous sulfate, theready-to-eat breakfast cereals (92%) were alsoforti- enterthe common pool of nonhemeiron completely and Ž edwith iron (together with a selectionof vitamins) areabsorbed to the same degree as isintrinsic nonheme toprovide some 25% of the Recommended Daily Al- ironin the diet. This iron is well absorbed when the lowancesper serving. 18 Andas commercial cereal – dietcontains adequate amounts of ascorbic acid and/ or basedweaning foods became popular, they were forti Ž ed meat,but it is poorly absorbed from dietsin which withiron because infants are highly susceptible to iron 14 inhibitorsof iron absorption predominate. Ferrous deŽ ciency.19,20 sulfateand other soluble iron complexes can only be Mandatoryenrichment of white wheat  our with usedwhen the forti Ž edcereal is consumed shortly ironwas introducedin the United Kingdom and Canada afterproduction; this is because they are chemically in1953 and many other countries have since introduced reactiveand tend to produce undesirable organoleptic eithermandatory or voluntary enrichment, usually add- changeswith time in the vehicles to which they are ing sufŽ cientiron to whitewheat  ourtorestorethe level 10,15,16 added. tothat in whole grain or 80%-extraction  our (U.K.). Whencereal products will be stored for longer Countriesthat require iron to be added to wheat  our periods,forti Ž cantsthat are less soluble in the upper includeChile (30 ppm), Guyana, Kenya, and Zambia (all gastrointestinaltract are frequently used. Although such 29–36ppm), Nigeria (35 ppm), United Kingdom (16.5 inertcompounds do not cause organoleptic changes ppm),United States (44 ppm), 21 Mexico(24 ppm), whenstored in a varietyof vehicles,they tend to be less andvarious Central American countries including wellabsorbed because they are less soluble in gastric ElSalvador, Costa Rica, Guatemala, Honduras, Nica- juice.Once dissolved, their absorption, like all iron ragua,and Panama. In Germany, Holland, Belgium, presentin thecommon pool, is dependenton theenhanc- Spain,and Switzerland, iron forti Ž cationof wheat  our ers andinhibitors of ironabsorption present in the meal isvoluntary. andon theiron status of the consumer. The most widely Becauseof its high nutritional bioavailability and usedof these compounds, particularly in cerealproducts, low cost, Ž nedried ferrous sulfate is often the best iron iselemental iron. Elemental iron is relatively inexpen- sourcefor forti Ž cation.It can be used in bakery  our siveand does not cause adverse  avorand color changes (whichis typically used within a monthafter milling), thatoften occur with prolonged storage of soluble iron insemolina, and in other types of low-moisture compounds.Wheat and maize  oursare selected as wheatproducts such as noodles, macaroni, and spaghetti. fortiŽ cationvehicles because these foods are usually Morewidespread use of ferrous sulfate is limited by centrallyprocessed and regularly consumed in suf Ž cient thefact that it often causes rancidity in stored cereal quantitiesby at-risk population groups. There are, how-  oursand unwanted color changes in some cereal ever,certain unanswered questions relating to the use of products.16,22 Analternative to ferrous sulfate is fer- elementaliron because it isnot a singleentity but rather rousfumarate, which, although more expensive and existsin various forms dependingon the manufacturing insolublein water, has a bioavailabilitysimilar to ferrous process. sulfate.It therefore causes fewer organolepticproblems Threedistinct families of elemental iron powders andsome European manufacturers use it tofortifyinfant havebeen used: iron reduced by hydrogen or carbon cereals.10 monoxide,electrolytic iron, and carbonyl iron. Each Elementaliron powders are, by far, themost widely manufacturingprocess produces a powderwith a distinct used fortiŽ cantsfor wheat  ourand other cereal prod- particlesize distribution, density, surface area, chemis- ucts,including breakfast and infant cereals. 23,24 Whereas try,and shape, all of which can affect iron bioavailabil- elementaliron powders are the most widely used iron ity.The unique qualities of the various powders have fortiŽ cants,many researchers have investigated whether largelybeen overlooked owing to the food industry ’s they are sufŽ cientlywell absorbed from cerealproducts frequentuse of the generic name “reducediron. ” It is tobe nutritionally useful. 24–28 Inseveral early human thereforenot possible to give a singlerecommendation absorptionstudies, discrepant results were obtained,with regardingthe use of elemental iron powers in cereal bioavailabilityranging from verylow to Ž guresequiva- fortiŽ cation. lentto those obtained with ferrous sulfate. 19,25–31 These

392 NutritionReviews ,Vol. 60,No. 12 differencescan be ascribed to the fact that the labeled (whichdepends on the method of manufacture), other metal experimentalpowders were notproduced in the same impurities,particle size, shape, and surface area. waysas commercial iron powders and, therefore, had Hydrogen-and CO-reduced sponge iron powders differentphysico-chemical characteristics. Attempts to aremade at an elevated temperature by using hydrogen characterizethe different iron forti Ž cationcompounds orcarbonmonoxide to reduceiron oxide to itselemental accordingto theirphysicochemical characteristics, solu- state.34 Twotypes of ironoxide are used to produce these bilityin diluteacid, and ability to replete hemoglobin in reducediron powders commonly referred toas “sponge” iron-deŽ cient rats32,33 revealedmany differences. Inter- ironpowders. The Ž rst ismill scale, a by-productof the pretationof the various Ž ndingsis complicatedby failure steelindustry; the second is natural iron ore. Mill scale tofully characterize the iron powders that were being mainlyconsists of Fe 3O4 (magnetite)and is usually tested.It was stillpossible to reach certain general reducedby hydrogen,whereas iron ore consists of Fe 2O3 conclusions:powders with smaller particle size, larger (hematite)and is usually reduced by carbon monoxide. surfacearea, and greater solubility in dilute acid tended Thesecompounds have the lowest purity of the food- tobe better absorbed. gradeiron powders ( 96%Fe) andmay contain ele- From these Ž ndingsit is clear that there is no generally mentssuch as C, Mg,Al, Si, P, S,Cr,Mn, Ni, and Cu, acceptedview whether or not elemental iron should be manyof which are present as acid insoluble oxides and recommendedfor foodforti Ž cation.To answer this ques- thereforewould be expected to reduce solubility. The tion,SUSTAIN organizeda workshopin Monterrey, Mex- ironpowders are ground by avarietyof differentmilling ico,in September 2000, that brought together specialists in techniques.Milling is usually carried out under an inert ironnutrition and iron forti Ž cationand representatives from atmosphereto limit surface oxidation, the greatest source companiesthat manufacture and distribute elemental iron ofimpurity of any iron powder. The particle shape is powders.Published evidence was reviewedand a consen- consideredsponge-like, irregular, and porous. QMP re- sus,which summarized the current knowledge and made ducediron powders are made by a differentprocess. recommendationsfor thefuture, was prepared.The current Detailsof the QMP processand other methods used to reportcontains the literature review, together with the produceiron powders used in food enrichment can be conclusionsand recommendations from theSUSTAIN foundin the Handbook of Powder Metal Technologies workshop.The following sections describe the characteris- andApplications. 36 ticsof elemental iron powders used in food forti Ž cation and Electrolyticiron is produced in brittle sheets of theirbioavailability as measured by in vitro methods, by rat elementaliron that are then ground into powders. The hemoglobinrepletion studies, by human bioavailability thinsheets are made by electrolytic migration of iron studies,using radioactive or stable isotopes, and by moni- from apureiron anode through a ferroussulfate solution toringiron status. ontoa stainlesssteel cathode. Electrolytic iron powders containsigni Ž cantlyfewer impuritiesthan reduced iron powders ( 99%Fe), aqualitythat makes them ductile. Elemental IronPowders Used in Food Theparticle shape is described as highly irregular and FortiŽcation fern-likewith a highsurface area. This material can Historically,three distinct families of elemental iron pow- easilybe ground to a Ž neparticle size, which, together dershave been used in food forti Ž cation.34 These are witha largesurface area and high purity, is animportant hydrogen-reducedand carbon monoxide –reduced “sponge” factorin improving the solubility of elemental iron iron,electrolytic iron, and carbonyl iron. More recently, powdersin gastric juice. reducediron powder manufactured by Quebec Metal Pow- Carbonyliron powders are manufactured directly ders(QMP) hasbeen added to the list of iron powders from reducedelemental iron or from scrapiron. The availablefor foodforti Ž cation.The QMP reducediron metalreacts with carbon monoxide under heat and pres- powderhas been referred toas “atomized” iron.35 Owing to sureto produce iron pentacarbonyl, which is then de- theirdifferent manufacturing methods, there are major dif- composedunder controlled conditions yielding carbonyl ferencesin the chemical and physical properties of these ironpowder and carbon monoxide gas. A secondreduc- familiesand their absorbability from foods.There are also tiontreatment with hydrogen is necessary to removethe considerabledifferences within individual powder types carbonimpurities to producepowders containing 98% owingto the different grinding and sieving procedures used iron,the major impurities being carbon and nitrogen. The becauseof different particle size distributions. All commer- carbonyliron particles are dense spheres of extremely cialelemental iron powders for foodforti Ž cationcontain smallparticle size (2 –10 m) whosestructure is charac- 96%iron. The powder characteristics that in  uence ab- terizedby concentricshells of ironarranged in anonion- sorptionare those that in  uenceits dissolution in the gastric likefashion. The particles have a smooth,dense outer juice.These include the microstructure of the particle layer,which exposes them to lesssurface oxidation than

