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10
Manganese

SUMMARY

Manganese is involved in the formation of bone and in amino acid, lipid, and carbohydrate metabolism. There were insufficient data to set an Estimated Average Requirement (EAR) for manganese. An Adequate Intake (AI) was set based on median intakes reported 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 for adults based on a no-observed-adverse-effect level for Western diets.

BACKGROUND INFORMATION

Function

Manganese is an essential nutrient involved in the formation of bone and in amino acid, cholesterol, and carbohydrate metabolism. Manganese metalloenzymes include arginase, glutamine synthetase, phosphoenolpyruvate decarboxylase, and manganese superoxide dismutase. Glycosyltransferases and xylosyltransferases, which are important in proteoglycan synthesis and thus bone formation, are sensitive to manganese status in animals. Several other manganese-activated enzymes, including pyruvate carboxylase, can also be activated 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 10 Manganese SUMMARY Manganese is involved in the formation of bone and in amino acid, lipid, and carbohydrate metabolism. There were insufficient data to set an Estimated Average Requirement (EAR) for manganese. An Adequate Intake (AI) was set based on median intakes reported 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 for adults based on a no-observed-adverse-effect level for Western diets. BACKGROUND INFORMATION Function Manganese is an essential nutrient involved in the formation of bone and in amino acid, cholesterol, and carbohydrate metabolism. Manganese metalloenzymes include arginase, glutamine synthetase, phosphoenolpyruvate decarboxylase, and manganese superoxide dismutase. Glycosyltransferases and xylosyltransferases, which are important in proteoglycan synthesis and thus bone formation, are sensitive to manganese status in animals. Several other manganese-activated enzymes, including pyruvate carboxylase, can also be activated 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 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 of absorption have been based on whole body retention curves at approximately 10 to 20 days after dosing with 54Mn. Using this method, Finley and coworkers (1994) estimated absorption from a test meal containing 1 mg manganese to be 1.35 ± 0.51 percent (standard deviation [SD]) for men and 3.55 ± 2.11 percent (SD) for women. From a test meal containing 0.3 to 0.34 mg of manganese, Davidsson and coworkers (1988) found the retention of 54Mn to be 5.0 ± 3.1 percent (SD) 10 days after administration to young adult women. Turnover of orally administered 54Mn was much more rapid after oral administration than after intravenous administration (Davidsson et al., 1989b; Sandstrom et al., 1986). Furthermore, absorption of manganese after 30 weeks of supplementation was 30 to 50 percent lower than had been observed in nonsupplemented subjects (Sandstrom et al., 1990). Some studies indicate that manganese is absorbed through an active transport mechanism (Garcia-Aranda et al., 1983), but passive diffusion has been suggested on the basis of studies indicating that manganese absorption occurs by a nonsaturable process (Bell et al., 1989). Manganese is taken up from the blood by the liver and transported to extrahepatic tissues by transferrin (Davidsson et al., 1989c) and possibly α2-macroglobulin (Rabin et al., 1993) and albumin (Davis et al., 1992). Manganese inhibited iron absorption, both from a solution 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 manganese absorption and plasma ferritin concentrations has recently been reported (Finley, 1999). Serum ferritin concentrations differ in men and women (Appendix Table G-3); therefore, a major factor in establishing manganese requirements may be gender. Manganese is excreted primarily in feces. Urinary excretion of manganese is low and has not been found to be sensitive to dietary manganese intake (Davis and Greger, 1992). Urinary excretion in a balance study of five healthy men varied from 0.04 to 0.14 percent of their intake, and absolute amounts in the urine decreased during the depletion phases of the study (Freeland-Graves et al., 1988). Therefore, potential risk for manganese toxicity is highest when bile excretion is low, such as in the neonate or in liver disease (Hauser et al., 1994). Plasma manganese concentrations can be-

