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Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2 (2007)

Chapter: Appendix 9 Manganese (Inorganic Salts)

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Suggested Citation:"Appendix 9 Manganese (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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9
Manganese (Inorganic Salts)

Raghupathy Ramanathan, Ph.D. NASA-Johnson Space Center Toxicology Group Houston, Texas

OCCURRENCE AND USE

Manganese (Mn) is a component of several minerals in the earth’s crust (rock, soil) and is an abundant element. It is found in most food and in drinking water and is distributed to the environment through dust and industrial emissions during the production of iron alloys and during coal burning. Manganese as methylcyclopentadienyl manganese tricarbonyl (MMT) was used as an additive to gasoline to improve octane rating, to replace tetraethyl lead as an antiknock agent. It has been used in Canada since 1977 (Crump 2000), but it was banned from use as a gasoline additive in the United States because of concerns about neurologic effects from the inhalation of particulate emissions of combustion products of MMT, namely manganese phosphate and manganese sulfate (MnSO4) (see Davis 1999). Manganese exists in several different oxidation states (see Table 9-1). The most common ones are the +2 and +4; the former is the one most commonly found in biologic systems including humans. Manganese chloride (MnCl2), MnSO4, and manganese acetate are the most soluble forms. Manganese oxide, although frequently encountered in the work place, is very insoluble.

Manganese as a metal is primarily used in steel manufacturing. It is also used as a micronutrient in fertilizers and in animal feeds. The sulfate salts are used extensively as nutritional supplements for humans and animals and in dyes and varnishes.

Manganese is an essential element needed for the normal physiologic function of all animal species, including humans. Deficiencies of manganese produce abnormalities in brain function, skeleton and cartilage formation, reproduction, and glucose tolerance and are associated with osteoporosis (see Freeland-Graves 1994). A variety of enzymes

Suggested Citation:"Appendix 9 Manganese (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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TABLE 9-1 Physical and Chemical Properties of Some Manganese Compoundsa

Chemical

Manganese

Manganese Chloride

Manganese Sulfate

Manganese Acetate

Manganese Dioxide

Formula

Mn

MnCl2

MnSO4

Mn (CH3COO)2

MnO2

Molecular weight

54.94

125.84

151

173

86.94

Percent manganese

100%

43.66%

36.38%

31.75%

63.19%

Solubility in water

Decomposes slowly

723 g/L at 25°C

529 g/L at 5°C

970 g/L at 25°C

Insoluble

General form

MnCl2·4H2O

MnSO4·H2O

MnAc·4H2O

 

Molecular weight

 

197.91

169

245

 

Percent manganese

 

27.76%

32.50%

22.40%

 

aOther common manganese-containing inorganic compounds, such as potassium permanganate (KMnO4), and other compounds, such as the tetraoxides, carbonate, and nitrates of manganese, are not included here.

Sources: Data from Aldrich Company 2006; Bingham et al. 2001; Merck 1989.

have been reported to interact with Mn+2 or depend on Mn+2 for either catalysis or regulatory properties. Thus, it plays an important role in energy metabolism, bone mineralization, protein and energy metabolism, and the metabolic regulation of several enzymes. Manganese has been reported to activate transferases, decarboxylases, and hydrolases (Wedler 1994). It is also an integral part of mitochondrial superoxide dismutase (thereby playing a role in the protection of free superoxide radical species), carboxylase, and liver arginase (NRC 1989).

Food is the major source of manganese, and different foods vary widely in manganese concentration. Nuts and grains contain a high concentration (18-46 parts per million [ppm]) (IOM 2001). For example, Greger (1999) reported that the average intake from Western and vegetarian diets was in the range of 0.7-10.9 mg/d. Milk products contain about 4 ppm. Other investigators have reported various values. The estimated dietary intakes of several nutritional elements for specific age groups have been reported in the U.S. Food and Drug Administration’s (FDA’s) Total Diet Study and updated at various times (1974-1982, 1982-1984, 1982-1986, 1982-1989, 1982-1991, and 1991-1997). Ac-

Suggested Citation:"Appendix 9 Manganese (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

cording to the dietary intake data the from FDA’s Total Diet Study, 1991-1997 (see IOM 2001, Appendix E), the mean daily intakes of manganese for men of age groups 19-30, 31-50, 51-70, and 71+ have been reported to be 3.07, 3.27, 3.07, and 2.82 mg/d, respectively. The corresponding intakes for women of the same age groups are 2.34, 2.43, 2.42, and 2.43 mg/d, respectively. As for the usual amounts of manganese taken as supplements by men and women, according to the National Health and Nutrition Examination Survey (NHANES III, 1988-1994), they are 2.49 mg/d (median or 50th percentile) for men and 2.37 mg/d (median) for women, and the 95th percentile is 5.07 mg/d for both men and women (see IOM 2001, Appendix C-20).

Dissolved manganese was detected in surface water in 51% of 1,577 samples, with a mean of 59 micrograms per liter (µg/L) (range of 0.3-3,230 µg/L). A later survey from 286 locations indicated the mean concentration was 24 µg/L and the range was from 11 µg/L (25th percentile) to more than 51 µg/L (75th percentile) (Smith et al. 1987). A 1962 survey of a public drinking water supply reported a concentration of 100 µg/L of manganese (Durfor and Becker 1964). Other reports estimated the values to be very low, between 4 and 32 µg/L (NRC 1980). The U.S. Environmental Protection Agency’s (EPA’s) secondary maximum contaminant limit (SMCL) of 50 µg/mL was exceeded a few times in both the recycled water and in the humidity condensate samples collected from space missions. At least once, a maximum of 150 µg/L was found in the reprocessed water. When a particular component is frequently found in water samples, even if it is at concentrations under the National Aeronautics and Space Administration (NASA) interim levels, a spacecraft water exposure guideline (SWEG) is determined. The main reasons for this are a concern that the component could break through the water processing system and the fact that no real-time monitoring instruments are on board the International Space Station (ISS).