NutritionReviews ,Vol. 60,No. 12 393 Table 1. Iron Powders Availablefor Food Forti Žcation in the Year 2000 Powder Type Manufacturer Particle Size* H-reduced(sponge) North American Ho ¨gana¨s, USA 325 mesh Reduced QMP, Canada 325 mesh CO-reduced(sponge) Ho ¨gana¨s AB, Sweden 325 mesh 300 mesh 100 mesh Electrolytic OMGAmericas,USA (GliddenA131) 325 mesh (39% 10 m, 35% 10–20 m, 16% 20–30 m, 8% 30–44 m) Electrolytic IMP, India 325 mesh Carbonyl BASF, Germany 325 mesh ( 99.5% Fe or 90% Fe) (10% 3.5 m, 50% 8.5 m, 100% 21 m) Carbonyl ISP, USA 325mesh (mean particle size 5 m)

*325mesh means that ca. 95% of particlesare 45 m;300 mesh means that ca. 95% of particles are 50 m;100 mesh means thatca. 95% of the particles are 150 m. reducediron powders or electrolytic iron powders. A powdersare QMP andIMP. QMP startedapproximately mixtureof ferrous oxides and ferric oxidesform onthe 20yearsago and IMP beganproducing electrolytic iron surfaceof iron powders. Some oxidation is considered inthe early 1970s. Manufacturing companies sell the nutritionallybene Ž cialbecause ferrous oxide is very ironpowders to the food ingredient suppliers and pre- solublein gastric acid and the oxidized areas provide mixmanufacturers who in turn supply the food industry. attacksites for particledissolution. 34 Thecharacteristics of the different iron powders avail- Themilling and sieving procedures used determine ableon the market today are given in Table 1. theparticle size of reducedand electrolytic iron powders. Hydrogen-reducediron and electrolytic iron are pro- Apowdergenerally consists of discrete particles of dry videdas well-characterized single powders that should materialwith a maximumdimension of 1 mm. Food differonly slightly from batchto batch. Carbon monox- ChemicalsCodex (FCC) speci Ž cations37 requirethat ide–reducediron powders can have variable composition reducediron powders used to fortify foods are passed dependingon the market requirement. Three major par- througha 100-meshsieve (particle size 149 m) and ticlesizes of CO-reduced iron are commercially avail- thatelectrolytic and carbonyl iron powders are passed able,including the large particle size 100-mesh, 300- througha 325-meshsieve (particle size 44 m). Man- meshfor Europe,and 325-mesh for theUnited States. ufacturersalso provide reduced iron powders that have Carbonyliron (BASF) isoffered as 99.5%iron or beenpassed through a 325-meshsieve. They form alarge 98%iron, but both products have the same particle size proportionof powderssold although this standard is not distributionwith all particles being 21 m. Food com- stipulatedin the FCC. Whereasit would seem that paniesin the United States and Europe mainly use the particlesize alone is insuf Ž cientto ensureenough iron is smallparticle size powders (i.e., 50 m or 45 m). absorbedto be nutritionally useful, other factors such as Thelarge particle size CO-reduced iron ( 150 m) is surfacearea, porosity, or purity have not been suf Ž - theleast expensive product and is commonly used in cientlyinvestigated to enable the formulation of clear manydeveloping countries. These reduced iron powders guidelines.Only a few companiesmanufacture the vast aremainly used to fortify cereal  oursand breakfast majorityof elementaliron powders used in food forti Ž - cereals.Electrolytic iron is mainlyused to fortify infant cationtoday. Each company manufactures one type of cereals,particularly in the United States; however, it is powderusing one manufacturing process. Reduced iron alsosometimes recommended for cereal  our fortiŽ ca- powdersare manufactured by Ho ¨gana¨s AB, Sweden tionand is thespeci Ž ediron compound in the micronu- (CO-reduced);North American Ho ¨gana¨s(formerlyPy- trientformula for wheat  our fortiŽ cationin six coun- ronCorporation), United States (H-reduced); and Que- triesin Central Asia. Carbonyl iron is only occasionally becMetal Powders (QMP), Canada(reduced). Electro- usedto fortify foods because of itsgreater cost. lyticiron powder is manufactured by OMG Americas, whichis in theUnited States (formerly Glidden, A131), Bioavailability ofElemental IronPowders andInternational Metal Powders (IMP) India.BASF, Germany,and International Speciality Products (ISP), InVitro Methods UnitedStates, manufacture carbonyl iron. The two new- Differentin vitromethods have been used to estimatethe estcompanies to enter the market for food-gradeiron bioavailabilityof elemental iron powders; there have

394 NutritionReviews ,Vol. 60,No. 12 Table 2. StudiesUsing RelativeBioavailability (RBV) in Ratsto EvaluateElectrolytic Iron Authors Description of Powders RBV Ranhotraet al. 43 Commercial 39 Pla et al.44 Commercial1 325mesh 50 Commercial2 325mesh 45 Pennellet al. 45 GliddenA131 325 mesh 47 Coccodrilliet al. 46 Commercial 98% 40 m 70 Shah et al.33 Commercial1 99% 40 m 32 Commercial2 99% 40 m 37 Commercial3 99% 40 m 16 Sacks& Houchin 47 GliddenA131 48 Motzoket al. 39 Glidden 99% 40 m 42 Shah& Belonje 48 Commercialsample for cereals 41–44 Romanik& Miller 49 GliddenA131 59 Hurrellet al. 22 GliddenA131 44 beenfew studies,however, comparing in vitro results Forbeset al. 40 alsoreported good agreement of iron directlywith rat hemoglobin repletion data or human absorptionin man from electrolyticiron and ferric or- absorptiondata. Results from invitro studies therefore thophosphatewith in vitro dialyzable iron from those donot provide information that can be used to predict compoundsas measured after a simulatedgastric and bioavailabilityof the different powders. In the future, intestinalenzymatic digestion. The same technique was however,these methods may provide a simpleapproach alsorecommended by Whittaker et al. 41 as a useful thatcould be used to optimize and characterize iron methodto predictthe bioavailability of forti Ž cation iron powdersfor foodforti Ž cation. inman, but a carefulevaluation of different elemental Severalauthors have evaluated solubility in dilute ironpowders using this method still remains to bemade. HCl,although the early studies of Pla and Fritz 38 found pooragreement between the solubility of arangeof iron Rat Studies compoundsin dilute HCl (pH 1.1)and their relative In1989, Forbes et al. 40 reportedthat the Association of bioavailabilityin rathemoglobin repletion studies. Shah OfŽ cialAnalytical Chemists (AOAC) hemoglobinreple- et al.33 proposedthat the suitability of elemental iron tiontest in rats 42 was agoodpredictor of the RBV ofan powdersfor foodforti Ž cationshould be judged by their iron fortiŽ cationcompound in humans. In this assay, solubilityin dilute HCl. To measure solubility, investi- weaningrats are Ž rst renderediron de Ž cientand anemic gatorsrecommended that 100 mg powder be shakenwith byfeedinga low-irondiet for 4weeks;the rats are then 250mL of0.2% HCl (pH 1.2)at 37 °C,andthat only repletedover 2 weekswith the test iron compounds. powdersthat are 90%soluble after 3 hoursshould be RBVoftheiron compound is obtainedby comparingthe usedfor foodforti Ž cation.Motzok et al., 39 using a increasein hemoglobin of the test iron compound with similarmethod, showed that the solubility of elemental theincrease in hemoglobin with ferrous sulfate. Many ironpowders after 10 minutesin diluteacid agreed with hemoglobinrepletion assays using the AOAC method relativebioavailability values (RBV) from ratstudies. were madeon commercial iron powders used in the Theyreported 44% solubility of electrolytic iron, 45% 1970sand 1980s for cerealforti Ž cationmainly in the and31% with two different batches of carbonyl iron, 8% UnitedStates. Results from theassays are now presented for CO-reducediron, and 8% each for twodifferent andreviewed. batchesof H-reducediron. Using the method of Shah et Electrolyticiron. Studieswith electrolytic iron (Ta- al.,33 Forbeset al. 40 reportedthat electrolytic iron was ble2) have reported RBV valuesfrom 16to 70, with a 75%dissolved in dilute HCl after 30 minutesand that the meanof 44, in commercial powders conforming to the relativehuman absorption of electrolytic iron compared FCC speciŽ cations37 thatwere passedthrough a 325- withferrous sulfate was also75%. The other compound meshsieve. The commercial powder Glidden A131 was testedin thisstudy was ferric orthophosphate,which was testedindependently Ž vetimesbetween 1975 and 1989, only3 to4% soluble in dilute acid after 30 minutes but yieldingRBV valuesfrom 42to 59, with a meanof 48. was 25%as well absorbed as ferrous sulfate in man. Thiselectrolytic iron powder is still widely used to Earlier,Bjo ¨rn-Rasmussenet al. 31 reporteda positive fortifyinfant cereals. 50 Most,but not all, of theelectro- correlationbetween the solubility of four experimental lyticiron powders had an RBV valueof 40. reducediron compounds in dilute HCl and their absorp- H-reducediron. H-reducediron powders (Table 3) tionin human subjects. reportedlyhave lower RBV valuesthan electrolytic iron