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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 come elevated in infants with choleostatic liver disease given supplemental manganese in total parenteral nutrition solutions (Kelly, 1998). It is not certain at what age human infants can maintain manganese homeostasis. Neonatal mice were unable to maintain manganese homeostasis until 17 to 18 days of age (Fechter, 1999). Clinical Effects of Inadequate Intake Manganese deficiency has been observed in various species of animals with the signs of deficiency, including impaired growth, impaired reproductive function, impaired glucose tolerance, and alterations in carbohydrate and lipid metabolism. Furthermore, manganese deficiency interferes with normal skeletal development in various animal species (Freeland-Graves, 1994; Hurley and Keen, 1987; Keen et al., 1994). Although a manganese deficiency may contribute to one or more clinical symptoms, a clinical deficiency has not been clearly associated with poor dietary intakes of healthy individuals. One man was depleted of vitamin K and inadvertently of manganese when fed a diet containing only 0.34 mg/day of manganese for 6.5 months. Symptoms included hypocholesterolemia, scaly dermatitis, hair depigmentation, and reduced vitamin K-dependent clotting proteins. Symptoms were not reversed with vitamin K supplementation but gradually disappeared after the study ended (Doisy, 1973). In a manganese depletion study, seven young men were fed a purified diet containing 0.01 mg/day of manganese for 10 days and 0.11 mg/day of manganese for 30 days after a 3-week baseline period when they consumed 2.59 mg/day (Friedman et al., 1987). After 35 days, five of the seven subjects developed a finely scaling, minimally erythematous rash that primarily covered the upper torso and was diagnosed as Miliaria crystallina. After two days of repletion, the blisters disappeared and the affected areas became scaly and then cleared. Plasma cholesterol concentrations declined during the depletion period, perhaps because manganese is required at several sites in the biosynthetic pathway of cholesterol (Krishna et al., 1966). Decreased plasma manganese concentrations have been reported in osteoporotic women. Furthermore, bone mineral density was improved when trace minerals, including manganese, were included with calcium in their diets or supplements (Freeland-Graves and Turnlund, 1996; Strause and Saltman, 1987; Strause et al., 1986, 1987). Penland and Johnson (1993) reported that diets containing only 1 mg/day of manganese altered mood and increased pain during the premenstrual phase of the estrous cycle in young women.

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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 SELECTION OF INDICATORS FOR ESTIMATING THE REQUIREMENT 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 infant formula to 14 healthy men and women, manganese retention ranged from 0.6 to 9.2 percent. Mean retention in these subjects was 2.9 ± 1.8 percent (standard deviation [SD]). Intraindividual variation 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 doses in six subjects (Davidsson et al., 1989b). In one study, seven healthy men, aged 19 to 22 years, were fed a purified low-protein diet containing 0.01 mg/day of manganese for days 1 to 10, followed by a protein-adequate diet containing 0.11 mg/day of manganese until day 39. Using a factorial method, the authors estimated that the minimum requirement for manganese was 0.74 mg/day and estimated on the basis of the percentage of manganese retention that 2.11 mg/day would be required (Friedman et al., 1987). Subsequently, five young men were fed a diet of ordinary foods (1.21 mg/day of manganese) supplemented with manganese sulfate or placebo at the evening meal to create five different levels of manganese intake (Freeland-Graves et al., 1988). Total manganese intakes were 2.89 mg/day for days 1 to 21, 2.06 mg/day for days 22 to 42, 1.21 mg/day for days 43 to 80, 3.79 mg/day for days 81 to 91 (repletion), and 2.65 mg/day for days 92 to 105. The mean manganese 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 slightly positive mean balance when consuming 2.5 mg/day of manganese. Some adolescent girls were observed to be in negative or slightly positive balance when consuming 3 mg/day of manganese (Greger et al., 1978a, 1978b). Balance studies are problematic for investigation of manganese requirement because of the rapid excretion of manganese into bile and because manganese balances during short- and moderate-term studies do not appear to be proportional to manganese intakes (Greger, 1998, 1999). For these reasons, a number of studies have achieved balance over a wide range of manganese intakes (Table 10-1). Therefore, balance data were not used for estimating an average requirement for manganese.

