Am IC/in Nuir 1987;45:66l-70. Printed in USA. © 1987 American Society for Clinical Nutrition 661

Recommended dietary intakes (RDI)of folate in humans1-3

Victor Herbert, MD, JD

ABSTRACT Extensive evidence is presented that 3 �g folate/kg (6.8 nmol/kg) body weight daily

will not only maintain adequate folate nutriture but also a substantial reserve body pool in normalpersons. Recommendations appropriate to this extensive evidence are presented. Am I Clin Nutr

1987;45:661-70.

KEY WORDS Folate requirement, folate, folic acid, folate body pool, folate absorption

Introduction

Folate and folacin are alternate generic de-scriptors for compounds that, at various oxi-dation states and with different numbers ofglutamate residues, have nutritional propertiesand chemical structures similar to those offolicacid:N-[4-[[(2-amino-l,4-dihydro-4-oxo-6 -ptendinyl)methyl]amino -benzoyl]- L-glu-tamic acid, also known as pteroylglutamic acid(PGA). The amount of the vitamin is com-monly measured by its ability to support thegrowth of folate-dependent organisms in anotherwise complete, chemically defined cul-tare medium. Lactobacillus casei is generally

accepted as the standard assay organism be-cause it responds to the greatest number ofdifferent folate derivatives, including thosewith up to three L-glutamic acid residues. Itsresponses to derivatives with four or more suchresidues are less complete. The amount of fo-late is also measurable by radioisotope dilutionand binding methods (1).

Requirements for folate can be met by avariety of chemical forms as long as the essen-tial subunit structure of PGA remains intact.If the parent molecule PGA-consisting ofpteridine, p-aminobenzoic acid, and glutamicacid-is broken, then nutritional activity islost. Folate is heat labile; a diet comprised ex-

clusively of thoroughly cooked foods is likelyto be low in folate (2).

All naturally occurring folates show a vari-able degree of instability due to endogenouspteroylpolyglutamyl hydrolases that removeglutamate residues but leave an active com-pound. Heat, oxidation, and ultraviolet lightcleave the folate molecule, rendering it mac-

live. Thus, naturally occurring, labile folatesare lost in storage and cooking. Reducingagents, such as ascorbate, preserve folate butcan damage vitamin B-12.

Although all members of the folate familymay possess biological properties of their par-ent molecule under some conditions, they varywidely in their nutritional effectiveness, sta-bility, and availability. Some of the tetrahy-drofolate forms of folate (eg, N5-formyl PGAH4, N’#{176}-formyl PGA 1I.4� and, to a lesser ex-tent, N5-methyl PGA H4) are relatively heatstable, whereas others (eg, unsubstituted PGA114) are destroyed rapidly by heat (3). Meth-ylene PGA 114 is destroyed by acid but meth-enyl PGA 114 is quite stable at low pH.

The principal function of PGA-containingcoenzymes is the transport of fragments con-taining a single carbon atom from one com-pound to another. Many of these steps are es-sential for the synthesis of nucleic acid and fornormal metabolism of certain amino acids.Hence, deficiency of the vitamin leads to im-paired cell division and to alterations of pro-tein synthesis-effects most noticeable in rap-idly growing tissues. The dU suppression test,a sensitive indicator of folate-deficient DNAsynthesis (2, 4), becomes clearly abnormalwhen intracellular folate levels fall below 0.2ng/106 cells (4.5 pmol/106 cells) (5, 6).

‘From the Hematology and Nutrition Laboratory,Bronx VA Medical Center, NY, and Mount Sinai MedicalCenter, NY.

2Supp�ed in part by the Research Service of the USVeterans Administration and USPHS grant #DK37509.

3Address reprint requests to Victor Herbert, MD, JD,130 West Kingsbridge Road, Bronx, NY 10468.

Received March 14, 1986.Accepted for publication May 27, 1986.