PHARMACOKINETICS AND METABOLISM

General

There are no systematic human studies on the pharmacokinetics of manganese after its ingestion. There are several reports of elimination rates of manganese in human subjects occupationally exposed to manganese via inhalation. In all these studies, the elimination was measured based on the injection of tracer doses of radioactive manganese and elimination based on the injection of tracer doses of radioactive manga-

Suggested Citation:"Appendix 9 Manganese (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

nese and elimination followed via whole-body disappearance of radioactivity over time. One must consider that the metabolic handling of manganese absorbed from the diet is different from that introduced through intravenous (iv) injection (Davidsson et al.1989a) in spite of the fact that in plasma 54Mn is carried by transferrin, regardless of the route, iv or oral, of administration (Davidsson et al.1989c).

In a study of five men and six women administered oral loads of elemental manganese at 40 mg per kilogram (kg) of body weight after fasting, the mean T-max (time to reach the peak plasma level) ranged from 1 to 3 hours (h). Then the concentrations gradually decreased to initial levels over the next 4 h. The time to reach the C-max (maximum blood concentration) varied with subjects (Freeland-Graves and Lin 1991). These authors did not calculate any other pharmacokinetic parameters.

In a recent study, the toxicokinetics of manganese were investigated in male and female rats following a single iv or oral dose of MnCl2 (6 mg/kg) (Zheng et al. 2000). For the oral dosing, rats were fasted for 12 h before dosing. Upon iv administration of MnCl2, manganese rapidly disappeared from blood, with a terminal elimination half-life (t½) of 1.83 h and plasma clearance (CL) of 0.43 L/h/kg. After oral administration of MnCl2, manganese was rapidly absorbed from the gastrointestinal (GI) tract and entered the systemic circulation (T-max = 0.25 h; C-max = 0.3 µg/mL). The absolute oral bioavailability was about 13% (calculated from the area under the curves from iv and oral dosing). The elimination half-life for the iv dose was 1.83 h compared to 4.6 h for the oral bolus. Plasma concentrations returned to predose levels 12 h after dosing.

Absorption

Orally ingested manganese is absorbed from the GI tract, but not very efficiently, and the review of literature indicates that only about 3-5% is absorbed in humans and animals. Under normal conditions, the absorption of Mn+2 is low because of poor solubility of the cationic Mn+2 such as in MnCl2 and MnSO4, in the alkaline pH of the intestine. Mn+2 absorption in the GI tract is controlled by homeostatic mechanisms; the absorption rate depends on the amount ingested and the plasma levels of Mn+2. The manganese ion is transported across gut walls by both active transport (based on in vitro studies using the everted intestinal sacs) and by diffusion (Cikrt and Vostal 1969, as cited in WHO 1981), with the diffusion process taking place in iron-overloaded states. However, Garcia-Aranda et al. (1983) using an in vivo perfusion system and perfusing

Suggested Citation:"Appendix 9 Manganese (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

segments of either jejunum or ileum with isotonic solutions containing MnSO4 at 0.0125-0.1 millimoles (mM) concluded that absorption of manganese in rat intestines takes place through a high-affinity, low-capacity, active transport mechanism and suggested that the diffusion-mediated transport plays only a limited role. Manganese absorption (fractional absorption) from diet has been found to vary according to the amount of manganese in the diet. For example, using a rat model and using 54Mn retention method, Davis et al. (1992a, b) found that the absorption of manganese from a manganese-deficient diet was at least two-fold higher than from a manganese-adequate diet or a diet containing higher concentrations of manganese measured after 7 weeks (wk) of feeding.

Lee and Johnson (1988) reported that in rats fed diets containing manganese at between 1.3 and 82.4 mg/kg for 7 or 14 d and administered a tracer dose of 54Mn by gavage, increasing dietary manganese reduced manganese absorption and enhanced 54Mn excretion. Absorption of 54Mn by fasted, gavaged rats was four times higher than in unfasted gavaged rats (Lee and Johnson 1988).

Mena et al. (1969) found that only about 3% of the administered dose of MnCl2 was absorbed by human subjects, and the difference between the lowest and highest value among the 11 normal subjects was fivefold, as measured by the retention of 54Mn and whole-body counting daily for 2 wk. Similar levels of absorption from oral ingestion have been reported by Davidsson et al. (1988, 1989a). It has to be noted that the estimation of absorption using nutrition-balance studies is confounded by the fact that the GI tract is not only the site of absorption but also the principal site of elimination and where the exsorption of endogenous manganese takes place. Estimated absorption measured using retention of 54Mn in 14 men for 10 d was 5.9% ± 4.8%; however, the range was 0.8-16%. The interindividual variation was large (Davidson et al. 1989b). Using a rat model, Davis et al. (1993) reported that young, growing rats fed manganese at 45 µg/g in their diet absorbed 8.2% of their manganese intake and then lost 37% of this absorbed manganese through gut endogenous losses.

The literature indicates the amount of manganese absorbed depends not only on the total amount of it present in food but also on several dietary ingredients that influence the absorption of manganese (Bales et al. 1987; Lee and Johnson 1989; Davidsson et al. 1991). For example, phytate, tannins, oxalates, and fiber inhibit manganese uptake (fractional absorption) from the GI tract. Phytate (myo-inositol hexaphosphate, IP6) is the major storage form of phosphorus in plants, and cereal foods contain large amounts of IP6. IP6 possesses a high potential for chelating

Suggested Citation:"Appendix 9 Manganese (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

minerals, such as iron (as Fe+2), zinc (as Zn+2), magnesium (as Mg+2), calcium (as Ca+2), and Mn+2, and, thus, IP6 has a negative influence on the bioavailability of elements from food. Davidsson et al. (1991) studied in humans the effect of adding phytate, phosphate, and ascorbic acid to infant formula and studied manganese absorption using radionuclide techniques. They found no significant differences in manganese absorption, although the addition of calcium to human milk decreased manganese absorption. This seems to contradict the report by Bales et al. (1987) who observed a decrease, apparently caused by the fiber and phytate content of food. In another study by Schwartz et al. (1986) in which adult human males ingested a high-fiber diet containing manganese at 12-17.7 mg/d via wheat bread and bran muffins, there was no net retention, or a negative balance or only a mild positive balance of manganese was observed. Johnson et al. (1991) found that in men and women, absorption of manganese from lettuce was higher than spinach and less so from sunflower seeds compared to that from wheat. Davidsson et al. (1991) reported humans absorbed a higher percentage of manganese from human milk than from cow’s milk or soy formula.