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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 TABLE 10-1 Manganese Balance Studies in Adults Reference Study Group Duration Diet (mg/d) Balance Data (mg/d) McLeod and Robinson, 1972 4 women, 19–22 y 27 d 2.78 0.32 Spencer et al., 1979 9 men, 41–63 y 18–24 d 2.23 –0.28 Johnson et al., 1982 8 men, 21–28 y 40 d 3.28 –10 to –21 Patterson et al., 1984 28 men and women, 20–53 y 7d 2.8 –0.16 3.0 –0.16 2.9 –0.21 3.2 –0.12 Behall et al., 1987 11 men, 23–62 y 4 wk 5.5 –0.4 Friedman et al., 1987 7 men, 29–22 y 39 d 0.11 –0.02 5 d 1.53 0.84 5 d 2.55 1.02 Hallfrisch et al., 1987 20 men, 23–56 y 1 wk duplicate food record 5.35 1.65   19 women, 21–48 y 6.14 3.19 Freeland-Graves et al., 1988 5 young men 21 d 2.89 0.083 20 d 2.06 0.018 37 d 1.21 –0.088 10 d 3.79 0.657 13 d 2.65 0.0136 Holbrook et al., 1989 19 men, 21–57 y 7 wk 2.4 to 2.9 –0.6 to 0.4 Johnson and Lykken, 1991 14 women, 27 y 39 d 5.66 0.1 5.52 0.3 0.95 –0.01 0.94 0.06 0.16 0.46

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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 Reference Study Group Duration Diet (mg/d) Balance Data (mg/d) Ivaturi and Kies, 1992 24 men and women 14 d 3.21 0.3 3.92 0.3 3.13 –0.2 2.64 0.23 3.13 0.51 3.15 0.32 Finley et al., 1994 20 men and 20 women, 18–40 y 14 d 5.43 (men) 0.27 4.01 (women) –0.12 Hunt et al., 1998 21 women, 20–42 y 8 wk 2.5 (non-vegetarian) 0.1 5.9 (lacto-ovo-vegetarian) 0.6 Serum and Plasma Manganese Concentration Several studies reported that serum or plasma manganese concentrations respond to dietary intake. Serum manganese concentration of women consuming 1.7 mg/day of manganese was lower than that of women ingesting 15 mg/day of supplemental manganese for more than 20 days (Davis and Greger, 1992). In a depletion trial (Freeland-Graves and Turnlund, 1996), plasma manganese concentration was 1.28 μg/L at baseline. Concentrations were significantly lower during the second (0.95 μg/L) and third (0.80 μg/L) dietary periods with manganese intakes of 2.06 and 1.21 mg/day, respectively. Values increased significantly to 1.11 ± 0.35 μg/L when the diet was repleted with 3.8 mg/day of manganese. During the final dietary periods, manganese intake was 2.65 mg/day, and plasma manganese concentration was 0.97 ± 0.33 μg/L. Plasma manganese concentration was not significantly correlated with manganese intake levels. In a study in which 10 men consumed 0.52 to 5.33 mg/day of manganese, serum manganese concentration did not respond to varied dietary intakes (Greger et al., 1990). Individual serum manganese concentrations varied from 0.4 to 2.12 μg/L with an average of 1.04 μg/L. However, serum manganese concentrations of four of five subjects who consumed 15 mg of chelated manganese as a

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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 dietary supplement for 5 days were 27 nmol/L (1.48 μg/L), whereas unsupplemented control subjects had a mean serum concentration of 20 nmol/L (1.1 μg/L). Serum or plasma manganese concentrations appear to be somewhat sensitive to large variations in manganese intake, but longer studies are needed to evaluate the usefulness of serum manganese concentrations as indicators of manganese status. Blood Manganese Concentration An advantage of whole blood manganese concentration over plasma or serum manganese concentration as an indicator is that slight hemolysis of samples can markedly increase plasma or serum manganese concentrations. Whole blood manganese seems to be extremely variable, however, which may preclude it as a viable status indicator. In a manganese depletion study, manganese concentration in whole blood was 9.57 μg/L (range 5.40 to 17.1) at the end of the baseline period and 6.01 μg/L (4.43 to 7.57) at the end of the 39-day depletion period, but there was not a significant difference between these values (Friedman et al., 1987). With 10 days of manganese repletion, whole blood manganese concentration increased to 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 significantly decreased from 8.64 to 2.45 μg/day, and it continued to decrease to as low as 0.39 μg/day after 35 days (Friedman et al., 1987). In a second manganese depletion trial, urinary manganese decreased significantly as manganese intake decreased from 2.9 to 2.1 to 1.2 mg/day (Freeland-Graves et al., 1988). After repletion with 3.8 mg/day, urinary manganese excretion increased then decreased following an intake of 2.65 mg/day. In contrast to the above findings, when ten men consumed 0.52 to 5.33 mg/day, urinary excretion of manganese did not correspond with manganese intake (Greger et al., 1990). Urinary losses of manganese averaged 0.38 μg/g creatinine. Also, Davis and Greger (1992) could not demonstrate that women given 15 mg/day of manganese during a 125-day supplementation period excreted more manganese in urine than women consuming 1.7 mg/day in food. Thus, there is controversy on the use of urinary manganese for