662 HERBERT

Folate is present in a variety of foods, espe-cially liver, leafy vegetables, fruit, pulses, andyeast (7-li). It has recently been reported thatbreakfast cereals (12) and tea (13) may makea significant folate contribution to westerndiets. As of 1985, the best available data onfolate in the food supply, as measured by mi-crobiologic assay using ascorbate protection,are those summarized in the US Departmentof Agriculture (USDA) Handbook (14), whichincluded Canadian data, and the UK data ofPaul and Southgate (15). However, extractionconditions are critical and incomplete recoverymay plague some of the data in these tables(16, 17).

Approximately three-fourths of the folate inmixed US diets is present in the form of poly-glutamates (18), which are incompletely mea-sured in microbiological assays unless pre-treated with exogenous enzymes known asconjugases (also known as pteroylpolygluta-myl hydrolases). However, these polygluta-mates may lose their extra glutamates and thenbe absorbed and utilized in higher organismsas a result of the presence of endogenous en-zymes in the digestive tract (19-22).

Metabolic-balance studies in which radio-active synthetic polyglutamates of PGA weregiven to humans (23) indicated that intestinalabsorption of heptaglutamyl folate rangedfrom 50% to 75% (103) and of triglutamyl fo-late, 90% or more (as estimated from fecallosses). In other studies (24) that used a dif-ferent quantity than the prior study, monog-lutamates and polyglutamates were absorbedequally well. Differences in the relative ab-sorption of folate measurable in different foodsmay relate to the presence of conjugase inhib-itors, binders, or other unknown factors (25-27). Babu and Srikantia (28) confirmed thatthe mean absorption of folate in seven separate

food items was close to 50% (range, 37-72%).In that study, the absorption of folate frombrewers’ yeast was only 10%. In a small sample(11 women), Iyenger and Babu (29) foundpercentage absorption of 2 mg of H3PGA roseas red cell folate fell. This phenomenon of en-hanced absorption as stores fall is similar towhat occurs in iron absorption and needs fur-ther study.

Approximately 90% of folate monogluta-mate and 50-90% of folate polyglutamate in-gested separately from food is absorbed, but

this percentage is decreased in the presence ofmany foods, irrespective of whether the folatewas derived from or added to the food (30,27). On the basis of food-composition andintestinal-absorption data, it is reasonable toassume that the bioavailability of folate in thetypical US diet is about one-half to two-thirdsthat of separately ingested PGA. It is not clearwhether polyglutamate absorbability decreaseswith increasing chain length. The absorbabilityof heptaglutamate has been reported to be 70-100% that of PGA (24, 31, 32, 105). About100 �ig (226 nmol) of free PGA taken orallyeach day will prevent the development of de-ficiency (33, 34).

There is relatively little conjugase activityin the contents of the intestinal lumen of hu-mans and certain animals (31, 35-37). Rather,the hydrolysis of polyglutamates of PGA ap-pears to be a function of mucosal cells (31,35, 38, 104). Folacin enters portal plasma inthe free, or monoglutamate, form followingingestion of the conjugated, or polygluta.myl,forms of the vitamin (35). Both the free andconjugated forms of folate can be utilized inmeeting human nutritional requirements.

The fecal excretion of -‘�-20O ig (453 nmol)of folate daily (39) is not a reliable indicatorof folate intake or absorption because the fecesalso contain folate synthesized by bacteria inthe colon. Normally nourished individualsexcrete 5-40 �ig (11-91 nmol) of free (ie, ml-crobiologically measurable) folate in the urinedaily (40). Moreover, the folate content of bileis approximately five times that of serum (41).Enterohepatic recirculation tends to conservethe body pool of folate (42, 43). Krumdiecket al (44) monitored complete stool and urinecollections for radioactivity at sequential in-tervals after the ingestion of radioactive PGAby a healthy subject. After a period of equili-bration, the disappearance curve indicated abiological half-life of 101 d. Fecal and urinarylosses were approximately equal.

The size of the body’s total folate pool hasnot been accurately determined but liver folateis a major part of the total (45). Of 560 assayedlivers from autopsies in Canada (46), only twohad a folate content of < 3 �g/g (< 6.8 nmol/g) of liver. Morphologic evidence of folate de-ficiency is not manifest until liver levels fallbelow 1 �g/g (2.3 nmol/g)(47). The mean 1ev-els of folate in the autopsied livers peaked at

FOLATE REQUIREMENTS 663

8.8 �igJg (20 nmol/g) between the ages of 11and 20 and then gradually decreased.