Johnson et al. (1991) stated that in humans, manganese absorption tended to be greater from MnCl2 in demineralized water (which ranged from 7.74% to 10.24%) than from foods (vegetables, wheat, and nuts). However, the biologic half-life of manganese from either source is the same. EPA has recommended using an additional factor of at least 3 if an assessment made from the ingestion of manganese from food is extrapolated to drinking water (EPA 1996). One might think, based on the characteristics of other divalent cationic metals, that manganese absorption from water would be much greater than from food. However, no definitive experiments have documented this. Davidsson et al. (1988, 1989a) reported that in humans, the absorption of manganese from these two sources is comparable. If a difference exists, it is masked by vast interindividual variations in (human) absorption of manganese (determined using 54Mn retention with intrinsic and extrinsic labeling of the meal). Mena (1974) reported an absorption of 70% from young rats compared to only 1-2% in adult rats. Similarly, Lonnerdal et al. (1987) reported that in neonatal rats, manganese is absorbed at a very high level (as high as 80%) until 14 d, where it drops to 30% by day 18 and to 3-4% when the animal reaches maturity. The proposed reason that this phenomenon is because of the lack of development of the excretory pathway in the neonates (Miller et al. 1975) has been debated by Ballatori et al. (1987), who in their studies on dose dependency of biliary excretion of intraperitonealy (ip) injected manganese in adult and 14-d-old rats, concluded

Suggested Citation:"Appendix 9 Manganese (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

that at doses higher than tracer doses used in previous studies neonatal rats can excrete as much as adult rats.

Manganese Absorption and the Influence of Other Minerals

Several minerals have been shown to interact with the absorption of manganese, including iron, calcium, zinc, magnesium, cobalt, and iodine. Interaction of iron with manganese has been the subject of numerous human and animal studies (see Finley and Davis 1999), which have shown metabolic interactions between these metals. Available evidence indicates body stores of iron and manganese inhibit each other’s absorption (Kies 1994), perhaps because of a competition via a common transport protein such as the divalent metal transporter. Diet-induced iron deficiency can increase the GI absorption of manganese, and supplementing the diet with iron suppresses this enhanced manganese absorption (Davis et al. 1992b; Chua and Morgan 1996). Chua and Morgan also observed that the supplementation of manganese via drinking water (manganese acetate at 2 g/L) increased 59Fe uptake from plasma in the brain, liver, and kidneys, which was not seen when iron was loaded in the diet (Chua and Morgan 1996). But a critical observation is that both iron depletion and loading in the diet increased the brain concentrations of manganese. In humans, supplementation of iron decreases not only the absorption of manganese from the diet (Lonnerdal et al. 1987) but also its retention in the body (Kies 1987). Pertinent to the objective of this document, excess manganese will inhibit the intestinal absorption of iron and could lead to iron deficiency and to anemia. However, Davis and Greger (1992) did not find any change in the iron status of 47 women supplemented with manganese at 15 mg/d for 124 d. Recent work by Zheng et al. (1999) on iron homeostasis in rats after chronic exposure to MnCl2 indicates that exposure to manganese alters iron homeostasis, possibly by expediting the influx of iron from the systemic circulation to the cerebral compartment of the brain. It is interesting to note that iron overload in the brain has been thought to be responsible for Parkinson’s disease (PD), causing iron-mediated oxidative stress in the brain and consequent degeneration of neurons. Finley (1999) and Finley et al. (1994) investigated possible gender differences in the influence of iron status (using serum ferritin concentration as the marker), especially on manganese absorption and half-life of manganese (using 54Mn) in men and women. They found that higher ferritin concentrations reduced manganese absorption in young women. Although men absorbed much less manganese than women, manganese had a longer half-life in men (Finley

Suggested Citation:"Appendix 9 Manganese (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

et al. 1994). These findings may be related to the differences in serum ferritin between men and women. In an another study (Finley 1999), it was reported that dietary-manganese concentrations did not affect manganese status, but the absorption of manganese from a low-manganese diet by women with high ferritin concentrations was very low compared to the absorption by women with low ferritin concentrations. In this study, 11-15 women received a diet containing manganese at 0.7 mg/d or 9.5 mg/d for 60 d. Retention of 54Mn, measured after 60 d, indicated that a greater percent of the test dose was retained by women on the low-manganese diet than by those consuming the high-manganese diet. Thus, for manganese absorption and biologic half-life, there was a significant interaction between ferritin status and dietary manganese. The results indicated that dietary manganese intake was not associated with any clinically significant changes, especially at the high dose (9.5 mg/d). It is worth noting that in a population-based study of manganese conducted in southwest Quebec, Baldwin et al. (1999) showed that blood manganese (Mn-B) was negatively correlated with age and serum iron in women, whereas serum iron was negatively correlated with age and not Mn-B in men.