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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 assessment of status when typical amounts of manganese are consumed. 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 plasma ammonia 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 dismutase (MnSOD) activity (Davis et al., 1992; Malecki et al., 1994; Zidenberg-Cherr et al., 1983). Davis and Greger (1992) demonstrated that lymphocyte MnSOD activity was elevated in 47 women supplemented with 15 mg/day of manganese for more than 90 days. However, other factors like ethanol (Dreosti et al., 1982) and dietary polyunsaturated fatty acids (Davis et al., 1990) may affect MnSOD activity. A fairly large blood sample is required to measure lymphocyte MnSOD. FACTORS AFFECTING THE MANGANESE REQUIREMENT Bioavailability Prior intakes of manganese and of other elements, such as calcium, iron, and phosphorus, have been found by some investigators to affect manganese retention (Freeland-Graves and Lin, 1991; Greger, 1998; Lutz et al., 1993). Adding calcium to human milk significantly reduced the absorption of 54Mn from 4.9 to 3.0 percent (Davidsson et al., 1991). Low ferritin concentrations are associated with increased manganese absorption, therefore having a gender effect on manganese bioavailability (Finley, 1999). Sandstrom and coworkers (1990) gave a multimineral supplement that included 18 mg of iron, 15 mg of zinc, and 2.5 mg of manganese for a minimum of 30 weeks. Neither whole blood manganese concentration nor superoxide dismutase activity was increased significantly from baseline with supplementation. Seven healthy volunteers subsequently consumed a tracer dose containing 54Mn, 75Se, and 65Zn. Manganese absorption was only 1 percent of the oral dose. Sandstrom and coworkers (1987) reported a higher rate of

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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 absorption from this dose in subjects without prior consumption of a supplement, but high interindividual variability of manganese absorption and other potential confounders would require a study specifically designed to test the effect of prior supplementation on 54Mn absorption. Davidsson and coworkers (1995) administered 54Mn in either a soy-based infant formula or a similar dephytinized formula to eight men and women. The geometric mean manganese absorption was 0.7 percent for the native formula and 1.6 percent for the dephytinized formula. Therefore, the presence of phytate reduced the efficiency of absorption of manganese. Johnson and colleagues (1991) reported that manganese absorption did not significantly differ between plant foods that were extrinsically or intrinsically labeled with 54MnCl2. Absorption of 54Mn from a meal, extrinsically labeled with 54MnCl2, was significantly higher (8.9 percent) than the absorption of 54Mn from lettuce (5.2 percent), spinach (3.8 percent), wheat (2.2 percent), or sunflower seeds (1.7 percent). Absorption of 54MnCl2 did not differ whether the dose was 0.53 or 1.24 mg (7 to 10 percent). Gender Finley and coworkers (1994) reported that men absorbed significantly less manganese than women and that this difference may be related to iron status. A subsequent study specifically demonstrated that high ferritin concentrations were associated with reduced 54Mn absorption (Finley, 1999). Serum ferritin concentrations are higher in men (Appendix Table G-3) and therefore may affect, in part, the lower 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 demonstrated that reflect response to dietary intake in infants. Thus, recommended intakes of manganese are based on an Adequate Intake (AI) that reflects the observed mean manganese intake of infants principally fed human milk.