The male adult’s total folate pool has beencalculated to be 7.5 ± 2.5 mg (17 ± 5.7 �zmol)(34,48-50). Studies of normal human subjects(34, 48, 50) and patients with neoplastic dis-ease (47) on low-folate diets containing <5�ig (11.3 nmol) of folate daily indicate that theearliest morphologic manifestations of defi-ciency in the red cells develop in ‘�‘ 16 wk.During a 6-wk observation period of a normalwoman in her mid-twenties on a no-folate diet(50), a daily oral supplement of 100 �g (227nmol) of PGA maintained the serum-folatelevels > 7 ng/mL (16 nmol/L), whereas with50 �ig (110 nmol) supplements in a secondsuch woman, they dropped to a diagnosticallyindeterminate range of 4-6.9 ng/mL (9.1-16nmol/L). At 25 �g (57 nmol), the serum folatelevels in a third woman dropped to <3ng/mL (6.8 nmol/L), clearly indicating nega-tive folate balance. Two alcoholic subjects withmarginal folate reserves developed signs of de-pletion in -�-8 wk (51) on a low-folate diet.Although some depleted subjects respond to50-pg oral supplements of PGA daily (52, 53),others with disease complications do not (54,55). Loss of folate from the liver on an intakeof 2 �g (4.5 nmol) folate daily, as assessed byliver biopsies (47), varies from 35 to 47 �g (79to 100 nmol) daily. Assuming that extrahe-patic stores are approximately half those inliver, total daily folate loss in an adult eatingessentially no folate would average -“60 �g(‘-“ 140 nmol). In such adults, morphologicevidence of folate deficiency in bone marrowand peripheral blood does not appear untilliver folate falls below 1 �ig/g (2.3 nmol/g)(47).

Human requirement and basis for RDI

Adults

The minimal daily requirement for folate is‘-50 �ig (--‘-1 pg/kg body weight) for adultsbased on observations that daily parenteraladministration of this amount successfullytreats uncomplicated folate-deficiency anemia(53, 56); however, Hoogstraten et al (57) andMarshall and Jandl (55) have reported thatmore complicated cases may fail to respondto such treatments. Approximately 85%(range, 50-94%) of a 10-200 ig (2.3-453nmol) oral dose of free PGA is absorbed (58-

61). Daily dietary folate intake correlates sig-nificantly with red cell folate (62).

Table 1 is a sequential list of events in thedevelopment of folate deficiency in personsconsuming an experimental diet containing<5 �tg(11 nmol) of folate daily (1, 2,4, 34,48, 63).

In Canada, the mean national daily folateintake for ages 12-65 yr is 205 �ig/d (465 nmol/d) for men and 149 �tg/d (338 nmol/d) forwomen (210, 221, and 183 �ig/d (476, 501,and 415 nmol/d) for males aged 12-19, 20-39, and 40-64, respectively, 153, 146, and 148�g/d (347, 331, and 335 nmol/d) for femalesaged 12-19, 20-39, and 40-64, respectively),or ‘-3 pg/kg (‘-‘-6.8 nmol/kg) body weight(64). This diet permits maintenance of normaland similar liver-folate levels (46, 65) in bothsexes (see Table 2). Forty adult males livingin a metabolic ward on a strictly controlleddiet containing 200±68 �g/d (66) maintainednormal serum and red cell folates; at the endof 6 mo, they had normal serum folates (5.8± 1.4 ng/mL or 13±3.2 nmol/L) and normal

TABLE 1Folate deficiency in persons consuming <5 �g (11nmol) folate daily

Sequential chanes

m� o(appcsi*n�

- aft�initiation o(diet)

Low serum folate (<3 ng/mL or 6.8nmolfL); slight increase in size ofaverage bone marrow normoblast 3