Erikson et al. (2002), from their studies on rats fed an iron-deficient diet and groups fed iron-deficient and manganese-supplemented diets (iron-deficient + manganese), concluded that both iron-deficient and iron-deficient + manganese diets significantly increased the concentration of manganese across the brain regions compared to control groups. Based on the concentrations of glutamate, gamma-aminobutyric acid (GABA), and taurin, the authors concluded that iron-deficiency is a significant risk for the central nervous system (CNS) because of increased manganese accumulation and also that the observed changes in the neurochemicals can be attributed to manganese accumulation (Erikson et al. 2002). Recently, Erikson et al. (2004) showed that in 21-d-old male Sprague-Dawley rats given an iron-deficient diet supplemented with manganese (100 mg/kg diet), there was not only an increased overall brain manganese concentration, but this increase was seen in the globus pallidus and substantia nigra in both the groups of rats on an iron-deficient diet and those on an iron-sufficient diet supplemented with manganese compared with controls. In the caudate putamen, the increase was seen only with the manganese-supplemented iron-deficient group (Erikson et al. 2004). An increase in manganese concentration in the globus pallidus, where increased accumulation causes manganism, and observed increased concentrations of divalent metal transporter (DMT-1) protein levels seen in globus pallidus in iron-deficient animals underscores the importance of the interaction of iron and manganese.

Suggested Citation:"Appendix 9 Manganese (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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Several animal investigations suggested that a high intake of calcium can affect manganese balance and vice versa. This has prompted several studies evaluating this interaction in humans because of concerns over increased use of calcium supplements for osteoporosis, particularly among postmenopausal women. Mixed results have been reported. Variations such as the chemical form of calcium, the concentration of calcium, and/or its ratio to manganese may be a reason. An inhibitory effect of calcium on manganese absorption in humans was found in women consuming calcium at 400 and 6.3 mg/d, and manganese negative balance was found in men who took supplements of calcium at 916 mg either as lactate or as milk (McDermott and Kies 1987). Freeland-Graves and Lin (1991) observed that the addition of calcium as calcium carbonate CaCO3 or 2% milk, which provided calcium at 800 mg and manganese at 40 mg, given to adult subjects essentially blocked the plasma uptake of manganese (indicating inhibition of absorption). Similar results were obtained by Davidsson et al. (1991). However, no effect was found by Johnson et al. (1991). The differences may be accounted for by the relative amounts of manganese and calcium. In the study by Johnson et al. (1991), the human subjects were fed conventional diets containing manganese at 1 or 5.6 mg/d with calcium at 587 or 1,336 mg/d in a 2 × 2 factorial design. 54Mn was used to study the absorption of manganese. Biologic half-life was unaffected by calcium concentration. Spencer et al. (1979) found little effect on the excretion or the retention of manganese in adults when 200 or 800 or 1,500 mg/d of calcium was provided as a supplement.

Transport of Manganese Absorbed from Oral Ingestion

Considerable speculation exists in the literature about the oxidation state of manganese that binds to the manganese transport protein in the plasma and is speculated to be responsible for manganese toxicity. Several carrier/transfer proteins have been proposed for manganese, including serum albumin, transferrin (Scheuhammer and Cherian 1985), transmanganin (Cotzias 1962), and beta-1-globulin (Foradori et al. 1967). The finding of significantly different turnover rates of manganese in humans (as measured by the whole-body retention of 54Mn) after iv and oral administration of 54Mn seems to indicate that humans have at least two different Mn+ binding proteins. Davidsson et al. (1989c) identified transferrin as the only major plasma carrier protein when manganese is administered orally or by iv. It has been proposed that after ingestion of Mn+2 and after absorption from the gut, manganese binds to alpha-2-macro-

Suggested Citation:"Appendix 9 Manganese (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

globulin in the plasma (Gibbons et al. 1976) and reaches the liver. While Mn+2 is traversing the liver, a major amount of it is secreted into the bile while a small amount is oxidized by liver ceruloplasmin to Mn+3. Transferrin has a high binding affinity for Mn+3. This enters the circulation as Mn+3-transferrin conjugate and is transported to tissues (Aisen et al. 1969; Aschner and Aschner 1991). That transferrin is the only transport mechanism of manganese from liver to the brain through the systemic circulation has been questioned by other investigators. For example, in the transferrin knock-out mice, the uptake of injected 54Mn in the brain (and other tissues) was comparable to that found in wild mice (Dickinson et al. 1996).

In the last few years, a significant amount of research has been carried out to delineate the complex diffusion-mediated and transporter-mediated processes by which manganese is taken up and transported into the brain and the dependence of these mechanisms on the route of administration. In short, the results indicate that the transport of manganese into the brain takes place in three different ways, and some of these are more relevant to inhaled manganese than to exposure by other routes. One of them is the uptake and transport of manganese via primary and secondary olfactory neurons in pike and has received significant attention by researchers (see Tjalve and Henriksson 1999). Because systemically absorbed manganese enters the brain through the blood brain barrier, olfactory transport through olfactory neurons, relevant to transport of inhaled manganese, will not be relevant here. The other proposed routes are a saturable, transferrin-independent transport across the blood brain barrier, the transferrin-dependent transferring receptor, and DMT-1, which is also an iron-transporter protein in the brain. There is a considerable amount of speculation as to which of these is most important (see Aschner and Gannon 1994; Aschner et al. 1999; Malecki et al. 1999; Aschner 2000; Crossgrove and Yokel 2004) and whether the distribution of manganese among the target brain regions are different depending on the transport system.

Distribution

Normal human and animal tissues contain manganese. Human tissues contain manganese at 0.1-1 µg/g tissue (Tipton and Cook 1963; Sumino et al. 1975), with the highest concentrations in the liver, pancreas, and kidney. Tissue manganese concentrations are controlled by the homeostatic control mechanism through absorption and elimination; thus, the liver and intestines play important roles in maintaining manga-

Suggested Citation:"Appendix 9 Manganese (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

nese status (see, for example, Bertinchamps et al. 1966; Papavasiliou et al. 1966; Abrams et al. 1976). The profile of tissue distribution of manganese seems to vary with the routes of administration and various salt forms of manganese (see Davis et al. 1993 and Roels et al. 1997). Therefore, descriptions of studies on other routes of administration will be limited. Maximal concentration depends on time, due to different rates of uptake by the tissues, and different rates of tissue elimination half-lives for manganese. For example, after a single dose, it takes several days for the brain to reach the maximum concentrations (see Newland et al. 1987).