NutritionReviews ,Vol. 60,No. 12 395 Table 3. StudiesUsing RelativeBioavailability (RBV) in Ratsto EvaluateH-Reduced Iron Authors Description of Powders RBV Ranhotraet al. 43 Commercial 37 Ranhotraet al. 51 Commercial 325 mesh 42–48 Pla et al.44 Commercial 325 mesh 32 Commercial 100 mesh 18 Fritz et al.32 Commercial 27 Coccodrilliet al. 46 Commercial 97% 40 m 25 Shah et al.33 Commercial 92% 40 m 18 Commercial 88% 40 m 24 Motzoket al. 39 Glidden 92% 40 m 14 Pyron 99% 40 m 13 Sacks& Houchin 47 Mallinkrodtno 4350 (mean particle size 7 m) Mallinkrodtno 4353 5% 10 m 27 25% 20 m 32 GliddenB 131 3% 10 m 35 Mallinkrodt —100 mesh 22% 20 m 24 Ranhotraet al. 52 Commercial 49 Shah& Belonje 48 Mallinkrodt —325 mesh 96% 44 m 28 Hurrellet al. 22 Commercial—Riedel,Germany 54 powders.Coarse powders that conform to FCC speci Ž - between27 and66 (mean47), and clearly depend on the cations37 bypassingthrough a 100-meshsieve (149 m) meanparticle size (Table 4). Powders in which 90% of haveyielded RBV valuesof approximately20. 32,47 The theparticles are 5 mhaveyielded a meanRBV value reportedRBV valuesfor othercommercial powders have of56,whereas the largest particle size commercial pow- variedfrom 13to 54, with a meanof 30. Commercial der,in which 80%of theparticles were 20 m, had powders,most of which pass through a 325-meshsieve, an RBV of 39. havealso occasionally given low RBV values,i.e., 13 39 Particlesize versus method of manufacture. and 25.46 Themost recent commercial powder, tested in Whereasit is clear that particle size reduction increases 1989,however, gave an RBV of54. 22 theRBV ofall iron powders, elemental iron powders of CO-reducediron. Onlythree studies have reported identicalparticle size manufactured by differentmethods dataon commercialCO-reduced iron powders (Table 4), haveyielded different RBV values.Thus the RBV values yieldingRBV valuesfrom 12to 32 (mean 19); this for electrolyticiron powders of a speci Ž edparticle size indicatesthese powders have generally low bioavaila- arehigher than those for H-reducediron of the same bility. particlesize, which is, in turn, higher than those for Carbonyliron. Allcarbonyl iron powders pass CO-reducediron. 54 (Table5) Whereas direct compari- througha 325-meshsieve. Reported RBV valuesare sonsbetween carbonyl iron powder and electrolytic pow-

Table 4. StudiesUsing RelativeBioavailability (RBV) in Ratsto EvaluateCarbonyl andCO-Reduced Iron Authors Description of Powders RBV Carbonyliron Pla et al.44 95% 5 m 47 Shah et al.33 meanparticle size 4 m 61 meanparticle size 3 m 51 Motzoket al. 39 86% 10 m 31 93% 10 m 27 Sacks& Houchin 47 90% 5 m 66 90% 8 m 63 80% 20 m 39 Hurrellet al. 22 BASF 52 Kosonen& Mutanen 53 Lohmann 35 CO-reducediron Coccodrilliet al. 46 88% 40 m 32 Shah et al.33 84% 40 m 12 Motzoket al. 39 Mallinkrodt60% 40 m 12

396 NutritionReviews ,Vol. 60,No. 12 Table 5. Inuence of Particle Size on ketedtoday (Table 1) compare with those studied in rats Bioavailabilityof Elemental Iron Powders 20to 30 years ago. The manufacturing process for Production Method Particle Size( m) RBV electrolyticiron would appear to have remained essen- Electrolytic1 7–10 64 tiallyunchanged although there is no documented evi- 27–40 38 dencethat the current electrolytic iron powders are iden- Electrolytic2 0–10 76 ticalto Glidden A-131. The manufacture of H-reduced 10–20 75 andCO-reduced sponge iron powders and carbonyl pow- 20–40 48 dersmay have changed to someextent although the basic 40 45 processesare still the same. There are no clearly recog- H reduction 10–20 54 nizablerat studies testing the bioavailability of the newer 40 34 ironpowders, such as theQMP reducediron or theIMP COreduction 6–10 36 electrolyticiron, which have been introduced within the 14–19 21 last30 years. 27–40 13 Carbonyl 4 69 HumanBioavailability Studies 4–8 64 Sevenhuman studies have been carried out to measure 5 4 Adaptedfrom Fritz. thebioavailability of elemental iron powders added to breador infant cereal. (Table 6) In most studies, bio- dersof identical particle size have not been made, car- availabilityof the iron powder was compareddirectly bonyliron powders have yielded similar RBV valuesto withthat of ferroussulfate added to thecereal product in electrolyticiron of the smallest particle size (0 –10 m or anidentical manner. Two studies compared the absorp- 7–10 m)inrathemoglobin repletion studies. (Table 5) tionof the iron powder with that of the common pool Effectof processing. Animalstudies indicate that ironusing an extrinsic radio-iron tag. The latter value neitherbread baking nor infant cereal processing (wet shouldapproximate the absorption of ferrous sulfate mixingand drying) in  uenceRBV. Pennell et al. 45 providedthat the iron concentration of the pool iron is reportedthat the RBV ofanelectrolytic iron powder was similarto that of the forti Ž cationiron. Six studies were 47whenadded directly to the rat diet, 49 whenadded to madewith experimental iron powders labeled with radio- therat diet with the unforti Ž edrice infant cereal, and 45 ironor stableiron isotopes. Although these experimental whenadded to thedietafter being processed with the rice powderswere sometimesvery different from commer- cereal.Similarly, Shah & Belonge 48 reportedthat the cialpowders, in most cases they were suf Ž cientlywell RBVofa reducediron powder was 26,28, and 30, characterizedso as to provide useful information. The respectively,when added to the rat diet directly, when remainingstudy by Hallberget al. 28 istheonly study that addedas partof ironforti Ž ed  our,and when baked into hasmeasured the absorption of a commercialiron pow- bread. der(carbonyl iron) irradiated to produce labeled mate- Extrapolationfrom rats to humans. Therat studies rial.The amount of iron added per meal varied in the usingthe AOAC hemoglobinrepletion test would there- sevenstudies from 1to5mg.In general, as theamount fore predictthat the relative bioavailability to humansof ofiron added per meal increased, fractional absorption thedifferent commercial elemental iron powders, at least decreased,but the absolute amount of iron absorbed thosemarketed in the 1970s and 1980s, is variable and increased.55 Studiesdone prior to 1969 have not been dependsboth on particlesize and method of production. consideredbecause of dif Ž cultiesin de Ž ningthe charac- Electrolyticand carbonyl iron powders that pass through teristicsof the iron powders tested. a325-meshsieve had the highest reported RBV valuesin ratsand would be predicted to be approximately half as Hydrogen-reduced Iron wellabsorbed in humans as ferrous sulfate. The rat Ironabsorption by human subjects from H-reducediron studiesindicate that reduced iron powders are less well powdersadded to bread or infant cereal has been mea- absorbedthan carbonyl or electrolyticiron powders and suredfour times. (Table 6) Afurtherstudy was donewith havea morevariable absorption. The coarse H-reduced reducediron 55 butthe method of production was not powders,which pass only through a 100-meshsieve, like stated.The isotopically labeled iron powders tested were thecommercial CO-reduced powders, are predicted to be sometimesvery different from theiron powders mar- approximately20% as well absorbed as ferrous sulfate. ketedtoday. In the one infant cereal study, 19 absorption The Ž nerH-reduced powders, which pass through a byinfants from asmallparticle size powder (5 –10 m) 325-meshsieve, are predicted to be 20 to 50% as well was 4%and equivalent to the absorption of ferrous absorbedas ferrous sulfate. sulfate.The relatively low absorption can be explained Itis unclear how the elemental iron powders mar- bythehigh iron dose (5 mg/ 10gcerealmeal) and by the