Hypersegmentation in neutrophils inbone marrow (lobe average> 3.5);

dU suppression test abnormal inbone marrow

Hypersegmentation in neutrophils;bone marrow shows increased andabnormal mitoses and basophilicintermediate megaloblasts; dUsuppression test abnormal inperipheral blood lymphocytes 7

Bone marrow shows some largemetamyelocytes and a number ofpolychromatophilic intermediatemegaloblasts 10

High urine formiminoglutamate(FIGLU) 13

Orthochromatic intermediatemegaloblasts in bone marrow 14

Low red blood cell folate 17Macroovalocytosis; many large

metamyelocytes in bone marrow 18Overtly megaloblastic marrow 19Anemia 20

664 HERBERT

TABLE 2Liver-folacinlevelsin relation to age and sex*

Charactetisticof subject n

Folate levels

Range Mean ± SD

iig/gliverf

Age (yr)Atbirtht 7 3.3-8.5 5.9± 1.7

0-1 18 3.8-11.3 7.4±2.01-10 13 4.3-10.5 7.4±2.1

11-20 19 6.0-14.0 8.8±2.221-30 32 3.6-14.8 8.0±2.831-40 32 3.6-11.5 7.7± 1.741-50 61 4.1-14.6 7.1 ±2.051-60 86 3.2-12.6 7.3± 1.961-70 128 3.2-15.6 7.7 ±2.271-80 117 2.9-14.7 6.9 ±2.180+ 47 2.7-12.7 7.0 ± 2.0

SexMale 370 2.7-15.9� 7.4 ± 2.2�Female 190 3.2-l4.0� 7.3 ± 2.9�* Based on data in Happner and Lampi (46).

t To convert to SI (nmol/g) multiply by 2.266.f Stillborn.§ Average at all ages.

red cell folates (229±44 ng/mL or 519± 100nmol/L).

Red cell folate reflects liver folate fairlyclosely (45,67,68); by a coincidence of nature,the red cell life-span is 4 mo and the liver-folate stores will last for 4 mo (67). Not morethan 8% of Canadian men and 10% of Cana-dian women have low folate stores as judgedby red cell concentrations < 140 ng folate/mL(317 nmol/L) (69). The N}IANES II data (70)for American men is also 8%, and for Amer-ican women 13%. Therefore, for ‘--90% of theadult population, Canadian and Americandiets provide not only adequate folate for dailymetabolic needs but also adequate folate tosustain a substantial folate storage (> 140 ngfolate/mL red cells) against periods of dietarydeprivation.

Tamura and Stokstad (personal commu-nication cited in ref 71) calculated the US di-etary folate intake as 227 zg (514 nmol) percapita daily. This estimate is likely to be highbecause they did not account for food wastageor nutrients lost in home food preparation(71). It is important to remember that heatdestroys folate. Earlier, higher estimates of av-erage folate intake in various countries werebased on older methodology; because theywere apparently in error, they need reevalua-tion (9, 62, 72).

Recognition that diets contain about half asmuch folate as previously believed and stillresult in liver stores > 3 ;ig/g (6.8 nmol/g)provides the basis forlowering the folate RDA(Table 3) below that stated in 1980. Becausefolate absorbability from an average NorthAmerican diet is adequate to sustain normalliver stores and the diet contains an averageof 3 �g folate/kg body weight (46, 64, 65), therecommended dietary intake (RDI) for folateis set at 3 jig/kg (6.8 nmol/g) body weight (asmeasured in a microbiological assay) for nor-mal nonpregnant, nonlactating adults and ad-olescents-that is, 240 �ig (544 nmol)(rounded) for a 79-kg reference man and 190,Lg (43 1 nmol) for a 62-kg reference woman.This allowance appears to provide an adequatemargin of safety for adequate storage in theliver against periods of negative folate balanceand is well above the ‘--50 �g/d (-- 110 nmol/d) minimal adult requirement (---1 gig/kg or‘--2.3 nmol/kg body weight) delineated above.