Rats given a single, oral dose of manganese as MnCl2 at 416 mg/kg had little tissue accumulation of manganese 14 d later (Holbrook et al. 1975). This pattern is thought to result from a homeostatic mechanism that leads to decreased absorption and/or increased excretion of manganese when the intake of manganese is high (Mena et al. 1967; Abrams et al. 1976; Ballatori et al. 1987).

A study in which the retention of a single oral dose of radiolabeled manganese was measured in adult and neonatal rats indicated that 6 d after exposure, tissue retention of the label was much greater in pups (67%) than in adults (0.18%) (Kostial et al. 1989).

A study by Lai et al. (1991) confirmed that chronic exposure to MnCl2 (1 and 10 mg/mL) in drinking water increased brain manganese concentrations; rats exposed to manganese from conception to 120 d had much higher concentrations than controls. Lai et al. (1992) determined several neurochemical parameters in brain regions of rats chronically treated with MnCl2·4H2O at 20 mg/mL drinking water throughout development until adulthood. The highest increases of manganese accumulation in manganese-treated rats were found in the hypothalamus, (increase of 530%) and striatum (an increase of 479%), and the increase in other regions were between 152% and 250%. Chronic MnCl2 exposure in drinking water (20 mg/mL) throughout development until adulthood was found to alter brain regional manganese concentrations in neonatal rats. However, the regional manganese differences were less pronounced in weanling and adult rats (Chan et al. 1992). These results indicate that manganese accumulates in the brain particularly during neonatal exposure.

Manganese content as a function of the salt form of various tissues was reported in a dietary study (Komura and Sakamoto 1991). Elevated manganese concentrations were found in the organs of male mice fed MnCl2, manganese acetate, manganese carbonate (MnCO3), or manganese dioxide (MnO2) at about 200 mg/kg/day for 100 d. Concentrations of manganese in the tissues were generally higher from MnCO3 and

Suggested Citation:"Appendix 9 Manganese (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

manganese acetate than from MnCl2, but the pattern of tissue storage (µg/g tissue) was very similar, in the order of liver > kidney > bone > pancreas > brain > spleen > muscle. Manganese concentrations in the tissues were lowest from MnO2.

Prolonged oral exposure to manganese compounds results in increased manganese concentrations in all tissues, but the magnitude of the increase diminishes over time. Rehnberg et al. (1980) reported that in animals receiving manganese as Mn3O4 at 3,550 ppm in their diet (compared to control animals receiving a normal diet [50 ppm]) the increases in manganese concentrations were in the order of liver > brain > kidney > testes. The concentrations observed after 60 and 224 d indicated that elimination of the excess manganese was slower from the brain than from liver and kidney. Such data are not available for soluble manganese compounds.

Several studies in the literature have described the regional brain distribution of manganese in rodents, primates, and in humans occupationally exposed to manganese. Positron Emission Tomography (PET) scans, magnetic resonance imaging (MRI) scans, and neutron activation analysis techniques had been used. The primary goal was to see whether there is preferential accumulation of manganese in regions associated with the extrapyramidal system that may explain the extrapyrimidal effects from manganese intoxication. But in most of these studies, manganese was administered either via iv or ip injection and not as an oral dose. However, some results are important. In humans, manganese is primarily found in the striatum, globus pallidus, and substantia nigra (Newland et al. 1989; Calne et al. 1994; Pal et al. 1999; and references cited therein). Newland et al. (1989), using proton nuclear magnetic resonance, studied the distribution of manganese in several separate and specific brain regions after manganese administration. Monkeys either inhaled MnCl2 aerosol or were iv injected various doses. Data suggested selective affinity for manganese in globus pallidus and in the pituitary gland. Effects in caudate and putamen effects were intermediate and little effect appeared in gray and white matter, compared to pre-exposure to manganese (Newland et al. 1989). According to Newland and Weiss (1992), there was a correlation between the intensity of MRI and the behavioral effects of manganese, which corresponded to an increase in the manganese content of the globus pallidus and substantia nigra. Scheuhammer and Cherian (1981) reported the rate of uptake and regional distribution of manganese in 13 different regions of the brains of rats administered manganese as MnCl2 as an ip injection for 30 d. The results indicated that manganese accumulated more rapidly in the striatum, thalamus, and midbrain compared to other brain regions. Also, a signifi-

Suggested Citation:"Appendix 9 Manganese (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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cant positive correlation between iron and manganese distribution was noted (Scheuhammer and Cherian 1981).

Roels et al. (1997) studied the absorption and cerebral distribution of manganese with respect to the route of administration and the chemical form of manganese. Male adult rats received either MnCl2·4H2O or MnO2 once a week for 4 wk at a dose of 24.3 of mg/kg body weight by gavage or 1.22 mg/kg by ip or intratracheal instillation. Four days after the last administration, the rats were killed, and the concentration of manganese was measured in blood, liver, and cerebral tissues (cortex, cerebellum, and striatum). The concentration of liver manganese was affected by neither the route of administration nor its chemical form. This was not so when the concentrations of manganese in the brain were determined. The extent of increase in cortex manganese concentration in the MnCl2-gavaged group was less than in the MnO2-gavaged groups. Gavage resulted in a lower increase in cerebellum manganese than other routes did. However, when the results from the oral doses of the chloride and the oxide form of manganese were compared, the increase in steady-state blood manganese concentrations over those of the controls (about 1,000 nanograms [ng] per 100 mL) was about the same, even though blood concentrations reached a maximum very rapidly (Roels et al. 1997).