NutritionReviews ,Vol. 60,No. 12 397 Table 6. Human StudiesMeasuring the Absorption of Elemental Iron Powders from Bread andCereal Products Percent Absorption fromFerrous Percent Sulfate or Absorption from Common Author Method Compound Meal Subjects Elemental Iron Pool* Ho¨glund & Radioactive Reduced iron. 60 g wheat Adults 8–13/ Course: 3.0 0.8 19.8 5.7 Reizenstein 5 5 WBC Coarse: roll with group, 23% 20–30 1 mg Fe separate m, 48% groups 30 m Fine: 97% ca. Fine: 9.0 5.7 5 m Cook et al.2 7 Radioactive H-reduced 60 g wheat Adults, 8.6 9.1 WBC iron, roll with 8/group, 5–10 m 3 mg Fe separate groups Rios et al.19 Radioactive H-reduced 10 g cereal Infants (5–7 4.0 (SEM 2.7 (SEM WBC iron, (wheat, oat, m) 12/25 3.4–4.9) 2.3–3.2) 5–10 m malt) with group, 5 mg Fe separate plus groups formula Bjo¨rn-Rasmussen WBC plus H-reduced 60 g wheat Adults, 6–8/ E11 15.6 6.8 18.5 7.7 31 et al. erythrocyte iron roll with group, E12 19.2 4.7 21.8 5.8 incorporation 1 mg Fe paired E12 7.0 1.9 10.6 2.8 E14 2.5 0.3 19.9 2.1 Hallberg etal. 28 Radioactive BASF, 40 g bread Adults, 8–10/ 1.0 5.6 WBC plus carbonyl (1 mg Fe) group, erythrocyte iron with paired incorporation margarine, marmalade, and coffee 40 g bread 0.5 5.5 (1 mg Fe) with margarine, and milk 40 g bread 1.7 12.7 (1 mg Fe) with hamburger, potatoes, and beans 40 g bread 1.1 20.1 (1 mg Fe) with meat soup Forbes etal. 4 0 Radioactive Electrolytic, 40 g wheat Adults, 10/ 3.37 (SEM 4.52 (SEM erythrocyte 10–30 m farina, 120 group, 2.62, 4.35) 3.53, 5.78) incorporation mL milk, paired and 1 mg Fe Roe & Stable H-reduced Breadroll Adults, 10/ 64.8 4.2 — Fairweather- isotopes, with 1 mg group Tait5 6 fecal Fe and monitoring Coca Cola

*Absorptionof ferroussulfate added to cereal products in anidentical manner to the elemental iron (References 19, 27, 40, 55) or absorptionof pool iron as measured by extrinsic tag (References 28, 31). WBC wholebody counter.

398 NutritionReviews ,Vol. 60,No. 12 presenceof phytic acid, even though the cereal was fed rollswere fedwith Coca Cola ¨ ,abeverageof low pH, mixedwith an infant formula, which can be assumed to whichcould have facilitated the dissolution of the iron containascorbic acid. The same small particle size iron powderin the gastric juice and thus elevated absorption. powder (5–10 m) orferrous sulfate, added to a low- Althoughthe high absorption reported in this study is extractionbread roll at a levelof 3mgiron, gave an iron inconsistentwith previous studies using radioisotopes absorptionof approximately 9% in adults. 27 Compared andwhole body counting, the results suggest that re- withferrous sulfate, the RBV ofH-reducediron was 95; ducediron powders of high relative bioavailability can thiswas muchhigher than the RBV valuesof 31 and 5 beproduced. This conclusion is in agreement with the reportedfor ferric orthophosphateand sodium iron py- resultsfrom earlierstudies, 19,27 whichreported similar rophosphate,respectively. absorptionvalues from H-reducediron powders and Inthe three other studies with reduced iron, 1 mgof ferroussulfate. ironwas addedand fed in a breadroll. Two of these studieswere donewith radioisotopes and used either a Electrolytic Iron 40 wholebody counter or erythrocyte incorporation of the Theelectrolytic iron powder tested by Forbes et al. was radioisotopesto evaluate iron absorption. In the study of similarbut not identical to commercial electrolytic iron Ho¨glundand Reizenstein, 55 30g whitebread was forti- passingthrough a 325-meshsieve (Glidden A-131). Ž edwith 1 mgradio-labeled reduced iron of the Ž ne (ca. Absorptionfrom a3mgiron dose by adultvolunteers of 5 m) orcoarse ( 48%of the particles 30 m) normaliron status from amealof wheatfarina and milk variety.Using a wholebody counter, they compared was 3.4%,which represented 75% of the absorption of elementaliron absorption in humanvolunteers with that ferroussulfate from thesame meal. The addition of 100 mgascorbic acid to the test meal increased the absorp- offerrous sulfate. Mean absorption of the “coarse” ele- tionof electrolyticiron to 8% without greatly changing mentaliron was 3%andabsorption of the “Ž ne” elemen- itsRBV value. taliron was 6%,representing an RBVrelativeto ferrous sulfateof 15 and 45, respectively. Bjo ¨rn-Rasmussenet CarbonylIron al.31 alsofed 1 mgof differentradio-labeled experimen- After extensivestudies on the bioavailability in humans talreduced iron powders in 60 gwheatrolls, made from 28 ofcarbonyl iron added to bread rolls, Hallberg et al. 60%-extractionwheat  our,to healthy volunteers and recommendedthe need to reconsider the rationale for measurediron absorption by both hemoglobin incorpo- usingelemental iron powders for foodforti Ž cation. rationand whole body counting. Absorption depended Theseinvestigators irradiated food-grade carbonyl iron onthesolubility of thepowder in diluteacid, the surface (BASF) inanuclearreactor for approximately10 daysat areaof theiron particles, and the particle size. In subjects atemperatureof 100°C.Thepowder was leftto stand withrelatively low iron stores, iron absorption was 2.5to for atleast500 days so astoallowfor thedecay of 59Fe 19%,representing RBV valuesof 13 to 90% relative to andother unwanted radioisotopes, after which time the absorptionof nativebread iron labeled extrinsically with 55Fe-labeledcarbonyl iron was addedto 60%-extraction 59 FeCl3. wheat  ourand baked into bread rolls. One, two, and Thethird, more recent study was donewith stable threemg of carbonyl iron were addedto each 40 g roll isotopes.Iron absorption was measuredfrom theamount representingforti Ž cationlevels of 2.5, 5.0, and 7.5 mg/ ofadded iron isotope excreted in the stool in ten non- 100 g  our.A totalof 15separateiron absorption studies anemicadult females with moderately low iron stores were carriedout in seven to ten human subjects per 56 (meanplasma ferritin 24 g/L). Thereported absorp- study;forti Ž edrolls were fedwith marmalade, marga- tionwas 65%,much higher than any previously reported rine,and coffee for breakfastor as part of a composite values.The reduced iron powder used in this study was mealwith either hamburger or vegetable/ meatsoup. producedexperimentally by a stableisotope manufac- Meaniron absorption from thebreakfast meals was 1.4% turerand was reportedto have a solubilityin diluteacid (range 0.5–2.7%),which represented a meanRBV value similarto that of a commercialreduced iron powder. of22(range 9 –33)when compared with the absorption 59 Therewas nodirect comparison with ferrous sulfate ofnativemeal iron labeled with FeCl3.MeanRBV was addedto bread. There are two possible explanations for evenlower with the hamburger meals and meat/ vegeta- thisunusually high absorption. Firstly, it ispossible that blesoup at 13 and 5, respectively. thefecal monitoring technique used generated falsely Theseresults were somewhatsurprising at the time highabsorption values. This is suggested by the high becausethe reported RBV valuesin rats for carbonyl meaniron absorption (50%) from areferencedose of 3 ironwere closerto 50. 47 Thedata on solubility and mgiron as ferrous sulfate and 30 mg ascorbic acid. A particlesize, as well as the rat studies, had suggested 40%reference dose absorption usually indicates that carbonyliron was atleast as good as, if notbetter than, subjectshave reduced iron stores. Secondly, the bread reducediron and electrolytic iron. 47 Thecarbonyl iron

