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394

10Manganese

SUMMARY

Manganese is involved in the formation of bone and in aminoacid, lipid, and carbohydrate metabolism. There were insufficientdata to set an Estimated Average Requirement (EAR) for manga-nese. An Adequate Intake (AI) was set based on median intakesreported from the Food and Drug Administration Total Diet Study.The AI for adult men and women is 2.3 and 1.8 mg/day, respectively.A Tolerable Upper Intake Level (UL) of 11 mg/day was set foradults based on a no-observed-adverse-effect level for Western diets.

BACKGROUND INFORMATION

Function

Manganese is an essential nutrient involved in the formation ofbone and in amino acid, cholesterol, and carbohydrate metabolism.Manganese metalloenzymes include arginase, glutamine synthetase,phosphoenolpyruvate decarboxylase, and manganese superoxidedismutase. Glycosyltransferases and xylosyltransferases, which areimportant in proteoglycan synthesis and thus bone formation, aresensitive to manganese status in animals. Several other manganese-activated enzymes, including pyruvate carboxylase, can also be acti-vated by other ions, such as magnesium.

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Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc http://www.nap.edu/catalog/10026.html

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MANGANESE 395

Physiology of Absorption, Metabolism, and Excretion

Only a small percentage of dietary manganese is absorbed.Absorbed manganese is excreted very rapidly into the gut via bile(Britton and Cotzias, 1966; Davis et al., 1993). Most estimates ofabsorption have been based on whole body retention curves atapproximately 10 to 20 days after dosing with 54Mn. Using thismethod, Finley and coworkers (1994) estimated absorption from atest meal containing 1 mg manganese to be 1.35 ± 0.51 percent(standard deviation [SD]) for men and 3.55 ± 2.11 percent (SD) forwomen. From a test meal containing 0.3 to 0.34 mg of manganese,Davidsson and coworkers (1988) found the retention of 54Mn to be5.0 ± 3.1 percent (SD) 10 days after administration to young adultwomen. Turnover of orally administered 54Mn was much more rapidafter oral administration than after intravenous administration(Davidsson et al., 1989b; Sandstrom et al., 1986). Furthermore,absorption of manganese after 30 weeks of supplementation was 30to 50 percent lower than had been observed in nonsupplementedsubjects (Sandstrom et al., 1990). Some studies indicate that man-ganese is absorbed through an active transport mechanism (Garcia-Aranda et al., 1983), but passive diffusion has been suggested onthe basis of studies indicating that manganese absorption occurs bya nonsaturable process (Bell et al., 1989).

Manganese is taken up from the blood by the liver and transportedto extrahepatic tissues by transferrin (Davidsson et al., 1989c) andpossibly α2-macroglobulin (Rabin et al., 1993) and albumin (Davis etal., 1992). Manganese inhibited iron absorption, both from a solu-tion and from a hamburger meal (Rossander-Hulten et al., 1991).54Mn has a longer half-life in men than in women (Finley et al.,1994). A significant negative association between manganeseabsorption and plasma ferritin concentrations has recently beenreported (Finley, 1999). Serum ferritin concentrations differ in menand women (Appendix Table G-3); therefore, a major factor inestablishing manganese requirements may be gender.

Manganese is excreted primarily in feces. Urinary excretion ofmanganese is low and has not been found to be sensitive to dietarymanganese intake (Davis and Greger, 1992). Urinary excretion in abalance study of five healthy men varied from 0.04 to 0.14 percentof their intake, and absolute amounts in the urine decreased dur-ing the depletion phases of the study (Freeland-Graves et al., 1988).Therefore, potential risk for manganese toxicity is highest whenbile excretion is low, such as in the neonate or in liver disease(Hauser et al., 1994). Plasma manganese concentrations can be-




396 DIETARY REFERENCE INTAKES

come elevated in infants with choleostatic liver disease given sup-plemental manganese in total parenteral nutrition solutions (Kelly,1998). It is not certain at what age human infants can maintainmanganese homeostasis. Neonatal mice were unable to maintainmanganese homeostasis until 17 to 18 days of age (Fechter, 1999).

Clinical Effects of Inadequate Intake

Manganese deficiency has been observed in various species ofanimals with the signs of deficiency, including impaired growth,impaired reproductive function, impaired glucose tolerance, andalterations in carbohydrate and lipid metabolism. Furthermore,manganese deficiency interferes with normal skeletal developmentin various animal species (Freeland-Graves, 1994; Hurley and Keen,1987; Keen et al., 1994). Although a manganese deficiency maycontribute to one or more clinical symptoms, a clinical deficiencyhas not been clearly associated with poor dietary intakes of healthyindividuals. One man was depleted of vitamin K and inadvertentlyof manganese when fed a diet containing only 0.34 mg/day of man-ganese for 6.5 months. Symptoms included hypocholesterolemia,scaly dermatitis, hair depigmentation, and reduced vitamin K-dependent clotting proteins. Symptoms were not reversed with vita-min K supplementation but gradually disappeared after the studyended (Doisy, 1973).