Excretion

Earlier studies reported that injected radioactive manganese quickly disappears from the blood and enters the mitochondria in the liver and the pancreas. Excess manganese is excreted primarily via bile (Bertin-champs et al. 1966; Papavasiliou et al. 1966; Klaassen 1976). The liver is the major excretory organ for manganese; the concentrations in bile can be more than 150-fold higher than in plasma. Fifty percent of a MnCl2 dose was excreted in the feces within 1 d (Klaassen 1974, 1976), and 85% by day 23 (Dastur et al. 1971). It has been shown that hepatic dysfunction leads to manganese overload in the brain as indicated by the abnormal T1-weighted MRI (Hauser et al. 1996). Less than 1% of a dose of manganese is excreted in the urine within 5 d after an iv injection (Klaassen 1974). However, when the hepatic passage is blocked, the pancreas serves as the reserve organ of excretion (Papavasiliou et al. 1966). The fact that the liver is a major organ for the disposition of manganese has been realized in terms of manganese neurotoxicity in many clinical instances of progressive liver failure, end-stage liver disease,

Suggested Citation:"Appendix 9 Manganese (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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cholestasis, and chronic hepatic encephalopathy (Layrargues et al. 1998; Malecki et al. 1999).

In a recent study by Davis et al. (1993), it was reported that the intestinal wall could also contribute significantly to manganese that is excreted. It was shown in this study that young rats fed manganese at 45 mg/kg/d absorbed 8% of the manganese intake and that 37% of the amount absorbed was lost through the intestinal wall. Although manganese is excreted in urine, urinary manganese did not increase with an increasing duration of supplemental oral manganese intake (Davis and Greger 1992).

Newland et al. (1987, 1989) studied the kinetics of uptake and elimination of manganese administered to monkeys via inhalation (of tracer as aerosol) and also via subchronic subcutaneous (sc) administration using an osmotic mini pump for 50 d (a total of MnCl2 at 400 mg mixed with a radioactive tracer of manganese). In this investigation, two female macaque monkeys were used for the inhalation study, and one for the sc infusion study. The gamma emission from the tracer was counted to determine uptake and elimination of manganese from the chest and head and elimination by fecal route. Radioactivity was monitored for over a year. The authors observed different rates of elimination from the brain after inhalation and after sc infusion. Inhalation exposure led to slow uptake, and the peak activity in the head was reached in about 40 d (the head uptake phase had a half-life of 10 d). Elimination from the head occurred with a t½ of 223-267 d, and it appeared to take place in a single phase. Manganese was detected in the chest area (probably lung) even after 500 d, and the disappearance of manganese from the chest had three elimination phases. The slowest phase had a half-life of 94-187 d. The monkey that received sc doses of manganese received a cumulative dose of MnCl2 at 400 mg and 54MnCl2 at 200 microcuries (µCi) as an sc continuous infusion from ALZET osmotic pumps over 6 wk. In this monkey, the head activity increased gradually, and after the pump was removed, the concentrations in head and feces declined abruptly. The disappearance of manganese from the head was biphasic in this treatment protocol and occurred at a rate 4.5 times higher than after acute inhalation of the aerosol.

Fecal elimination from these routes also differed significantly, although the clearance followed two-phase kinetics. According to the authors, the kinetics of inhalation exposure indicated that the lungs served as a primary reservoir for replenishing head concentrations long after the cessation of exposure and also that elimination of manganese from the lungs is very slow. The authors acknowledged the fact that the differences in the rate of elimination from the brain taken up by these routes

Suggested Citation:"Appendix 9 Manganese (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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may have been because of the vast difference in the doses used (Newland 1999).

Cotzias et al. (1968) reported that after a single iv injection of 54Mn, normal human subjects had a whole-body manganese clearance of 37.5 d and a brain clearance of about 54 d (similar to the infusion in monkeys, as described above), whereas the elimination times from individual tissues were different. These results indicate that tissue storage and tissuespecific uptake are important. Mena et al. (1969) reported that in irondeficient anemic patients (four men and nine women), the half-life of elimination (measured by total body retention of 54Mn) was only 23 d compared to a t½ of 37 ± 7 d in normal individuals. This indicates that iron reserves affect manganese retention in the body. The biologic half-life of manganese in blood ranges from 12 h in healthy miners to 40 h in healthy volunteers iv injected with 54Mn. (Mahoney and Small 1968). Based on the retention of manganese in the whole body in three subjects, it was reported by these authors that manganese elimination from the body could be described by two phases. The faster phase has an elimination half-life of 4 d, and the slower phase has a half-life of 39 d from the whole body from normal subjects (an average of 70% of the injected dose was eliminated in this phase). Sixty days after the initiation of the study (with an injection of a radioactive dose of manganese), one of the subjects began to ingest a solution containing manganese as MnCl2 at 800 mg/d for the subsequent 35 d (Mahoney and Small 1968). One must note that the number of subjects was only two. According to Mena et al. (1969), in subjects with higher oral intake, manganese was eliminated at an increased rate. In miners suffering from manganese intoxication, the half-life of manganese is 34 d, whereas healthy miners had a fast turnover of only 15 d. Also, in mice, Britton and Cotzias (1966) reported a two-compartmental whole-body clearance of manganese, as reported in humans. However, the amount and the half-time of elimination from fast and slow compartments were different from humans. These studies show that with high- and low-manganese diets, these half-lives changed considerably. When the manganese intake is high, the slow elimination phase essentially disappeared (Mahoney and Small 1966).

Suzuki et al. (1974, as cited in WHO 1981) demonstrated that in mice, the whole-body clearance half-life, as measured by the administration of a radioactive tracer dose at the end of the treatment periods, varied with the dose (the preloading). For example, in mice that received MnCl2 at 20, 100, and 2,000 mg/L for 26-30 d, the half-lives were 6, 3, and 1.5 d, respectively. Lee and Johnson (1988) observed that orally administered 54Mn had a shorter biologic half-life than injected 54Mn and tissue distribution of 54Mn differed in rats given 54Mn by different routes.