Pregnancy and lactation

The added burden of pregnancy increasesthe risk and incidence of folate deficiencyamong populations with low or marginal in-takes of the vitamin (73-75). The usual prob-lems of establishing folate requirements arefurther complicated by necessary safeguardsagainst the use of radioactive tracers and otherexperimental procedures in pregnant subjects.PGA supplements ranging from 100 to 1000�g/d (227-2266 nmol/d) have been recom-mended by different investigators in additionto the folate present in a mixed diet of goodquality (30, 76-78). The report of Baumsiaget al (79) was confirmed by data (80) indicatingthat an oral PGA supplement of 500 �g/d(1130 nmol/d) was associated with a 50% re-duction in the incidence of small-for-datebirths among 134 pregnant women in India.In women consuming a usual diet in theUnited Kingdom, a daily oral supplement of100 ig of PGA prevented any fall in the meanred cell folate during pregnancy (76). The di-etary folate content in that country was sub-sequently reported to be 190 �g/d (--431nmol/d) (9, 62, 81). All manifestations of fo-late deficiency in women who start pregnancywith moderate folate stores could probably beprevented by diets containing the equivalentof 299 �g PGA/d (678 nmol/d)(67). In women

TABLE 3Recommended dietary intakes (RDI) for folate

FOLATE REQUIREMENTS 665

RDI for referenceRDI indsvidual

MgWeight

kg

4.5

6.6

8.8

Infants 0-2.9 mo 16 pg�(36.26 nmol)

3-5.9 mo 24 �gt(54.38 nmol)

6-ll.9mo 32�tgt(72.51 nmol)

Children 1-1.9 yr 3.3,ug/kg 35(7.5 nmol/kg) (79 nmol)

2-5.9 yr 3.3�ig/kg 50(7.Snmol/kg) (110)

6-9.9 yr 3.3pgJkg 80(7.5 nmol/kg) (180)

Males ll-ll.9yr 3paJkg 110(6.8 nmol/kg) (249)

l2-l7.9yr 31sgJkg 170(6.8 nmol/kg) (385)

18-24.9 yr 3 �igJkg 220(6.8 nmol/kg) (499)

25-49.9 yr 3 pg/kg 240(6.8 nmol/kg) (544)

50-69.9 yr 3 pg/kg 230(6.8 nmol/kg) (521)

70+yr 3pg/kg 220(6.8 nmol/kg) (499)

Females 11-14.9 yr 3 pg/kg 130(6.8 nmol/kg) (295)

l5-17.9yr 3pg/kg 170(6.8 nmol/kg) (385)

18-24.9yr 3pgjkg 170(6.8 nmol/kg) (385)

25-49.9 yr 3 pg/kg 190(6.8 nmol/kg) (431)

50-69.9 yr 3 pg/kg 190(6.8 nmol/kg) (431)

70+yr 3pgJkg 190(6.8 nmol/kg) (431)

Pregnancy 0-2.9 mo 500 pg/d 500(Il3Onmol/d) (1130)

3-5.9 mo 500 pg/d 500(ll3Onmol/d) (1130)

6-9 mo 500 pg/d 500(ll30nmol/d) (1130)

Lactation 0-5.9 mo 3 pg/kg + 100 pg/d 280(6.8 nmol/kg + 227 nmol/d) (635)

6+mo 3pgJkg+loopg/d 280(6.8 nmol/kg + 227 nmol/d) (635)

* Values in this column are for a reference individual. Actual figures expressed per kilogram of body weight are 3.3

pg/kg (7.5 nmol/kg) for ages 1-9.9 and 3 pg/kg (6.8 nmol/kg) for males and nonpregnant nonlactating females ages10-70+. (Assumes reference lactating woman is 59 kg). SI (nmol) are given in parentheses.

t Human milk or 3.6 pg/kg (8.2 nmol/kg).

Catego� Age

666 HERBERT

with poor folate stores who received essentiallyno other dietary folate, the progression of fo-late deficiency was as effectively prevented byadministering 300 �g PGA/d (680 nmol/d) ina food that impaired availability by 44% (re-ducing effective dose to 168 Mg PGA/d or 381nmol/d) as it was by higher doses or more ef-ficient vehicles (30).