In a manganese depletion study, seven young men were fed apurified diet containing 0.01 mg/day of manganese for 10 days and0.11 mg/day of manganese for 30 days after a 3-week baseline periodwhen they consumed 2.59 mg/day (Friedman et al., 1987). After 35days, five of the seven subjects developed a finely scaling, minimallyerythematous rash that primarily covered the upper torso and wasdiagnosed as Miliaria crystallina. After two days of repletion, theblisters disappeared and the affected areas became scaly and thencleared. Plasma cholesterol concentrations declined during the deple-tion period, perhaps because manganese is required at several sitesin the biosynthetic pathway of cholesterol (Krishna et al., 1966).

Decreased plasma manganese concentrations have been reportedin osteoporotic women. Furthermore, bone mineral density was im-proved when trace minerals, including manganese, were includedwith calcium in their diets or supplements (Freeland-Graves andTurnlund, 1996; Strause and Saltman, 1987; Strause et al., 1986, 1987).

Penland and Johnson (1993) reported that diets containing only1 mg/day of manganese altered mood and increased pain duringthe premenstrual phase of the estrous cycle in young women.




MANGANESE 397

SELECTION OF INDICATORS FOR ESTIMATING THEREQUIREMENT FOR MANGANESE

Balance and Depletion Studies

Interindividual variations in manganese retention can be large(Davidsson et al., 1989b). Ten days after giving 54Mn in an infantformula to 14 healthy men and women, manganese retentionranged from 0.6 to 9.2 percent. Mean retention in these subjectswas 2.9 ± 1.8 percent (standard deviation [SD]). Intraindividualvariation was not as large, and retention values of 2.3 ± 1.1, 3.3 ± 3.1,and 2.4 ± 1.4 percent (SD) were observed for three repeated dosesin six subjects (Davidsson et al., 1989b).

In one study, seven healthy men, aged 19 to 22 years, were fed apurified low-protein diet containing 0.01 mg/day of manganese fordays 1 to 10, followed by a protein-adequate diet containing 0.11mg/day of manganese until day 39. Using a factorial method, theauthors estimated that the minimum requirement for manganesewas 0.74 mg/day and estimated on the basis of the percentage ofmanganese retention that 2.11 mg/day would be required (Friedmanet al., 1987). Subsequently, five young men were fed a diet of ordinaryfoods (1.21 mg/day of manganese) supplemented with manganesesulfate or placebo at the evening meal to create five different levelsof manganese intake (Freeland-Graves et al., 1988). Total manga-nese intakes were 2.89 mg/day for days 1 to 21, 2.06 mg/day fordays 22 to 42, 1.21 mg/day for days 43 to 80, 3.79 mg/day for days81 to 91 (repletion), and 2.65 mg/day for days 92 to 105. The meanmanganese balances for the corresponding days were 0.083, -0.018,-0.088, +0.657, and +0.0136 mg/day, respectively.

An 8-week balance study conducted by Hunt and coworkers(1998) showed that women, aged 20 to 42 years, were in slightlypositive mean balance when consuming 2.5 mg/day of manganese.

Some adolescent girls were observed to be in negative or slightlypositive balance when consuming 3 mg/day of manganese (Gregeret al., 1978a, 1978b).

Balance studies are problematic for investigation of manganeserequirement because of the rapid excretion of manganese into bileand because manganese balances during short- and moderate-termstudies do not appear to be proportional to manganese intakes(Greger, 1998, 1999). For these reasons, a number of studies haveachieved balance over a wide range of manganese intakes (Table10-1). Therefore, balance data were not used for estimating an aver-age requirement for manganese.





TABLE 10-1 Manganese Balance Studies in Adults

BalanceData

Reference Study Group Duration Diet (mg/d) (mg/d)