Suggested Citation:"Appendix 9 Manganese (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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Toxicity Summary

A vast amount of the existing literature on the adverse effects of exposure to manganese indicates that the CNS is the most important target of manganese toxicity. The most important event of neurotoxicity is the performance degradation, irrespective of route of exposure. Optimum crew performance is of paramount importance for NASA’s mission success. Therefore, an overview of manganese-induced neurotoxicity will be presented here.

In humans, neurotoxicity from manganese is usually a consequence of chronic inhalation over a period of several years, of high concentrations of airborne manganese in the form of manganese fumes and manganese oxide dusts in occupational and industrial settings (ferromanganese factories or mining operations). Although the primary objective of this document is to derive a SWEG for manganese from data relevant to exposures through the oral route, a review of the neurophysiologic, neurofunctional, and neuropathologic effects of manganese exposure from inhalation-exposure studies has led to a valuable understanding of the progression of adverse health effects from the early signs of manganese toxicity to the onset of clinically observable conditions, such as manganism, a disease that resembles PD. For this reason, results from studies of inhalation exposures to manganese are important and thus have been described here.

However, it must be mentioned that NASA does not anticipate having a high concentration of manganese in processed water, so the neurologic symptoms and neuropathology seen in the established phase of manganese neurotoxicity in chronically exposed subjects are not likely to occur. NASA is interested in subtle neurobehavioral effects usually seen in the early phase of manganese toxicity and in understanding how neurobiologists have attempted to relate tests to performance decrements (see the Mergler et al. [1999] study discussed below).

Manganese Neurotoxicity in General

A review of the metabolism of manganese indicates that although clear differences exist in the kinetics of uptake, distribution, and excretion of manganese between inhalation exposure and the oral route, the critical adverse effect is on the CNS as stated above.

The basal ganglia are the part of the nervous system that coordinates movement and motor functions and are implicated as being affected when abnormal movements (hypo- and hyperkinesia) and neuro-

Suggested Citation:"Appendix 9 Manganese (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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psychiatric symptoms are present. The basal ganglia include the caudate nucleus and putamen (which are collectively called the striatum) and the globus pallidus, subthalamic nuclei, and substantia nigra. It has been reported in several investigations with human and nonhuman primate models that upon exposure to manganese, increased deposition of manganese occurs in the globus pallidus, striatum, and substantia nigra. This leads to a depletion of dopamine (DA) (and perhaps other biogenic amines) in the basal ganglia because of accelerated oxidation and consequently to the degeneration of neurons and associated nuclei of the extrapyramidal system. Damage to neurons leads to an extrapyramidal disorder called manganism, which resembles PD. Symptoms include generalized weakness, apathy, anorexia, stiffness of the legs, and muscle pain. (Mena et al. 1967; Tanaka and Lieben 1969) (see Table 9-2). One of the most important differences between PD and manganism is the lack of clinical response by patients with the latter disease to the drug levodopa (Olanow et al. 1996).

In “manganese madness” (Pal et al. 1999), the initial acute psychotic episodes lead to more serious symptoms similar to those of PD, such as mask-like faces, stooped posture, tremors, impaired speech, and rigidity of limbs, along with dystonia and severe gait disturbance (motor effects). These symptoms exhibit several years after the cessation of exposure to manganese fumes or dust. In cases of low-dose exposure, one can detect changes in neuromotor functions such as poorer subtle motor activity.

Manganese Neurotoxicity from Inhalation Exposures

A vast amount of data has accumulated regarding the toxicity of manganese to nervous system parameters and functions. Inhalation exposure to high concentrations of manganese as dust or manganese oxide fumes has been known to result in a syndrome of profound neurologic effects in humans. Scanty evidence is available that oral exposure to manganese leads to neurologic effects in humans. The results strongly indicate that neurotoxic effects are progressive and continue even in the absence of continued exposure. The results of a few population-based studies designed to assess early CNS alterations, to develop sensitive methods to identify dysfunction on a continuous scale, and to examine doses of manganese associated with neurotoxic outcomes are discussed below. In the recent past, astrocytes have been implicated as playing a very important role in the pathophysiologic mechanism in manganese

Suggested Citation:"Appendix 9 Manganese (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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TABLE 9-2 Phases of Manganese Neurotoxicitya

Phase

Neurologic Outcome and Parameters

First phase

Characterized by nonspecific symptoms: anorexia, apathy, headache, hypersomnia, spasms, weariness in legs, irritability, pain in the joints

Second phase (established phase)

Signs of basal ganglial dysfunction: speech disturbance, expressionless face, altered gait, and fine tremor

Third phase (final phase)

Muscular rigidity, staggering gait (“cock walk”), fine tremor

aCourse and degree of manganese toxicity varies with individuals. Psychiatric symptoms (“manganese madness,” compulsive and aberrant behavior, emotional lability) may also be manifested.

Source: Data from Mergler 1999.

neurotoxicity, at least for chronic-exposure scenarios. Astrocytes have a high affinity for manganese; this leads to sequestration of manganese in mitochondria followed by the disruption of several key cell functions, including oxidative phosphorylation (see Normandin et al. 2002; Normandin and Hazell 2002).