Oral supplementation or food fortificationappears desirable to maintain maternal stores(9, 30, 71, 73) and to keep pace with the in-creased folate turnover in rapidly growing tis-sue. On the basis of a 50% food-folate absorp-tion, the RDI for folate is set at 500 �g/d (1130nmol/d) during pregnancy (Table 3) with therecognition that this level cannot usually bemet without oral supplementation. This RDIis higher than needed for most pregnantwomen; it is intended to meet the needs ofthose with poor folate stores, essentially noother dietary folate, and multiple or twinpregnancies.

The burden of lactation on maternal folatereserves was estimated to be 20 �g/d (45 nmol/d) (82), varying with the folate content andvolume of milk. This estimate was based ondaily production of 850 mL of milk with anaverage folate content; however, content maybe as high as 50-60 �g folate/L (110-140nmol/L) (83). Ek (84) reported that supple-mentation was unnecessary in women in themiddle socioeconomic class in Sweden. On thebasis of a daily production of 750 mL of milkand 50% absorption of food folate, the allow-ance for folate during lactation is set at 3 pg/kg (6.8 nmol/kg) body weight plus 100 Mg/d(227 nmol/d) (Table 3).

Infants and children

Folacin deficiency is the most commoncause of megaloblastic anemia in infants andchildren (85, 86). Although serum folate atbirth is three times that of maternal folate,body stores at birth are small and are rapidlydepleted by the requirements for growth,especially in small premature infants whoseliver stores are --“ 159 Mg (360 nmol) (87). By2 wk of age, serum and red cell folate of new-borns fall below adult values and remain lowfor several months (83, 86-88). In a prematureinfant, an appropriate maintenance dose is 50-100 pg/d (100-227 nmol/d), which is adequateto prevent the folate deficiency that commonly

accompanies childhood hemolytic anemias(85). In full-term infants, liver stores are ---224

Mg (508 nmol) (89). In a study of 20 infantsaged 2-li mo, Asfour et al (90) demonstratedthe nutritional adequacy of diets providing 3.6

�g folate/kg (8.2 nmol) body weight daily for6- to 9-mo periods.

Human and cow’s milk both contain 50-

60 Mg free folate/L (110-140 nmol/L), al-though the concentration of folate in humancolostrum and early milk is much lower (83).Hoppner et al (91) reported that fresh cow’smilk contains 5 �g folate/lOO g(50 Mg/L). Theneeds of infants are adequately met by humanor cow’s milk, but not by goat’s milk, whichhas a much lower folate content (83, 85).

Heat sterilization of infant formulas maydestroy portions of the folate content, de-pending on the quantity of reducing agentadded to the formula to protect its folate con-tent against heat destruction. Milk from hu-mans, cows, and goats contains a factor thatis essentially unaffected by pasteurization andthat facilitates folate uptake by gut cells (92,93). Presumably, this factor facilitates bothabsorption of dietary folate and reabsorptionof bile folate. Boiling, or the preparation ofevaporated milk, destroys an average of 50%of the folate in cow’s milk (88) so that infantsreceiving boiled formulas prepared from pas-teurized, sterilized, or powdered cow’s milkshould be given additional folate to ensure anadequate intake (94). If the diet consists ofgoat’s milk, folic acid supplementation shouldbe given.

Megaloblastic anemia due to dietary folatedeficiency is rare in children who drink veg-etable or fruit juice or eat one fresh, uncookedfruit or vegetable each day (85). However, thisdisease is common among children whose en-tire diet consists of thoroughly cooked foods,especially finely particulate foods cooked fora long period (eg, diets consisting primarily ofbeans and rice). The cooking of beans not onlydestroys part of their folate content but alsocauses them to release a substance that mayreduce folate absorbability (95, 96). Up to age2 yr, 3.5 Mg (7.9 nmol) dietary folate/kg bodyweight appears to be adequate (61).