McLeod and 4 women, 27 d 2.78 0.32Robinson, 1972 19–22 y

Spencer et al., 9 men, 18–24 d 2.23 –0.281979 41–63 y

Johnson et al., 8 men, 40 d 3.28 –10 to –211982 21–28 y

Patterson et al., 28 men and 7d 2.8 –0.161984 women, 3.0 –0.16

20–53 y 2.9 –0.213.2 –0.12

Behall et al., 11 men, 4 wk 5.5 –0.41987 23–62 y

Friedman et al., 7 men, 39 d 0.11 –0.021987 29–22 y 5 d 1.53 0.84

5 d 2.55 1.02

Hallfrisch et al., 20 men, 1 wk 5.35 1.651987 23–56 y duplicate

19 women, food 6.14 3.1921–48 y record

Freeland-Graves 5 young 21 d 2.89 0.083et al., 1988 men 20 d 2.06 0.018

37 d 1.21 –0.08810 d 3.79 0.65713 d 2.65 0.0136

Holbrook et al., 19 men, 7 wk 2.4 to 2.9 –0.6 to 0.41989 21–57 y

Johnson and 14 women, 39 d 5.66 0.1Lykken, 1991 27 y 5.52 0.3

0.95 –0.010.94 0.060.16 0.46

continued




MANGANESE 399

Serum and Plasma Manganese Concentration

Several studies reported that serum or plasma manganese con-centrations respond to dietary intake. Serum manganese concentra-tion of women consuming 1.7 mg/day of manganese was lower thanthat of women ingesting 15 mg/day of supplemental manganesefor more than 20 days (Davis and Greger, 1992). In a depletion trial(Freeland-Graves and Turnlund, 1996), plasma manganese concen-tration was 1.28 µg/L at baseline. Concentrations were significantlylower during the second (0.95 µg/L) and third (0.80 µg/L) dietaryperiods with manganese intakes of 2.06 and 1.21 mg/day, respec-tively. Values increased significantly to 1.11 ± 0.35 µg/L when thediet was repleted with 3.8 mg/day of manganese. During the finaldietary periods, manganese intake was 2.65 mg/day, and plasmamanganese concentration was 0.97 ± 0.33 µg/L. Plasma manganeseconcentration was not significantly correlated with manganese in-take levels.

In a study in which 10 men consumed 0.52 to 5.33 mg/day ofmanganese, serum manganese concentration did not respond tovaried dietary intakes (Greger et al., 1990). Individual serum man-ganese concentrations varied from 0.4 to 2.12 µg/L with an averageof 1.04 µg/L. However, serum manganese concentrations of four offive subjects who consumed 15 mg of chelated manganese as a

TABLE 10-1 Continued

BalanceData

Reference Study Group Duration Diet (mg/d) (mg/d)

Ivaturi and 24 men and 14 d 3.21 0.3Kies, 1992 women 3.92 0.3

3.13 –0.22.64 0.233.13 0.513.15 0.32

Finley et al., 20 men and 14 d 5.43 (men) 0.271994 20 women, 4.01 (women) –0.12

18–40 y

Hunt et al., 21 women, 8 wk 2.5 (non- 0.11998 20–42 y vegetarian)

5.9 (lacto-ovo- 0.6vegetarian)





dietary supplement for 5 days were 27 nmol/L (1.48 µg/L), whereasunsupplemented control subjects had a mean serum concentrationof 20 nmol/L (1.1 µg/L).

Serum or plasma manganese concentrations appear to be some-what sensitive to large variations in manganese intake, but longerstudies are needed to evaluate the usefulness of serum manganeseconcentrations as indicators of manganese status.

Blood Manganese Concentration

An advantage of whole blood manganese concentration overplasma or serum manganese concentration as an indicator is thatslight hemolysis of samples can markedly increase plasma or serummanganese concentrations. Whole blood manganese seems to beextremely variable, however, which may preclude it as a viable statusindicator. In a manganese depletion study, manganese concentra-tion in whole blood was 9.57 µg/L (range 5.40 to 17.1) at the end ofthe baseline period and 6.01 µg/L (4.43 to 7.57) at the end of the39-day depletion period, but there was not a significant differencebetween these values (Friedman et al., 1987). With 10 days of man-ganese repletion, whole blood manganese concentration increasedto 6.99 µg/L (3.93 to 18.3).

Urinary Manganese

Urinary manganese is responsive to severe manganese depletion.After a patient spent 7 days on a depletion diet containing 0.11 mg/day of manganese, the patient’s urinary manganese excretion sig-nificantly decreased from 8.64 to 2.45 µg/day, and it continued todecrease to as low as 0.39 µg/day after 35 days (Friedman et al.,1987). In a second manganese depletion trial, urinary manganesedecreased significantly as manganese intake decreased from 2.9 to2.1 to 1.2 mg/day (Freeland-Graves et al., 1988). After repletionwith 3.8 mg/day, urinary manganese excretion increased then de-creased following an intake of 2.65 mg/day.

In contrast to the above findings, when ten men consumed 0.52to 5.33 mg/day, urinary excretion of manganese did not correspondwith manganese intake (Greger et al., 1990). Urinary losses ofmanganese averaged 0.38 µg/g creatinine. Also, Davis and Greger(1992) could not demonstrate that women given 15 mg/day of man-ganese during a 125-day supplementation period excreted moremanganese in urine than women consuming 1.7 mg/day in food.Thus, there is controversy on the use of urinary manganese for




MANGANESE 401

assessment of status when typical amounts of manganese areconsumed.

Arginase Activity

Arginase is depressed in the livers of manganese-deficient rats(Paynter, 1980). Brock and coworkers (1994) noted that manganese-deficient rats also had depressed plasma urea and elevated plasmaammonia concentrations. Arginase is affected by a variety of factors,however, including high protein diet and liver disease (Morris, 1992).

Manganese-Superoxide Dismutase Activity

Manganese-deficient animals have low manganese-superoxide dis-mutase (MnSOD) activity (Davis et al., 1992; Malecki et al., 1994;Zidenberg-Cherr et al., 1983). Davis and Greger (1992) demonstratedthat lymphocyte MnSOD activity was elevated in 47 women supple-mented with 15 mg/day of manganese for more than 90 days. How-ever, other factors like ethanol (Dreosti et al., 1982) and dietarypolyunsaturated fatty acids (Davis et al., 1990) may affect MnSODactivity. A fairly large blood sample is required to measure lympho-cyte MnSOD.