NutritionReviews ,Vol. 60,No. 12 399 irradiatedby Hallberget al. 28 was subsequentlyreported additionof ascorbicacid, iron absorption by adultsfrom tohave an RBV valuein rats of 35. 53 One might be aferroussulfate –fortiŽ edwheat porridge was 2.2%;this temptedto suggest that the irradiation and storage of the numberfell to 1%when soy protein isolate was commercialcarbonyl iron powder may have changed its added.61 Ironabsorption by infants from wholemeal properties,but its solubility in diluteHCl at pH 1andpH bread fortiŽ edwith ferrous sulfate increased from 3.1% 3was unchangedand similar to that of a commercial to7.5% when the bread was consumedwith a drink electrolyticiron powder (Glidden A-131). After 30min- containing50 mg ascorbic acid. 57 utes,85% of alltested compounds dissolved at pH1but only6% dissolved at pH 3. Hallberg et al. 28 suggested Extrapolation ofFindings toElemental Iron thatdifferences in gastric pH after a mealand different Thereare two concerns when attempting to predict the gastricresidence time could be extremely important absorptionof an elemental iron powder from aforti Ž ed factorsbecause the variation in RBV ofcarbonyl iron cerealproduct. The Ž rst concernis that the elemental observedwith the different meals was probablydue to ironpowder is less bioavailable than ferrous sulfate differentrates and extent of solubility of theiron powder becauseit does not dissolve as well in the gastric juice. inthe gastric juice. Owing in part to the results of this Thesecond concern relates to thenature of thediet. The study,iron forti Ž cationof wheat  ourwith carbonyl iron proportionof elemental powder that is available for was discontinuedin Sweden some 10 years later. absorptionis then exposed to inhibitors, such as phytic acid,so that the amount Ž nallyabsorbed may be reduced tounacceptably low levels. From thepublished human Predicting theAbsorption of Elemental Iron 28 Based onthe Measured Absorptionof Ferrous bioavailabilitystudies, only Hallberg et al. tested a Sulfate commercialiron powder and reported absorption values of1to2%in subjectswith normal iron status consuming Anotherway to predict the absorption of elementaliron compositemeals together with the forti Ž edbread roll. powdersfrom acerealproduct is to relate it to the Forbeset al. 40 testedan experimental electrolytic iron measuredabsorption of ferrous sulfate. At best,the powderof similarparticle size to thecommercial powder absorptionof anelementaliron powder would be equiv- thatwas passedthrough a 325-meshsieve and reported alentto that of ferrous sulfate, but, in most cases, it anabsorption of 3.4%for amealbased on wheat farina wouldbe much less. Rat assays would predict that and milk. electrolyticand carbonyl iron powders are approximately Muchhigher absorption values from experimental halfas well absorbed as ferroussulfate and that reduced elementaliron powders and ferrous sulfate have been ironpowders are 20 to 50%as well absorbed as ferrous reportedwhen the iron compound is fed with a simple sulfate.(Tables 2 – 4)Studies reporting iron absorption breadmeal and when low-extraction  ourcontaining byhuman subjects from ferroussulfate –fortiŽ ed bread littleor nophyticacid is usedto makethe bread. With 1 andinfant cereals are listed in Table 7. Iron absorption mgadded iron, absorption values as high as 10 to 20% byadultswith normal iron status from breadrolls made havebeen reported in subjects with normal iron status from 60%-extraction  ourcontaining 1.7 to 2.5mg iron (Table6) for bothelemental iron powders and ferrous 60,61 asferrous sulfate was reportedto be 5.7 to 8.6%. sulfate.With 1.7 to 2.5 mg added iron, reported absorp- Ironabsorption by adults from wheatrolls made from tionis intherange of 6to9%.(Table 7) In the presence 80%-extraction  our,however, fell to approximately1%, ofphytic acid, however, such as in bread made from presumablyowing to the high phytic acid content. Iron 80%-extractionor whole meal  our,iron absorption absorptionby infants from wholegrain infant cereal, from ferroussulfate may fall to 1% or less. (Table 7) wholemeal bread, and a breakfastcereal was similarly low (3.1–3.8%).57,59 Phyticacid is a potentinhibitor of HumanStudies MonitoringIron Status ironabsorption 62,63 butcan be partiallydegraded during theyeast fermentation step of the bread baking process, Elwoodet al. 64 tried,in twoseparate studies, to demon- andcompletely degraded if low-extraction  our and stratethe bene Ž cialeffect of the U.K.  ourenrichment prolongedfermentation times are used. 61,62 Another ef- program(16 mg iron/ kg)on theiron status of free-living fectivemeans of increasingthe bioavailability of forti Ž - women. The Ž rst studywas atherapeutictrial monitoring cationiron is to add ascorbic acid —apotentenhancer of the in uenceof iron-forti Ž edbreadas anintegralpart of ironabsorption —tocereal porridges and infant cereals. 35 thenormal diet on the hemoglobin concentration of Its effectivenesshas been shown in several studies. For mildlyanemic women. The second study was termeda example,iron absorption from acommercialinfant ce- prophylactictrial because the anemic women were Ž rst real,based on wheat and cow ’smilkand forti Ž ed with treatedwith iron to increase their hemoglobin concen- ferroussulfate and ascorbic acid, was reportedto be tration;then the ability of the iron-forti Ž ed bread to 8.7%in infants 58 and2.6 to 4.3% in adults. 22 Without the maintainthe higher hemoglobin levels was monitored.In

400 NutritionReviews ,Vol. 60,No. 12 Table 7. Iron Absorption in Human Subjectsfrom Ferrous Sulfate –fortiŽedBread and Infant Cereals Author Method Meal Subjects %Iron Absorption Hurrellet al. 22 Radioisotopes, 100g wheat/milk Adults, 10–13subjects/ 2.58(SEM 1.82,3.66) erythrocyte infantcereal study 4.28(SEM 3.17,5.78) incorporation 300mL water,7.5 mg Fe,35 mg ascorbic acid Faiweather-Taitet al. 57 Stableisotopes, Weetabixbreakfast, 20 Infants,9 months,10 3.0(SD 1.1,8.3) erythrocyte gcereal,85 g milk, subjects/group incorporation 0.7mg Fe, 4 mg ascorbicacid 22g wholewheat 3.1(SD 1.4,6.7) bread, 6 g margarine,0.5 g marmite,0.6 mg Fe, 0.3mg ascorbic acid Davidssonet al. 58 Stableisotopes, 25g wheat/milkinfant Infants, 5–9 months, 8.7(range 3.8 –10.9) erythrocyte cereal,100 mL 12subjects/ study incorporation water,2.5 mg Fe, ascorbicacid/ Fe 2:1 molar ratio Fox et al.59 Stableisotopes, 20g wholegrain Infants,9 months,24 3.8(SEM 2.9,4.7) erythrocyte weaningcereal subjects/study incorporation (wheat,rice, oat, rye,wheat bran), 1.6 mg Fe Hurrellet al. 60 Radioisotopes, 50g 60%-extraction Adults, 7 8.64(SEM 6.0,12.4) erythrocyte wheatbread roll, 1.7 subjects/study incorporation mg Fe Hurrellet al. 61 Radioisotopes, 50g 60%-extraction Adults, 8–10subjects/ 5.7(SEM 4.30,7.55) erythrocyte wheatbread roll, 2.5 study incorporation mg Fe 50g 80%-extraction 0.99(SEM 0.72,1.36) wheatbread roll, 2.5 mg Fe 50g 60%-extraction 2.2(SEM 1.36,2.91) wheatcereal porridge,5 mgFe 50g wheat/soycereal 0.73(SEM 0.49,1.07) porridge,5 mgFe the Ž rst trial,bread was forti Ž edwitheither reduced iron tientsin amentalhospital. He foundno bene Ž cial effect orferric ammoniumcitrate and provided approximately onhemoglobin after periods of 3to6 months,although 1mgextra iron per day, which increases the daily iron asimilaramount of iron given as ferrous gluconate intakeby approximately 10%. In the second trial, bread causeda risein mean hemoglobin in another group of was fortiŽ edwith ferric ammoniumcitrate at a higher anemicpatients. level(27 mg/ kginstead of 16 mg/ kg),which provided Thereis only one published study reporting im- 2.7mg extrairon per day. Elwood et al. 64 concludedthat provediron status in a populationfed regularly with an neithertrial provided conclusive evidence of any bene- elementaliron –fortiŽ edcereal. This study was donein Ž cialeffect of wheat  our fortiŽ cationon iron status, Chileby feeding an infant cereal forti Ž edwith Glidden eventhough the reduced iron –fortiŽ edbread gave a A131electrolytic iron. 50 Ironstatus was monitoredin smallbut statistically signi Ž cantincrease in hemoglobin groupsof approximately100 infants from 4monthsto 15 (0.24g/ dL)after 9 monthsof intervention. In another monthsof age.The infants consumed 25 –30griceinfant study,Elwood 30 carriedout a therapeutictrial that fed cerealper day, either unforti Ž ed, or fortiŽ ed with 55 mg reducediron –fortiŽ edbread to a groupof anemic pa- electrolyticiron/ 100g, whichprovided some 14 to17mg