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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 Ages 0 through 6 Months. On the basis of the method described in Chapter 2 and the manganese concentration of milk produced by well-nourished mothers, the AI reflects the observed mean manganese intake of infants exclusively fed human milk during their first 6 months. There are no reports of full-term infants exclusively and freely fed human milk by U.S. or Canadian mothers who manifested any signs of manganese deficiency (Davidsson et al., 1989a). Mean manganese concentrations of human milk at 1 month were approximately 4.0 μg/L (Aquilio et al., 1996; Casey et al., 1985, 1989) and declined to 1.87 μg/L by 3 months postpartum (Casey et al., 1989) (Table 10-2). Total manganese secretion in human milk averaged 1.9 μg/day over the first 3 months and 1.6 μg/day over the second 3 months (Casey et al., 1989). Based on the above data, the AI is set according to average milk volume consumption (0.78 L/day) × the average manganese concentration in human milk (3.5 μg/L), or 3 μg/day, after rounding (see Chapter 2). TABLE 10-2 Manganese Concentration in Human Milk Reference Study Group Stage of Lactation Milk Concentration (μg/L) Estimated Manganese Intake of Infants (μg/d)a Stastny et al., 1984 24 women 4 wk 6.6 5.2 8 wk 4.8 3.7 12 wk 3.5 2.7 Casey et al., 1985 11 women, 26–39 y 8 d 3.7 2.9 14 d 3.8 2.9 21 d 3.2 2.5 28 d 4.1 3.2 Casey et al., 1989 22 women 1 mo 3.5 2.7 3 mo 1.87 1.5 Anderson, 1992 10 women Up to 5 mo 6.97 5.4 Aquilio et al., 1996 14 women 2–6 d 3.9 3.0 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.

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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 Ages 7 through 12 Months. With the introduction of complementary foods, it has been estimated that the average consumption of manganese by 6- and 12-month-old infants is 71 and 80 μg/kg, respectively (Gibson and De Wolfe, 1980). Based on reference weights of 7 and 9 kg for these two ages, the total manganese intake would be 500 and 720 μg/day. Using the reference body weight method described in Chapter 2 to extrapolate from adults, the average intake is 567 μg/day. Based on these two approaches, the AI is set at 600 μg/day for older infants. The AI for older infants is markedly greater than the AI for younger infants because the concentration of manganese is higher in foods than in human milk. Manganese AI Summary, Ages 0 through 12 Months AI for Infants 0–6 months 0.003 mg/day (3 μg/day) of manganese 7–12 months 0.6 mg/day of manganese Special Considerations The manganese concentration in cow milk has been reported to range from 20 to 50 μg/L (Lonnerdal et al., 1981), which is significantly greater than the concentration in human milk (Table 10-2). Manganese is partly present in the fat globule membrane in cow milk (Murthy, 1974). Davidsson and coworkers (1989a) reported that the fractional manganese absorption from human milk (8.2 percent) 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 Method Used to Set the Adequate Intake Ages 1 through 3 Years. There are insufficient data to set an Estimated Average Requirement (EAR) for manganese for children ages 1 through 3 years. Therefore, median intake data were used to set the AI. Data from the Food and Drug Administration Total Diet Study indicate a median intake of 1.22 mg/day of manganese for children aged 1 through 3 years (Appendix Table E-6). Ages 4 through 13 Years. There have been a few manganese balance studies with children and all are subject to the caveats previously

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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 Hazard Identification Adverse Effects Manganese toxicity in humans is a well-recognized occupational hazard for people who inhale manganese dust. The most prominent effect is central nervous system pathology, especially in the extra-pyramidal motor system. The lesions and symptoms are similar to those of Parkinson’s disease (Barceloux, 1999; Keen et al., 1994). Manganese is probably transported into the brain via transferrin (Aschner et al., 1999). These authors hypothesize that the greater vulnerability of the extrapyramidal system (globus pallidus and substantia nigra) for manganese accumulation could be due to the fact that these are areas that are efferent to areas of high transferrin receptor density. These same efferent areas are also regions of high iron content. Neurotoxicity of orally ingested manganese at relatively low doses is more controversial. However, several lines of evidence suggest this possibility. The data on manganese neurotoxicity are reviewed below. Elevated Blood Manganese and Neurotoxicity. People with chronic liver disease have neurological pathology and behavioral signs of manganese neurotoxicity, probably because elimination of manganese in bile is impaired (Butterworth et al., 1995; Hauser et al., 1994; Spahr et al., 1996). This impairment results in higher circulating concentrations of manganese, which then has access to the brain via transferrin. Hauser and coworkers (1994) reported whole blood manganese concentrations of 18.8 to 45 μg/L in three patients with chronic liver disease, as compared to a normal range of 4.2 to 14.3 μg/L. Spahr and coworkers (1996) reported blood manganese concentrations of 124.7 nmol/L (6.85 μg/L) in control subjects versus 331.4 nmol/L (18.2 μg/L) in patients with cirrhosis. High concentrations of circulating manganese as a result of total parenteral nutrition have also been associated with manganese toxicity (Keen et al., 1999). Davis and Greger (1992) reported that women who ingested 15 mg/day of supplemental manganese had serum manganese concentrations that increased gradually throughout the 125-day study; significant differences were reported after 25 days of supplementation. Neurotoxicity in Laboratory Animals. High subchronic or chronic doses of manganese given to animals in food or water result in