FACTORS AFFECTING THE MANGANESE REQUIREMENT

Bioavailability

Prior intakes of manganese and of other elements, such as cal-cium, iron, and phosphorus, have been found by some investigatorsto affect manganese retention (Freeland-Graves and Lin, 1991;Greger, 1998; Lutz et al., 1993). Adding calcium to human milksignificantly reduced the absorption of 54Mn from 4.9 to 3.0 per-cent (Davidsson et al., 1991). Low ferritin concentrations are associ-ated with increased manganese absorption, therefore having agender effect on manganese bioavailability (Finley, 1999).

Sandstrom and coworkers (1990) gave a multimineral supplementthat included 18 mg of iron, 15 mg of zinc, and 2.5 mg of manga-nese for a minimum of 30 weeks. Neither whole blood manganeseconcentration nor superoxide dismutase activity was increased sig-nificantly from baseline with supplementation. Seven healthy vol-unteers subsequently consumed a tracer dose containing 54Mn, 75Se,and 65Zn. Manganese absorption was only 1 percent of the oraldose. Sandstrom and coworkers (1987) reported a higher rate of





absorption from this dose in subjects without prior consumption ofa supplement, but high interindividual variability of manganeseabsorption and other potential confounders would require a studyspecifically designed to test the effect of prior supplementation on54Mn absorption.

Davidsson and coworkers (1995) administered 54Mn in either asoy-based infant formula or a similar dephytinized formula to eightmen and women. The geometric mean manganese absorption was0.7 percent for the native formula and 1.6 percent for thedephytinized formula. Therefore, the presence of phytate reducedthe efficiency of absorption of manganese.

Johnson and colleagues (1991) reported that manganese absorp-tion did not significantly differ between plant foods that wereextrinsically or intrinsically labeled with 54MnCl2. Absorption of54Mn from a meal, extrinsically labeled with 54MnCl2, was signifi-cantly higher (8.9 percent) than the absorption of 54Mn fromlettuce (5.2 percent), spinach (3.8 percent), wheat (2.2 percent),or sunflower seeds (1.7 percent). Absorption of 54MnCl2 did notdiffer whether the dose was 0.53 or 1.24 mg (7 to 10 percent).

Gender

Finley and coworkers (1994) reported that men absorbed signifi-cantly less manganese than women and that this difference may berelated to iron status. A subsequent study specifically demonstratedthat high ferritin concentrations were associated with reduced 54Mnabsorption (Finley, 1999). Serum ferritin concentrations are higherin men (Appendix Table G-3) and therefore may affect, in part, thelower bioavailability of manganese observed in men.

FINDINGS BY LIFE STAGE AND GENDER GROUP

Infants Ages 0 through 12 Months

Method Used to Set the Adequate Intake

No functional criteria of manganese status have been demonstratedthat reflect response to dietary intake in infants. Thus, recommendedintakes of manganese are based on an Adequate Intake (AI) thatreflects the observed mean manganese intake of infants principallyfed human milk.




MANGANESE 403

Ages 0 through 6 Months. On the basis of the method described inChapter 2 and the manganese concentration of milk produced bywell-nourished mothers, the AI reflects the observed mean manga-nese intake of infants exclusively fed human milk during their first6 months. There are no reports of full-term infants exclusively andfreely fed human milk by U.S. or Canadian mothers who manifestedany signs of manganese deficiency (Davidsson et al., 1989a). Meanmanganese concentrations of human milk at 1 month were approx-imately 4.0 µg/L (Aquilio et al., 1996; Casey et al., 1985, 1989) anddeclined to 1.87 µg/L by 3 months postpartum (Casey et al., 1989)(Table 10-2). Total manganese secretion in human milk averaged1.9 µg/day over the first 3 months and 1.6 µg/day over the second 3months (Casey et al., 1989). Based on the above data, the AI is setaccording to average milk volume consumption (0.78 L/day) × theaverage manganese concentration in human milk (3.5 µg/L), or 3µg/day, after rounding (see Chapter 2).

TABLE 10-2 Manganese Concentration in Human Milk

EstimatedMilk Manganese

Stage of Concentration Intake ofReference Study Group Lactation (µg/L) Infants (µg/d)a

Stastny et al., 24 women 4 wk 6.6 5.21984 8 wk 4.8 3.7

12 wk 3.5 2.7

Casey et al., 11 women, 8 d 3.7 2.91985 26–39 y 14 d 3.8 2.9

21 d 3.2 2.528 d 4.1 3.2

Casey et al., 22 women 1 mo 3.5 2.71989 3 mo 1.87 1.5

Anderson, 10 women Up to 6.97 5.41992 5 mo

Aquilio et al., 14 women 2–6 d 3.9 3.01996 12–16 d 3.9 3.0

21 d 4.1 3.2

NOTE: Maternal intakes were not reported in these studies.a Manganese intake based on reported data or concentration (µg/L) × 0.78 L/day.