NutritionReviews ,Vol. 60,No. 12 401 additionaliron per day. The cereals were mixedwith a poorbioavailability of ironfrom cereal-baseddiets, hel- non-iron–fortiŽ edformula containing 66 mg ascorbic minthinfections and particularly blood loss from hook- acid/L.Someinfants continued to bebreastfed, whereas worm infections 66 contributeto the problem of iron otherswere fedthe non-iron –fortiŽ edformula, both in deŽ ciencyin manyareas. Other important etiologic fac- additionto theirnormal diet that included fruits and fruit torsexpected to bluntthe effect of forti Ž cationprograms juicesfrom 3months,meat, and vegetables from 4 includefolate de Ž ciency,67 vitamin A deŽ ciency,68 a months,and regular table foods from 9months.At 15 varietyof infections including malaria and HIV infec- months,15% of the breastfed infants consuming the tion,69 andhemoglobinopath ies. 70 non-iron–fortiŽ edcerealwere diagnosedwith IDA, com- As mentionedabove, it is possible to enhance iron paredwith only 3% ofthose infants consuming the cereal absorptionfrom commercialinfant cereals forti Ž ed with fortiŽ edwith electrolytic iron. In the infants fed the elementaliron powders and other iron compounds by the non-iron–fortiŽ edformula, the corresponding numbers additionof ascorbic acid 35,42 orby phytate degrada- were 17and 6%. The authors concluded that cereal tion.35,58 Itis muchmore dif Ž cultto dosoin developing fortiŽ edwith electrolytic iron could contribute substan- countries,however, because ascorbic acid is unstable tiallyto preventing IDA. Whereasthis is true, it should whenstored in hot and humid climates unless it is beemphasized that IDA was noteradicated completely encapsulatedor stored in sophisticated packaging. inthis study even though the cereal provided an extra 14 Whereasnutritional campaigns to encourage the con- to17 mg iron per day. The iron was ingestedwith a sumptionof morefruits and vegetables or muscle tissue formulacontaining ascorbic acid, which facilitates ab- inthe diet are highly desirable, such approaches are not sorption,and was inaddition to theiron provided in the alwayspossible or practical. Sodium EDTA, whichis normaldiet. Assuming 5% absorption from theforti Ž - stableduring storage, is another potential enhancer of cationiron, enough iron would be absorbed from the fortiŽ cationiron absorption. It has been demonstrated to cerealto provide most of theiron requirement of a 6-to enhancethe absorption of ferrous sulfate from cereal 12-month-oldinfant, which is estimated to be 0.9 mg/ foods,61 but its in uenceon the absorption of elemental day.65 ironpowders remains to be established.

AdaptingIron Forti Žcation toDifferent Dietary Conclusionsand Recommendations Settings Thefollowing conclusions are based on the preceding Ultimately,the usefulness of elemental iron for food literaturereview and discussions, which took place at fortiŽ cationdepends on the ability of the forti Ž ed food, andafter the SUSTAIN workshopin Monterrey. whenconsumed as part of the normal diet, to prevent FortiŽ cationof milled, re Ž nedcereals is a conve- iron deŽ ciencyin at-risk population groups. Iron bio- nientway to deliver iron and other micronutrients to a availability,which is a keyfactor in this process, de- generalpopulation whose diets are de Ž cientin those pendson thenature and level of elementaliron added to micronutrients.Iron should be included in cereal forti Ž - thefood, the amount of forti Ž edfoodconsumed, the iron cationor enrichmentprograms in countries in which IDA statusof theconsumer, and the presence of inhibitorsand isprevalent. enhancersof iron absorption in the cereal vehicle and the Becauseof its high bioavailability and low cost, overalldiet. FCC-gradedried ferrous sulfate is often the best iron Asuccessfuliron forti Ž cationstrategy is muchmore sourcewhen cereals are to be stored for onlyshort easilyestablished in industrialized countries than in de- periods.It can be used in bakery  our,semolina, and velopingcountries. From alogisticstandpoint, the prep- othertypes of low-extraction wheat  ours,which are arationand distribution of forti Ž edcereals are usually normallyused within one to two months after produc- more efŽ cientand the mixed diets consumed by such tion.Ferrous sulfate should be a Ž ne–particlesize, dried populationscontain fewer inhibitorsof iron absorption material.FCC-grade ferrous fumarate is another good andmore enhancers, such as meat and ascorbic acid. By choicebecause it has a bioavailabilitysimilar to that of contrast,central distribution is oftena problemin devel- ferroussulfate. It is insoluble in water and therefore opingcountries. In addition, staple cereal diets have high causesfewer organolepticproblems than the more solu- phytateand low ascorbic contents, whereas other inhib- bleferrous sulfate. However, it is typically more costly itors,such as polyphenols, which are present in tea, thanferrous sulfate. legumes,and sorghum, often pose an added prob- Elementaliron powders have been used for cereal lem.13,14 As aresult,the absorption of all forti Ž cation fortiŽ cationfor morethan 50 years and continue to be compoundswould be expected to be low. 61 In develop- themost widely used iron compound for thispurpose. ingcountries, the problem of iron forti Ž cationis also Theyhave the advantage of causing few, ifany, color complicatedby anumberof otherfactors. In addition to and  avorproblems in stored food vehicles. They are

402 NutritionReviews ,Vol. 60,No. 12 inexpensiveand suitable for forti Ž cationof staplefoods ironpowders currently used for foodforti Ž cation.Until it suchas wheat  ourand maize  our.Absorption of canbe demonstratedthat large particle size reduced iron elementaliron powders is lower than that of other iron powders of 150 m(100mesh) have a bioavailability fortiŽ cants,such as ferrous sulfate and ferrous fumarate, equivalentto 45 m(325mesh) powder, they cannot andis less predictable. berecommended for foodforti Ž cation. From theinformation currently available, there are Humanbioavailability studies with isotopes have threemajor types of ironpowders in use: shownthat small particle size powders ( 10 m) are Reducediron (North American Ho ¨gana¨s[H-reduced], absorbedas well as ferrous sulfate. However, the tech- Ho¨gana¨sAB[CO-reduced],Quebec Metal Powders nicalfeasibility and cost of producingsuch powders have [reduced]) notbeen evaluated. Whereas particle size has been a Electrolyticiron (OMG Americas;Industrial Metal majorcriterion in assessing reduced iron powders, it is Powders) possiblethat novel production techniques may lead to Carbonyliron (BASF, InternationalSpeciality Pow- solubleparticles of larger size in the future. ders) FCCguidelinesspecify that reduced iron powders Electrolytic Iron musthave a particlesize of 150 m(100mesh). Theinformation currently available suggests that elec- Electrolyticand carbonyl iron powders must have a trolyticiron ( 45 m,325mesh, with a dendriticstruc- particlesize of 45 m(325mesh). Based on current turesimilar to Glidden A131) should be a usefuliron information,the relative costs of availableelemental iron fortiŽ cant.This is based on the following evidence: an powdersvary by a factorof approximately seven, with improvementin iron status of infants consuming an carbonyliron being the most expensive and 100-mesh electrolyticiron –fortiŽ edinfant cereal; a humanbio- reducediron the least expensive. Most reduced iron availabilitystudy with radio-labeled electrolytic iron powderscurrently used to fortify foods in NorthAmerica havingsimilar but not identical characteristics to the andEurope have a particlesize of 300 or 325 mesh. commercialproducts resulting in an absorption 75% of Reducediron of larger particle size (100 mesh), how- thatof ferrous sulfate; and rat hemoglobin repletion ever,is being used in some developing countries, pre- studieswith electrolytic iron powders similar to those sumablybecause of the lower cost. beingmarketed today showing a relativebioavailability Elementaliron powders have been evaluated in approximately50% of that of ferrous sulfate. severalways in relation to potential absorption in man. Themethods used include the measurements of physico- CarbonylIron chemicalcharacteristics, solubility in dilute acid, dialys- Carbonyliron has limited value in food forti Ž cation abilityin vitro, hemoglobin repletion in anemic rats, becauseof its high cost. There is also con  icting evi- bioavailabilityin human isotopic studies, and human denceconcerning its bioavailability. Rat hemoglobin efŽ cacystudies. Although useful information has been repletionstudies with carbonyl iron powders have shown obtainedfrom allof these studies, it is important to relativebioavailability of approximately 50% of that of emphasizethe lack of uniformity in solubility and dia- ferroussulfate; whereas it hasbeen used therapeutically lysabilityexperiments. By contrast, hemoglobin reple- invery large doses ( 1.5g/ day),however, the absorp- tionstudies in ratshave provided seemingly valid data on tionhas been found to be very low (0.5 –2.0%).Finally, thecommercial elemental iron powders in useat thetime extensivebioavailability studies with irradiated carbonyl ofthe studies. The powders tested between 1971 and ironin avarietyof mealshave demonstrated a lowRBV 1991,however, may have had different characteristics of 5% to 33%. from thosecurrently available. With one or two excep- tions,the elemental powders tested in human bioavail- FortiŽcation EfŽcacy abilitystudies were verydifferent from commercially Iron fortiŽ cationof cereals has been used widely as a availableproducts. publichealth intervention strategy. In industrialized countrieswith high bioavailability diets, this strategy has Reduced IronPowders beenassumed to have a bene Ž cialeffect on ironstatus. In Resultsfrom ratstudies on commercial reduced iron populationsconsuming low bioavailability diets, such as powdersdone between 1971 and 1991 indicated that thoseconsumed in many developing countries, the po- hydrogen-reducedpowders were lesswell absorbed than tentialbene Ž tmaybe much less, and much greater electrolyticiron and that carbon monoxide –reduced amountsof forti Ž cationiron may have to be added. powderswere verypoorly absorbed. Because it is not Becausethe impact of fortifyinglow bioavailability diets knownwhether the reduced iron powders tested are the maybe limited and because changes in iron status take sameas those presently being produced, there is no placeslowly, forti Ž cationshould be considered as only availableevidence to evaluate the usefulness of reduced oneof several strategies. Other strategies could include