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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 central nervous system pathology and behavioral changes, although these changes are not necessarily identical to those seen in humans. A review by Newland (1999) suggests that manganese toxicity occurs at progressively lower doses when manganese is administered in food, in water, or by injection, respectively. Differences in toxic potency by route of administration may be an order of magnitude or more. The lowest dose study of manganese administered in food identified by Newland (1999) was by Komura and Sakamoto (1992). They fed male mice diets high in manganese (2 g/kg food) for 12 months (either as MnCl2, manganese acetate, MnCO3, or MnO2). Thus, a 30-gram mouse eating 4 g/day of food would have ingested about 266 mg/kg/day of manganese. Changes in brain regional biogenic amines and decreases in locomotor activity were observed, but changes were somewhat different for each salt. In general, manganese dioxide was found to be more toxic than other forms, and manganese chloride was least toxic. Several studies have examined neurotoxic effects of manganese in drinking water or administered by gavage. The two lowest dose studies are reviewed here. Bonilla (1984) gave male rats 0.1 or 5.0 mg/mL of manganese in drinking water for 8 months and measured locomotor activity throughout this period. A significant increase in activity during the first month was found at both doses. Activity returned to normal for months 2 through 6, but in the seventh and eighth months, activity was less than that of control subjects 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 8 months. They observed decreases of norepinephrine in striatum and pons of rats treated with the lower dose. Increases in the dopamine metabolite dihydroxyphenylacetic acid were found in striatum and hypothalamus at both doses. Homovanillic acid (another dopamine metabolite) decreased in striatum of the lower dose group. Changes in serotonin and its metabolite, 5-hydroxyindole acetic acid, were seen in some brain regions in the high dose group. As with the Komura and Sakamoto (1992) study, the actual doses of manganese in this study can only be approximated. Assuming that a 300 g rat ingests about 30 mL/day of water, then the daily dose of manganese 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 39 days. Manganese levels in brain regions were elevated, and learning in a T-maze task was retarded. The learning impairment was associated with hypercholesterolemia, and the impairment was not seen

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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 when rats were co-administered mevilonin (a cholesterol biosynthesis inhibitor). The doses used in this study were very low. While no animal data exist showing that the neonate exhibits neurotoxic effects at lower doses of manganese than do adults, effects could be more severe in the developing brain. Pappas and colleagues (1997) exposed dams and litters to 2 or 10 mg/mL of manganese (as MnCl2) in drinking water from conception until postnatal day 20. Thinning of the cerebral cortex was observed in neonates exposed to both low and high doses. Keen and colleagues (1994) and Fechter (1999) suggested that the developing neonatal brain of animals may be more sensitive to high intakes of manganese. This sensitivity could be due to the greater expression of transferrin receptors in developing neurons or to an immature liver bile elimination system (Cotzias et al., 1976). Transfer of manganese to the fetus appears to be limited by the placenta (Fechter, 1999); therefore, the lack of development of manganese transport and elimination mechanisms is probably insignificant in the fetus. Ecological Studies in Humans. There is some indication that high manganese intake in drinking water is associated with neuromotor deficits similar to Parkinson’s disease. Kondakis and coworkers (1989) studied people 50 years of age or older in three villages in Greece 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 manganese had signs and symptoms of motor deficits. Kawamura and coworkers (1941) reported severe neurological symptoms in 25 people who drank water contaminated with manganese from dry cell batteries for 2 to 3 months. The concentration of manganese in the water 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 concentration between 300 and 2,160 μg/L (n = 41); they were compared with 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 manganese in drinking water is more bioavailable than manganese in food (Velazquez and Du, 1994), and it is also possible that manganese in drinking water could be more toxic in people who already consume large amounts of dietary manganese from diets high in plant products.