Ages 7 through 12 Months. With the introduction of complementaryfoods, it has been estimated that the average consumption of man-ganese by 6- and 12-month-old infants is 71 and 80 µg/kg, respec-tively (Gibson and De Wolfe, 1980). Based on reference weights of7 and 9 kg for these two ages, the total manganese intake would be500 and 720 µg/day.

Using the reference body weight method described in Chapter 2to extrapolate from adults, the average intake is 567 µg/day. Basedon these two approaches, the AI is set at 600 µg/day for olderinfants. The AI for older infants is markedly greater than the AI foryounger infants because the concentration of manganese is higherin foods than in human milk.

Manganese AI Summary, Ages 0 through 12 Months

AI for Infants0–6 months 0.003 mg/day (3 µg/day) of manganese7–12 months 0.6 mg/day of manganese

Special Considerations

The manganese concentration in cow milk has been reported torange from 20 to 50 µg/L (Lonnerdal et al., 1981), which is signifi-cantly greater than the concentration in human milk (Table 10-2).Manganese is partly present in the fat globule membrane in cowmilk (Murthy, 1974). Davidsson and coworkers (1989a) reportedthat the fractional manganese absorption from human milk (8.2percent) was higher than from soy formula (0.7 percent) and whey-preponderant cow’s milk formula (3.1 percent).

Children and Adolescents Ages 1 through 18 Years


Ages 1 through 3 Years. There are insufficient data to set an EstimatedAverage Requirement (EAR) for manganese for children ages 1through 3 years. Therefore, median intake data were used to set theAI. Data from the Food and Drug Administration Total Diet Studyindicate a median intake of 1.22 mg/day of manganese for childrenaged 1 through 3 years (Appendix Table E-6).

Ages 4 through 13 Years. There have been a few manganese balancestudies with children and all are subject to the caveats previously




MANGANESE 405

discussed. Therefore, they were not considered in setting an EAR.The Total Diet Study indicates a median intake of 1.48 mg/day forchildren aged 4 through 8 years. Median intakes for girls and boys,ages 9 through 13 years, were 1.57 and 1.91 mg/day, respectively(Appendix Table E-6).

Ages 14 through 18 Years. A few studies have been conducted toassess the manganese requirement in adolescent girls. Adolescentgirls were observed to be in negative (Greger et al., 1978a) or slightpositive balance (Greger et al., 1978b) when consuming 3 mg/dayof manganese. These varied findings in adolescent girls may be dueto a variation in iron status given that a significant negative associa-tion between manganese absorption and plasma ferritin concentra-tions has been reported recently (Finley, 1999). Because of thelimitations of balance data, as previously discussed, these data werenot used to set the EAR.

The Total Diet Study indicates that the median manganese intakefor adolescent girls and boys was 1.55 and 2.17 mg/day, respectively(Appendix Table E-6). Because clear associations between low man-ganese intake and clinical symptoms of a manganese deficiency havenot been observed, the AI is based on median intakes for each ofthe age groups.

Manganese AI Summary, Ages 1 through 18 Years

AI for Children1–3 years 1.2 mg/day of manganese4–8 years 1.5 mg/day of manganese

AI for Boys 9–13 years 1.9 mg/day of manganese

14–18 years 2.2 mg/day of manganese

AI for Girls 9–13 years 1.6 mg/day of manganese

14–18 years 1.6 mg/day of manganese

Adults Ages 19 Years and Older


Because a wide range of manganese intakes can result in manga-nese balance, balance data could not be used to set an EAR. Several





balance studies have collectively concluded that manganese balancecan be achieved at around 2.1 to 2.5 mg/day (Freeland-Graves etal., 1988; Friedman et al., 1987; Hunt et al., 1998). Based on acoefficient of variation of 10 percent, balance data would yield aRecommended Dietary Allowance (RDA) of 2.5 to 3 mg/day. Basedon the Total Diet Study (Appendix Table E-6), the median manga-nese intake for men was 2.1 to 2.3 mg/day, and the median intakefor women was 1.6 to 1.8 mg/day. Because overt symptoms of amanganese deficiency are not apparent in North America, an RDAbased on balance data most likely overestimates the requirementfor most North American individuals. Therefore, intake data areused to set an AI for manganese. Because dietary intake assessmentmethods tend to underestimate the actual daily intake of foods, thehighest intake value reported for the four adult age groups wasused to set the AI for each gender.

Manganese AI Summary, Ages 19 Years and Older

AI for Men19–30 years 2.3 mg/day of manganese31–50 years 2.3 mg/day of manganese51–70 years 2.3 mg/day of manganese

> 70 years 2.3 mg/day of manganese

AI for Women19–30 years 1.8 mg/day of manganese31–50 years 1.8 mg/day of manganese51–70 years 1.8 mg/day of manganese

> 70 years 1.8 mg/day of manganese

Pregnancy


There are limited data, such as fetal manganese concentration,on which to base an EAR specific to pregnancy. Casey and Robinson(1978) reported that manganese concentrations in fetal tissuesranged from 0.35 to 9.27 µg/g dry weight. In animals, manganesedeficiency in utero produces ataxia and impaired otolith develop-ment, but these defects have not been reported in humans.