On the basis of the above considerations(82-91), the RDI for folate is set at 3.6�g’ kg’ . d’ (8.2 nmol kg’ ‘d�) for healthyoffspring from birth to age 1.9 yr. This value

FOLATE REQUIREMENTS 667

should provide an adequate margin of safetyand is compatible with the folate content ofhuman milk.

In Canadians, whose average diet contains

3 Mg folate/kg (6.8 nmol/kg) body weight, fo-late stores in the liver appear to be satisfactoryin children as well as in adults (46). The folateRDI for healthy children 2-9.9 yr of age isinterpolated from the allowances for infantsand adolescents to be 3.3 Mg/kg (7.5 Mmol/kg)body weight (Table 3).

The elderly

The elderly are considered in the same cat-egory as other adults with respect to folateneeds (97). On diets estimated to contain 135

�g folate/d, all of 21 elderly men and womenliving at home sustained red cell folate> 100ng/mL (> 227 nmol/L) and were hematolog-ically normal; nine had red cell folate < 150ng/mL (<340 nmol/L) (98).

Other data sources

Rodriguez (24) published an extensive re-view of human folate requirements that covers818 references. For further discussion, thereader is referred to the published proceedingsof a workshop held by the Food and NutritionBoard in 1975 (9), a technical report preparedfor the Food and Drug Administration by An-derson and Talbot (71), and a book by Chana-sin (45) that contains 4258 references.

Toxicity

Folic acid and the anticonvulsant drug phe-nytoin inhibit uptake of each other at the gutcell wall and possibly at the brain cell wall (45,72). Very large doses of folic acid (100 or moretimes the RDA) may precipitate convulsionsin persons whose epilepsy is in continuouscontrol by phenytoin (72). As little as 1 mg ofintravenous POA produced an abnormal EEGin an adult with phenobarbitol-controlled epi-lepsy (99). In experimental animals, very largedoses of folic acid given parenterally may pre-cipitate in the kidneys, producing kidneydamage and hypertrophy (72). Although frag-ile chromosomes are associated with folatedeficiency, it does not necessarily follow thatexcesses of folate protect against malignancy.In fact, large excesses may promote the growthof certain tumors (100).

In January 1987 it was reported that “preg-nancy supplements” containing 100 mg (1.79mmol) iron and 350 Mg (0.79 Mmol) folate sig-nificantly reduce zinc absorption, as do ironalone and folate alone, and may promote ma-ternal zinc depletion, resulting in intrauterinegrowth retardation (101). This adverse nu-trient-nutrient interaction from widely usedpregnancy supplements provides further sup-port for the recommended reduction by the1980-1985 RDA Committee of the size ofsupplemental dietary intakes. With respect toiron, the Committee in its draft report rec-ommended only a 10 mg (180 Mmol) iron sup-plement in pregnancy, but raised it to 30 mg(540 Mmol) on the strong recommendation ofthe draft’s reviewers (102).

I thank the other members of, and all the consultantsto, the 1980-1985 RDA Committee (“Kamin Commit-tee”) for their input into this review. The history of thecommittee is delineated in Nutrition Today 1985;20(6):4-23.

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2. Herbert V. Biology of disease: megaloblastic anemias.Lab Invest 1985;52:3-19.

3. O’Broin JD, Temperley U, Brown JP, Scott JM. Nu-tritional stability of various naturally occuringmonoglutamate derivatives of folic acid. Am J ClinNutr l975�,28:438-44.

4. Herbert V. Folate status and folate requirement In:Proceedings of the Xffl International Congress ofNutrition. Brighton, Great Britain, 18-23 August1985. London: John Libbey and Co, Ltd. 1986.

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9. National Researeh Council. Folic acid. biochemistryand physiology in relation to the human nutritionrequirement Proceedings of a workshop on humanfolate requirements, June 2-3, 1975. WashingtonDC: Food and Nutrition Board, National Academyof Sciences, 1977.

10. Streifl’R. Folate levels in citrus and other juices. AmJ Clin Nutr l971�,24:l390-2.

668 HERBERT

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16. Phillips DR, Wright AJA. Studies on the responseof L casei to different folate monoglutainates. Br JNutr 1982;47:183-4.

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