NutritionReviews ,Vol. 60,No. 12 403 improvingthe overall quality of the diet by including tion,Mexico City, Mexico; Fredrik Eklund, Ho ¨gana¨s promotersof ironabsorption (e.g., ascorbic acid in citrus AB, Ho¨gana¨s,Sweden; Steven Harrison, Trace Science fruits,ripe papaya, and guavas, etc.); adding a facilitator International,Ontario, Canada; Erhard Klar, OMG ofironabsorption, such as EDTA orascorbicacid, to the Americas,North Carolina, USA; AlbertoMorales Lira, fortiŽ edfood vehicle; reducing the content of inhibitors MINSA, Edo,Mexico; Peter Ranum, SUSTAIN, Wash- consumedwith meals (e.g., tea, coffee, or cocoa prod- ingtonDC, USA; SteveSchorn, Research Products, ucts);and adding the forti Ž cationiron to a foodvehicle Salina,Kansas, USA; andWolfgang Vogl and Dr. Paul consumedseparately from themain inhibitory meals. Lohmann,Emmerthal, Germany. Alfonso Tirado (SUS- TAIN) collectedinformation on current iron powders The Way Ahead andElizabeth Turner (SUSTAIN) helpedin editing the Notenough is knownabout the characteristics and rela- manuscript.This review is a modi Ž edversionof onethat tivebioavailability of the commercial elemental iron was commissionedby SUSTAIN (SharingUnited States powdersthat are currently available. Because only a few Technologyto Aid in theImprovement of Nutrition) and powdersare used, it issuggestedthat these powders can preparedfor aworkshopto address con  ictingdata on bescreened using a varietyof established methods. absorptionof elemental iron and evaluate its usefulness Initially,these tests should all be conductedon thesame asa cerealforti Ž cant.The workshop was convenedin batchof ironpowder to establishcomparability between Monterrey,Mexico in September 2000. laboratoriesand should include physicochemical charac- 1. Lozoff B,Jime ´ nez E,Xolf AW.Long term develop- teristics,solubility in dilute acid, in vitro dialysability, ment outcome ofinfants with ironde Žciency. N Engl CaCo-2cell uptake, and hemoglobin repletion test in J Med 1991;325:687 –694. rats.At thesame time, human bioavailability can be 2. SchollTO, HedigerM, FischerRL, Shearer JW. evaluatedby serum iron curves, isotopic measurements Anemia vsiron de Žciency:increased risk of pre- ofabsorption (the labeled powders used in such studies term deliveryin aprospectivestudy. Am JClin Nutr 1992;55:985 –988. mustbe preparedwith characteristics as closeas possible 3. Rush D.Nutrition and maternal mortalityin the de- tothe commercial powders), and by measuring the effect velopingworld. Am JClin Nutr 2000;72:212S –240S. oniron status of human populations in Ž eld efŽ cacy 4. MurphyJF, O ’RiardonJ, Newcombe RG,ColesEC, trials. PearsonJF. Relation ofhaemoglobin levelsin Žrst Thecurrent speci Ž cationsfor elementaliron pow- and second trimestersto outcome ofpregnancy. dersare based on particlesize, but there is evidence that Lancet 1986;i:992–994. 5. BastaSS, Soekirman MS,KaryadiD, Scrimshaw otherfactors may be asimportant, or moreimportant, in NS. Iron deŽciency anemia and the productivityof predictingbioavailability. By correlating the results of adult males in Indonesia. Am JClin Nutr 1979;32: bioavailabilitystudies with in-vitro tests, it should be 916 –925. possibleto develop standardized techniques for predict- 6. Edgerton VR,Gardner GW,OhirayY, Gunawadena ingbioavailability. The development of a standardized KA,Senewiratne B.Iron-de Žciency anaemia and its effect on workerproductivity pattern. BMJ 1979;2: test,based on solubility within a speci Ž c pH range, 1546 –1549. appearsto be an attractive option. Once we havebetter 7. RossJ, Horten S.Economic consequences ofiron characterizedthe iron powders available today, and de- deŽciency.Ottawa: The Micronutrient Initiative; velopedsimple, reliable quality control methodologies, it 1998. shouldbe possible to manufacture and select suitable 8. Levin HM,Pollitt E, GallowayR, McGuireJ. Micro- nutrient deŽciency disorders.In: JamisonDT, Mos- elementaliron powders for foodforti Ž cation. leyWH, Measham AR,BobadillaJB, eds. Disease Combat Prioritiesin Developing Countries . New Acknowledgements York:University Press; 1993:421 – 451. 9. HallbergL, BengtssonC, GarbyL, Lennartsson J, Theauthors are grateful to SUSTAIN for commissioning RossanderL, TiblinE. Ananalysisof factorsleading thisliterature review and for organizingthe Monterrey to areduction inironde Žciency in Swedishwomen. workshop,and in particular to Liz Turner and Erica BullWorld Health Organ 1989;57:947 –954. 10. HurrellRF. Iron. In: HurrellRF, ed. The Mineral Stewartfor theirexcellent organization and administra- FortiŽcation ofFoods. 1st edition. Surrey:Leather- tionof the project. Appreciation is also extended to head Publishing;1999:54 –93. representativesfrom theiron powder industry for their 11. BothwellTH, MacPhail AP.Prevention ofiron de Ž- inputinto this review. In addition, the authors acknowl- ciency byfoodforti Žcation. In: Fomon SJ,Zlotkin S, edgethe technical contribution of thefollowing persons: eds. Nutritional Anaemias. Nestle´ Nutrition Work- GuillermoArteaga, MASECA, Monterrey, Mexico; shopseries 30. New York:Raven Press; 1992:183 – 192. MariaLeticia Bravo Gutierrez, Monterrey Institute of 12. HallbergL. Bioavailabilityof dietary iron in man. Technology,Monterrey, Mexico; Margarita Diaz Mar- Annu Rev Nutr 1981;1:123–147. tinez,National Institute of Medical Sciences and Nutri- 13. GilloolyM, BothwellTH, Torrance JD, et al.The