The additional manganese requirement during pregnancy isdetermined by extrapolating up from adolescent girls and adultwomen as described in Chapter 2. Carmichael and coworkers (1997)




MANGANESE 407

reported that the median weight gain of 7,002 women who hadgood pregnancy outcomes was 16 kg. No consistent relationshipbetween maternal age and weight gain was observed in six studies ofU.S. women (IOM, 1990). Therefore, 16 kg is added to the refer-ence weight for adolescent girls and adult women for extrapolation.The AI for pregnant adolescent girls and women is 2 mg/day afterrounding. This value is similar to dietary manganese intake dataobtained from the Total Diet Study (Appendix Table E-6).

Manganese AI Summary, Pregnancy

AI for Pregnancy14–18 years 2 mg/day of manganese19–30 years 2 mg/day of manganese31–50 years 2 mg/day of manganese

Lactation


There are no data available that directly assess the manganeserequirement in lactating women. Approximately 3 µg/day of man-ganese is secreted in human milk. Even though the requirementduring lactation does not appear to be greater than the require-ment for nonlactating women, the median intake of 2.56 mg/day ofmanganese is greater during lactation (Appendix Table E-6). Be-cause a manganese deficiency has not been observed in NorthAmerican lactating women, the AI is based on the median intakeand rounding to 2.6 mg/day.

Manganese AI Summary, Lactation

AI for Lactation14–18 years 2.6 mg/day of manganese19–30 years 2.6 mg/day of manganese31–50 years 2.6 mg/day of manganese

INTAKE OF MANGANESE

Food Sources

Based on the Total Diet Study, grain products contributed 37percent of dietary manganese, while beverages (tea) and vegetables





contributed 20 and 18 percent, respectively, to the adult male diet(Pennington and Young, 1991).

Dietary Intake

Patterson and coworkers (1984) analyzed manganese intakes for7 days during each of the four seasons for 28 healthy adults living athome. The mean nutrient density for all subjects was 1.6 mg/1,000kcal. Mean manganese intake for men was 3.4 mg/day and for wom-en, 2.7 mg/day. Greger and coworkers (1990) analyzed duplicateportions of all foods and beverages consumed for ten men. Withunrestricted diets, the mean manganese intake was 2.8 mg/day.Daily intakes of manganese throughout the study varied from 0.52to 5.33 mg/day. Based on the Total Diet Study (Appendix TableE-6), median intakes for women and men ranged from 1.6 to 2.3mg/day. In various surveys, average manganese intakes of adultseating Western-type and vegetarian diets ranged from 0.7 to 10.9mg/day (Freeland-Graves, 1994; Gibson, 1994).

Intake from Supplements

Approximately 12 percent of the adult U.S. population consumedsupplements containing manganese in 1986 (Moss et al., 1989; Table2-2). Based on the Third National Health and Nutrition Examina-tion Survey data, the median supplemental intake of manganese byadults who take supplements was approximately 2.4 mg/day, anamount similar to the dietary intake of manganese (Appendix TableC-20).

TOLERABLE UPPER INTAKE LEVELS

The Tolerable Upper Intake Level (UL) is the highest level ofdaily nutrient intake that is likely to pose no risk of adverse healtheffects in almost all individuals. Although members of the generalpopulation should be advised not to exceed the UL routinely, in-take above the UL may be appropriate for investigation within well-controlled clinical trials. Clinical trials of doses above the UL shouldnot be discouraged, as long as subjects participating in these trialshave signed informed consent documents regarding possible toxic-ity and as long as these trials employ appropriate safety monitoringof trial subjects. In addition, the UL is not meant to apply to indi-viduals who are receiving manganese under medical supervision.




MANGANESE 409

Hazard Identification

Adverse Effects

Manganese toxicity in humans is a well-recognized occupationalhazard for people who inhale manganese dust. The most promi-nent effect is central nervous system pathology, especially in theextra-pyramidal motor system. The lesions and symptoms are simi-lar to those of Parkinson’s disease (Barceloux, 1999; Keen et al.,1994). Manganese is probably transported into the brain via trans-ferrin (Aschner et al., 1999). These authors hypothesize that thegreater vulnerability of the extrapyramidal system (globus pallidusand substantia nigra) for manganese accumulation could be due tothe fact that these are areas that are efferent to areas of high trans-ferrin receptor density. These same efferent areas are also regionsof high iron content.

Neurotoxicity of orally ingested manganese at relatively low dosesis more controversial. However, several lines of evidence suggestthis possibility. The data on manganese neurotoxicity are reviewedbelow.