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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 Summary Elevated blood manganese concentrations and neurotoxicity were selected as the critical adverse effects on which to base a UL for manganese. The totality of evidence in animals and humans supports a causal association. Dose-Response Assessment Adults Data Selection. Human data, even if sparse, provide a better basis for determination of a UL than animal data. The low-dose animal studies do not establish a no-observed-adverse-effect level (NOAEL). Also, in the animal studies in which manganese was administered in food 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 against manganese neurotoxicity. Identification of NOAEL and Lowest-Observed-Adverse-Effect Level (LOAEL). A NOAEL of 11 mg/day of manganese from food was identified based on the data presented by Greger (1999). Greger (1999) reviewed information indicating that people eating Western-type and vegetarian diets may have intakes as high as 10.9 mg/day of manganese. 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 been noted, at least in people consuming Western diets, 11 mg/day is a reasonable NOAEL from food. A LOAEL of 15 mg/day can be identified on the basis of an earlier study by Davis and Greger (1992). At this dose, there were significant increases in serum manganese concentrations after 25 days of supplementation and in lymphocyte manganese-dependent superoxide dismutase activity after 90 days of supplementation. Uncertainty Assessment. Because of the lack of evidence of human toxicity 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 UF of 1.0 to obtain a UL of 11 mg/day of total manganese intake from food, water, and supplements for an adult.

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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 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 because of lack of data on adverse effects in this age group and concern about the infant’s ability to handle excess amounts. To prevent high levels of manganese intake, the only source of intake for infants should be from food or formula. Children and Adolescents. There are no reports of manganese toxicity in children and adolescents. Given the dearth of information, the UL values for children and adolescents are extrapolated from those established for adults. Thus, the adult UL of 11 mg/day was adjusted on the basis of relative body weight as described in Chapter 2 using reference weights from Chapter 1 (Table 1-1). Pregnancy and Lactation. There are no data showing increased susceptibility of pregnant or lactating women to manganese intake. Therefore, the ULs for pregnant and lactating women are the same as those for the nonpregnant and nonlactating women. Manganese UL Summary, Ages 0 through 18 Years, Pregnancy, Lactation UL for Infants 0–12 months Not possible to establish; source of intake should be from food and formula only UL for Children 1–3 years 2 mg/day of manganese 4–8 years 3 mg/day of manganese 9–13 years 6 mg/day of manganese UL for Adolescents 14–18 years 9 mg/day of manganese

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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 UL for Pregnancy 14–18 years 9 mg/day of manganese 19–50 years 11 mg/day of manganese UL for Lactation 14–18 years 9 mg/day of manganese 19–50 years 11 mg/day of manganese Special Considerations Because manganese in drinking water and supplements may be more bioavailable than manganese from food, caution should be taken when using manganese supplements, especially among those persons already consuming large amounts of manganese from diets high in plant products. In addition, a review of the literature revealed that individuals with liver disease may be distinctly susceptible to the adverse effects of excess manganese intake. Intake Assessment Based on the Total Diet Study (Appendix Table E-6), the highest dietary manganese intake at the ninety-fifth percentile was 6.3 mg/ day, which was the level consumed by men aged 31 to 50 years. Data from the Third National Health and Nutrition Examination Survey indicate that the highest supplemental intake of manganese at the ninety-fifth percentile was approximately 5 mg/day, which was consumed by men and women aged 19 years and older and pregnant women (Appendix Table C-20). Risk Characterization The risk of an adverse effect resulting from excess intake of manganese from food and supplements appears to be low at the highest intakes 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 appropriate functional indicator to provide an appropriate basis for setting an Estimated Average Requirement.

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