404 NutritionReviews ,Vol. 60,No. 12 effects oforganic acids, phytates and polyphenols ofthe bioavailabilityof iron. JAssoc Off Anal Chem onironabsorption from vegetables. Br J Nutr 1983; 1975;58:902 –905. 49:331–342. 33. Shah BG,GirouxA, BelonjeB. Speci Žcation for 14. Fairweather-TaitSJ, HurrellRF. Bioavailabilityof reduced ironas food additive. JAgricFood Chem mineralsand trace elements. Nutr Res Rev. 1996;9: 1977;253:592 –594. 295–324. 34. PatrickJ. Typesof iron forti Žcants. Elemental 15. CookJD, ReusserM. Iron forti Žcation: an update. sources.In: ClydesdaleFM, WiemerKL, eds. Iron Am JClin Nutr 1983;38:648 –659. FortiŽcation ofFoods. Orlando:Academic Press; 16. HurrellRF. Bioavailabilityof different ironcom- 1985:31–38. pounds to fortifyformulas and cereals:technologi- 35. HurrellRF. Forti Žcation: overcomingtechnical and cal problems.In: Steckel A,ed. Iron nutrition in practical barriers. J Nutr 2002;132:806S –812S. infancy and childhood. New York:Raven Press; 36. Handbook ofPowder Metal Technologies and Ap- 1984:147–178. plications. Volume 7. MaterialsPark, Ohio: Ameri- 17. BauernŽend C,DeRitter E.Foodsconsidered for can Societyof Metals; 1998. nutrient addition: cereal grainproducts. In: Bauern- 37. FoodChemicals Codex.Washington DC:National Žend JC,Lachance PA,eds. Nutrient Additions to Academy Press;1981. Foods. Connecticut: Foodand Nutrition Press; 38. PlaGW, FritzJC. Availabilityof iron. J Assoc Off 1991:143–209. Anal Chem 1970;53:791 –800. 18. Hayden EB.Breakfastcereals: trend foodsfor the 39. MotzokI, Verma RS,Chen SS,Rasper J, Hancock 1980’s. CerealFood World 1980;25:141 –143. RGV,Ross HU. Bioavailability,in vitrosolubility, and 19. RiosE, Hunter RE,Cook JD, Smith NJ,Finch CA. physicaland chemical propertiesof elemental iron The absorptionof iron as supplements in infant powders. JAssoc Off Anal Chem 1978;61:887 –893. cereal and infant formula. Pediatrics 1975;55:686 – 40. ForbesAL, Adams CE, Arnaud MJ,et al.Compari- 693. sonof invitro,animal and clinicaldeterminations of 20. Lynch SR,HurrellRF. Iron in formulasand baby ironbioavailability: International Nutritional Anemia foods.In: Lo ¨ nnerdal B,ed. Iron Metabolism in In- Consultative GroupTask Force report on ironbio- Am JClin Nutr fants. BocaRaton: CRCPress;1990:109 –126. availability. 1989;49:225 –238. 21. BarrettF, Ranum P.Wheat and blended foods.In: 41. Whittaker P,SpiveyFox MR, ForbesAR. In vitro prediction ofironbioavailability for food forti Žcation. ClydesdaleFM, WiemerKL, eds. Iron FortiŽcation of Nutr Rep Int 1990;39:1205 –1215. Food. Orlando:Academic Press;1985:75 –109. 42. PlaGW, FritzJC. Collaborativestudy of the hemo- 22. HurrellRF, FurnissDE, BurriJ, Whittaker P,Lynch globinrepletion test inchicksand ratsfor measuring SR,CookJD. Iron forti Žcation ofinfant cereals:a availabilityof iron. JAssoc Off Anal Chem 1971;54: proposalfor the use offerrous fumarate orferrous 13–17. succinate. Am JClin Nutr 1989;49:1274 –1282. 43. Ranhotra GS,Hepburn FN,BradleyWB. Availability 23. Anderson R.Breakfastcereals and drymilled corn ofiron in enriched bread. JAssoc Off Anal Chem products.In: ClydesdaleFM, WiemerKL, eds. Iron 1971;48:377 –384. FortiŽcation ofFoods. Orlando:Academic Press; 44. PlaGW, HarrisonBN, FritzJC. Comparisonof 1985:75–109. chicksand ratsas test animals forstudying the 24. Fomon J.Bioavailabilityof supplemental ironin bioavailabilityof iron, with specialreference to use commerciallyprepared dry infant cereals. J Pediatr ofreduced ironin enriched bread. JAssoc Off Anal 1987;110:660 –661. Chem 1973;56:1369 –1373. 25. Steinkamp R,Dubach R,MooreCV. Studies on the 45. Pennell MD,WiensWD, RasperJ, MotzoKI, Ross irontransportation and metabolism. VIII. Absorption HU.Factorsaffecting the relativebiological value of ofradioiron from iron-enriched bread. Arch Intern foodgrade elemental ironpowders for rats and Med 1955;95:181. humans. J Food Sci 1975;40:879 –883. 26. Callender ST,WarnerGT. Iron absorptionfrom 46. CoccodrilliGD, ReussnerGH, TheissenR. Relative bread. Am JClin Nutr 1968;21:1170 –1174. biologicalvalue of iron supplements in processed 27. CookJD, Minnich V, MooreCV, RasmussenA, foodproducts. JAgricFood Chem 1976;24:351 – BradleyWB, Finch CA. Absorptionof forti Žcation 353. ironin bread. Am JClin Nutr 1973;26:861 – 872. 47. SacksPV, Houchin DN.Comparative bioavailability 28. HallbergL, Brune M,RossanderL. Low availability ofelemental ironpowders for repair of iron de Ž- ofcarbonyliron in man: studieson ironforti Žcation ciency anemia in rats:studies of ef Žcacyand tox- of wheat our. Am JClin Nutr 1986;43:59 –67. icityof carbonyl iron. Am JClin Nutr 1978;31:566 – 29. HarrillIK, Hoene AE, Johnston FA.Iron absorbed 571. fromthree preparationsused to enrich bread. J Am 48. Shah BG,BelonjeB. Rat bioassayof hydrogen- Diet Assoc 1957;33:1010 –1014. reduced ironpowder in ourand bread. Nutr Rep Int 30. ElwoodPC. Aclinicaltrial of iron forti Žed bread. 1985;32:1171 –1178. BMJ 1963;1:224 –227. 49. Romanik EM,MillerDO. Iron bioavailabilityto rats 31. Bjo¨ rn-RasmussenE, HallbergL, RossanderL. Ab- fromiron forti Žed infant cereals:a comparisonof sorptionof forti Žcation iron.Bioavailability in man of oatmeal and ricecereals. Nutr Rev 1986;34:591 – different samplesof reduced iron,and prediction of 603. the effects ofiron forti Žcation. Br J Nutr 1977;37: 50. WalterT, Dallman PR,PizarroF, et al.Effectiveness 375–388. ofiron-forti Žed cereal in prevention ofiron de Ž- 32. FritzJC, Pla GW, HarrisonBN, ClarkGA. Estimation ciency anaemia. Pediatrics 1993;91:976 –982.

NutritionReviews ,Vol. 60,No. 12 405 51. Ranhotra GS,Loewe RJ,PuystLV. Availabilityof uation ofEDTA compounds foriron forti Žcation of ironin enriched sodacrackers. JAssoc Off Anal cereal-basedfoods. Br J Nutr 2000;84:903 –910. Chem 1973;50:745 –749. 62. HallbergL, RossanderL, Skanberg A-B.Phytates 52. Ranhotra GS,Lee C,Gelroth JA.Bioavailabilityof and the inhibitoryeffect ofbran on ironabsorption ironin somecommercial varietybreads. Nutr Rep in man. Am JClin Nutr 1987;45:988 –996. Int 1979;19:851 –857. 63. HurrellRF, JuilleratMA, ReddyMB, Lynch SR, 53. Kosonen T,Mutanen M.Relativebioavailability of DassenkoSA, CookJD. Soyprotein, phytate and ironin carbonyliron and complex ferricorthophos- ironabsorption in man. Am JClin Nutr 1992;56: phate to rat. Int JVitam Nutr Res 1992;62:60 –65. 573–578. 54. FritzJC. Bioavailability of mineral nutrients. 64. ElwoodPC, WatersWE, Sweetran P.The haema- Chemtech 1976;6:643–648. tinic effect ofironin our. Clin Sci 1971;40:31–37. 55. Ho¨ glund S,Reizenstein P.Studies on ironabsorp- 65. Stekel A.Iron requirements in infancy and child- tion. 5. Effect ofgastrointestinalfactors on the iron hood.In: Stekel A,ed. Iron Nutrition inInfancy and Blood absorption. 1969;34:496. Childhood. Nestle´ Nutrition WorkshopSeries No 4. 56. RoeMA, Fairweather-TaitSJ. High bioavailabilityof New York:Raven Press; 1984:1 –10. reduced ironadded to UK our. Lancet 1999;353: 66. Stolzfus RJ,DreyfussML, Chwaya HM,AlbonicoM. 1938 –1939. Hookwormcontrol as a strategyto prevent iron 57. Fairweather-TaitS, FoxTE, Wharf G,EaglesJ. The deŽciency. Nutr Rev 1997;55:223 –232. bioavailabilityof different weaning foodsand the enhancing effect ofa fruit drinkcontaining ascorbic 67. HercbergS, Galan P,Dupin H.Iron de Žciency in acid. Pediatr Res 1995;37:389 –394. Africa. WorldRev Nutr Diet 1987;54:201 –236. 58. DavidssonL, Galan P,CherouvrierF, et al.Iron 68. Suharno D,WestCE, Muhcial KaryadiD, Hautrast bioavailabilityfrom infant cerealsby infants: the JG.Supplementation with vitamin Aand ironfor effect ofdephytinization. Am JClin Nutr 1997;65: nutritional anaemias in pregnant women in West 916 –920. Java. Lancet 1993;342:1325 –1328. 59. FoxTE, Eagles J, Fairweather-TaitS. Bioavailability 69. van den BroekN, White SA,NielsonJP. The rela- ofiron glycine as a forti Žcant ininfant foods. Am J tionship between asymptomatic human immunode- Clin Nutr 1998;67:664 –668. Žciency virusinfection and the prevalence and se- 60. HurrellRF, ReddyMB, CookJD. Inhibition of verityof anemia inpregnant Malawian women. Am J non-haem ironabsorption in man bypolyphenol- Trop Med Hyg 1998;59:1004 –1007. containing beverages. Br J Nutr 1999;81:289 – 70. van den BroekN. Anaemia in pregnancy in devel- 295. opingcountries. BrJ Obstet Gynaecol 1998;105: 61. HurrellRF, ReddyMB, BurriJ, CookJ D.An eval- 385–90.

Erratum Inthe November 2002 issue of NutritionReviews, theissue number was erroneouslyprinted as No. 12. The correct issuenumber is No. 11.

406 NutritionReviews ,Vol. 60,No. 12