Elevated Blood Manganese and Neurotoxicity. People with chronic liverdisease have neurological pathology and behavioral signs of manga-nese neurotoxicity, probably because elimination of manganese inbile is impaired (Butterworth et al., 1995; Hauser et al., 1994; Spahret al., 1996). This impairment results in higher circulating concen-trations of manganese, which then has access to the brain via trans-ferrin. Hauser and coworkers (1994) reported whole blood manga-nese concentrations of 18.8 to 45 µg/L in three patients withchronic liver disease, as compared to a normal range of 4.2 to 14.3µg/L. Spahr and coworkers (1996) reported blood manganese con-centrations of 124.7 nmol/L (6.85 µg/L) in control subjects versus331.4 nmol/L (18.2 µg/L) in patients with cirrhosis. High concen-trations of circulating manganese as a result of total parenteralnutrition have also been associated with manganese toxicity (Keenet al., 1999). Davis and Greger (1992) reported that women whoingested 15 mg/day of supplemental manganese had serum manga-nese concentrations that increased gradually throughout the 125-day study; significant differences were reported after 25 days of sup-plementation.

Neurotoxicity in Laboratory Animals. High subchronic or chronicdoses of manganese given to animals in food or water result in





central nervous system pathology and behavioral changes, althoughthese changes are not necessarily identical to those seen in humans.A review by Newland (1999) suggests that manganese toxicity occursat progressively lower doses when manganese is administered infood, in water, or by injection, respectively. Differences in toxicpotency by route of administration may be an order of magnitudeor more. The lowest dose study of manganese administered in foodidentified by Newland (1999) was by Komura and Sakamoto (1992).They fed male mice diets high in manganese (2 g/kg food) for 12months (either as MnCl2, manganese acetate, MnCO3, or MnO2).Thus, a 30-gram mouse eating 4 g/day of food would have ingestedabout 266 mg/kg/day of manganese. Changes in brain regionalbiogenic amines and decreases in locomotor activity were observed,but changes were somewhat different for each salt. In general, man-ganese dioxide was found to be more toxic than other forms, andmanganese chloride was least toxic.

Several studies have examined neurotoxic effects of manganesein drinking water or administered by gavage. The two lowest dosestudies are reviewed here. Bonilla (1984) gave male rats 0.1 or 5.0mg/mL of manganese in drinking water for 8 months and mea-sured locomotor activity throughout this period. A significant in-crease in activity during the first month was found at both doses.Activity returned to normal for months 2 through 6, but in theseventh and eighth months, activity was less than that of controlsubjects in both groups. In a related study, Bonilla and Prasad (1984)gave rats 0.1 or 1.0 mg/L of manganese in drinking water for 8months. They observed decreases of norepinephrine in striatumand pons of rats treated with the lower dose. Increases in the dopaminemetabolite dihydroxyphenylacetic acid were found in striatum andhypothalamus at both doses. Homovanillic acid (another dopaminemetabolite) decreased in striatum of the lower dose group. Changesin serotonin and its metabolite, 5-hydroxyindole acetic acid, wereseen in some brain regions in the high dose group. As with theKomura and Sakamoto (1992) study, the actual doses of manganesein this study can only be approximated. Assuming that a 300 g ratingests about 30 mL/day of water, then the daily dose of manga-nese in this study was about 10 mg/kg/day.

Senturk and Oner (1996) exposed rats to 0.357 to 0.714 mg/kg/day of manganese (as MnCl2) by gavage in distilled water for 39days. Manganese levels in brain regions were elevated, and learningin a T-maze task was retarded. The learning impairment was asso-ciated with hypercholesterolemia, and the impairment was not seen




MANGANESE 411

when rats were co-administered mevilonin (a cholesterol biosynthesisinhibitor). The doses used in this study were very low.

While no animal data exist showing that the neonate exhibitsneurotoxic effects at lower doses of manganese than do adults,effects could be more severe in the developing brain. Pappas andcolleagues (1997) exposed dams and litters to 2 or 10 mg/mL ofmanganese (as MnCl2) in drinking water from conception untilpostnatal day 20. Thinning of the cerebral cortex was observed inneonates exposed to both low and high doses.

Keen and colleagues (1994) and Fechter (1999) suggested thatthe developing neonatal brain of animals may be more sensitive tohigh intakes of manganese. This sensitivity could be due to thegreater expression of transferrin receptors in developing neuronsor to an immature liver bile elimination system (Cotzias et al., 1976).Transfer of manganese to the fetus appears to be limited by theplacenta (Fechter, 1999); therefore, the lack of development ofmanganese transport and elimination mechanisms is probably in-significant in the fetus.

Ecological Studies in Humans. There is some indication that highmanganese intake in drinking water is associated with neuromotordeficits similar to Parkinson’s disease. Kondakis and coworkers(1989) studied people 50 years of age or older in three villages inGreece exposed to 3.6 to 14.6 µg/L of manganese in drinking water(n = 62), 81.6 to 252.6 µg/L (n = 49), or 1,800 to 2,300 µg/L (n = 77).People drinking the water with the highest concentration of manga-nese had signs and symptoms of motor deficits. Kawamura andcoworkers (1941) reported severe neurological symptoms in 25 peoplewho drank water contaminated with manganese from dry cellbatteries for 2 to 3 months. The concentration of manganese in thewater was between 14 and 28 mg/L. Vieregge and coworkers (1995)found no evidence of toxicity in people living in northern Germany(mean age of 57.5 years) drinking water with a manganese concen-tration between 300 and 2,160 µg/L (n = 41); they were comparedwith people drinking water with less than 50 µg/L of manganese.

None of these studies measured dietary intakes of manganese,and so total intake is not known. However, it is possible that manga-nese in drinking water is more bioavailable than manganese in food(Velazquez and Du, 1994), and it is also possible that manganese indrinking water could be more toxic in people who already consumelarge amounts of dietary manganese from diets high in plant prod-ucts.





Summary

Elevated blood manganese concentrations and neurotoxicity wereselected as the critical adverse effects on which to base a UL formanganese. The totality of evidence in animals and humans sup-ports a causal association.

Dose-Response Assessment

Adults

Data Selection. Human data, even if sparse, provide a better basisfor determination of a UL than animal data. The low-dose animalstudies do not establish a no-observed-adverse-effect level (NOAEL).Also, in the animal studies in which manganese was administered infood or water (Bonilla and Prasad, 1984; Komura and Sakamoto,1992), only approximate doses or average doses can be established.A conservative approach was followed in order to protect againstmanganese neurotoxicity.

Identification of NOAEL and Lowest-Observed-Adverse-Effect Level (LOAEL).A NOAEL of 11 mg/day of manganese from food was identifiedbased on the data presented by Greger (1999). Greger (1999) re-viewed information indicating that people eating Western-type andvegetarian diets may have intakes as high as 10.9 mg/day of manga-nese. Schroeder and coworkers (1966) reported that a manganese-rich vegetarian diet could contain 13 to 20 mg/day of manganese.Because no adverse effects due to manganese intake have beennoted, at least in people consuming Western diets, 11 mg/day is areasonable NOAEL from food. A LOAEL of 15 mg/day can be iden-tified on the basis of an earlier study by Davis and Greger (1992). Atthis dose, there were significant increases in serum manganese con-centrations after 25 days of supplementation and in lymphocytemanganese-dependent superoxide dismutase activity after 90 daysof supplementation.

Uncertainty Assessment. Because of the lack of evidence of humantoxicity from doses less than 11 mg/day of manganese from food,an uncertainty factor (UF) of 1.0 was selected.

Derivation of a UL. The NOAEL of 11 mg/day was divided by a UFof 1.0 to obtain a UL of 11 mg/day of total manganese intake fromfood, water, and supplements for an adult.




MANGANESE 413

UL = NOAEL = 11 mg/day = 11 mg/day UF 1.0

Manganese UL Summary, Ages 19 Years and Older

UL for Adults≥ 19 years 11 mg/day of manganese

Other Life Stage Groups

Infants. For infants, the UL was judged not determinable becauseof lack of data on adverse effects in this age group and concernabout the infant’s ability to handle excess amounts. To prevent highlevels of manganese intake, the only source of intake for infantsshould be from food or formula.

Children and Adolescents. There are no reports of manganese toxic-ity in children and adolescents. Given the dearth of information,the UL values for children and adolescents are extrapolated fromthose established for adults. Thus, the adult UL of 11 mg/day wasadjusted on the basis of relative body weight as described in Chap-ter 2 using reference weights from Chapter 1 (Table 1-1).

Pregnancy and Lactation. There are no data showing increased sus-ceptibility of pregnant or lactating women to manganese intake.Therefore, the ULs for pregnant and lactating women are the sameas those for the nonpregnant and nonlactating women.

Manganese UL Summary, Ages 0 through 18 Years, Pregnancy,Lactation

UL for Infants0–12 months Not possible to establish; source of intake

should be from food and formula only

UL for Children1–3 years 2 mg/day of manganese4–8 years 3 mg/day of manganese9–13 years 6 mg/day of manganese

UL for Adolescents14–18 years 9 mg/day of manganese





UL for Pregnancy14–18 years 9 mg/day of manganese19–50 years 11 mg/day of manganese

UL for Lactation14–18 years 9 mg/day of manganese19–50 years 11 mg/day of manganese

Special Considerations

Because manganese in drinking water and supplements may bemore bioavailable than manganese from food, caution should betaken when using manganese supplements, especially among thosepersons already consuming large amounts of manganese from dietshigh in plant products. In addition, a review of the literature re-vealed that individuals with liver disease may be distinctly suscepti-ble to the adverse effects of excess manganese intake.

Intake Assessment

Based on the Total Diet Study (Appendix Table E-6), the highestdietary manganese intake at the ninety-fifth percentile was 6.3 mg/day, which was the level consumed by men aged 31 to 50 years. Datafrom the Third National Health and Nutrition Examination Surveyindicate that the highest supplemental intake of manganese at theninety-fifth percentile was approximately 5 mg/day, which was con-sumed by men and women aged 19 years and older and pregnantwomen (Appendix Table C-20).

Risk Characterization

The risk of an adverse effect resulting from excess intake of man-ganese from food and supplements appears to be low at the highestintakes noted above.

RESEARCH RECOMMENDATIONS FOR MANGANESE

• Identification of functional indicators for manganese.• Analysis of effects of graded levels of dietary manganese intake

on leukocyte superoxide dismutase activity or another appropriatefunctional indicator to provide an appropriate basis for setting anEstimated Average Requirement.




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