Roels et al. (1987) conducted a cross-sectional epidemiologic study among 141 male subjects exposed to inorganic manganese in a plant that produced manganese oxide and salt (mean age, 34.3 years [y]; mean duration of exposure, 7.1 y; average exposure, 1 mg/m3). The authors of this study concluded that psychomotor tests are more sensitive than neurologic examinations and detect manganese neurotoxicity much earlier. They also tried to relate tissue manganese to the psychomotor test responses. A matched control group consisted of 104 subjects. The intensity of manganese exposure was moderate. Manganese was measured in blood and in urine. Mn-B in manganese-exposed male workers ranged from 0.10-3.59 µg per deciliter (dL), compared with 0.04-1.31 µg/dL in 104 control subjects. A significantly higher prevalence of cough in cold season, dyspnea, and episodes of acute bronchitis were found in the manganese group. Significant changes were found in simple reaction time (visual), audioverbal short-term memory capacity, and hand tremor (hand-eye coordination, hand steadiness). The concentration of manganese in urine did not correlate with either the exposure duration or the adverse effects measured in the tests. The significant observation was that the prevalence of disturbances in hand tremor was related to Mn-B. According to the authors, the response to the eye-hand coordination test suggests that a Mn-B threshold of about 1 µg/dL of whole blood exists, and that a person exposed to airborne manganese dust (total dust) at

Suggested Citation:"Appendix 9 Manganese (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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about 1 mg per cubic meter (m3) (time-weighted average [TWA]) for less than 20 y may present preclinical signs of manganese neurotoxicity (Roels et al. 1987).

Roels et al. (1992) conducted another study in 92 workers in a battery plant who had been exposed to MnO2 for an average of 5.3 y. The concentration of respirable and total manganese dust in air, as measured by personal sampling, was about 0.2 mg/m3 and 0.95 mg/m3, respectively. Although no differences in neurologic symptoms were found between exposed and control workers, the visual reaction time, hand-eye coordination, and hand steadiness of both group were significantly impaired. In a continuation of this study (a prospective study) aimed at assessing the reversibility of neurobehavioral effects in workers in the dry-alkaline battery plant in Belgium, Roels et al. (1999) noted that even though the amount of total manganese dust (MnO2 particulates) decreased in the plant because of abatement programs over the years, the time courses of the hand-steadiness and visual-reaction test results from these workers showed the absence of any improvement, suggesting that hand stability (postural tremor) and simple visual reaction time were irreversibly impaired (or performance leveled off even when the manganese concentration in air was reduced). In this study, the workers had been divided into low-, medium-, and high-dose exposure groups. In a separate follow-up study of 24 people who had previous occupational exposure to manganese but who had not been exposed to manganese for at least 3 y, a significant improvement in hand-eye coordination was measured, but there was no significant change in the deficit in hand steadiness or visual reaction time (Roels et al. 1999).

Mergler (1999) reviewed the effects of low-level exposure to manganese in a general population, and in this review, the author indicated that dose-effect relations may vary with the different parameters of neurotoxic outcome. For example, Lucchini et al. (1995) reported that there was a good relationship between Mn-B (used as a reflection of cumulative manganese body burden) and certain neurotoxicity parameters, such as finger tapping, visual perception speed, short-term memory, and the ability to add. Mergler et al. (1999) assessed nervous system functions in residents exposed to manganese from a variety of environmental sources (a nonoccupationally exposed population) in southwest Quebec, Canada. The subjects were drawn from seven postal code regions near a former manganese alloy plant that was a potential source of manganese pollution. MMT from gasoline used in Canada was the other main source of environmental manganese. The subjects were 273 persons (151 women and 122 men); blood lead, iron, and mercury concentrations were measured in addition to manganese. Mn-B ranged from 2.5-15.9 µg/L (me-

Suggested Citation:"Appendix 9 Manganese (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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dian: 7.3 µg/L). Mn-B was significantly higher in women (7.70 µg/L) than in men (geometric mean of 6.60 µg/L). Nervous system assessments included computer- and hand-administered neurobehavioral tests, computerized neuromotor tests, sensory evaluation, and a neurologic examination. Neurologic outcomes were examined with respect to Mn-B. Results revealed that higher concentrations of Mn-B (7.5 µg/L) were significantly associated with changes in coordinated upper-limb movements and poorer learning and recall. Further analyses revealed that with increasing log Mn-B, performance on a pointing task (hand-eye coordination) was poorer and frequency dispersion of hand-arm tremor decreased, and harmonic index increased and the velocity of a pronation/supination arm movement was slower. Men older than 50 y whose Mn-B was > 7.5 µg/L showed significant disturbances in several mood symptoms. In addition, the results indicated that motor slowing associated with increased Mn-B concentrations are most likely to manifest after age 50. Gender differences were observed for portions of the neurologic examination (finger, hand, arm, and foot movements) and in learning and recall tests. The gender differences were also observed for mood and postural stability. The results suggested that men might be at greater risk than women, although effects were also observed in women. It must be pointed out that samples of drinking water from participating residences were analyzed for manganese (Mn-W). Two hundred seventy-eight manganese-W samples were obtained and the geometric mean was 4.11 µg/L (0.5-71.1 µg/L). There was no relation between Mn-B and manganese-W. Mn-B was highest in geographical areas with the highest concentrations of airborne manganese, which suggests that neurobehavioral and neuro-physiologic alterations may be primarily caused by airborne manganese (Baldwin et al. 1999).

Acute, Subacute, Subchronic, and Chronic Toxicity Studies

Few reports exist of toxic effects of excess manganese in humans exposed via ingestion (water or food). A significant number of research reports on manganese in humans have focused on its bioavailability and mass balance to determine a reasonable recommended dietary allowance (RDA) for manganese and to elucidate the interaction of other minerals (especially iron and calcium) with manganese absorption. Several of these studies have also focused on infant nutrition and manganese status. Significant amounts of data have been obtained from animal experiments on the toxicity of supplemented manganese. However, some subacute, subchronic, and chronic studies have shown several interspecies and in-

Suggested Citation:"Appendix 9 Manganese (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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traspecies variations. This might result from a wide variation in the requirement for manganese among species. Rodents’ requirements are much higher than humans’. The estimated requirement of manganese of rats is a 50-mg/kg diet (Rogers 1979). This corresponds to 2.5 mg/kg, whereas the estimated safe and adequate daily dietary intake (ESADDI) for humans is 2-5 mg/d or 0.03-0.07 mg/kg/d (NRC 1989)—two orders of magnitude lower than that for rodents. Thus, extrapolation of rodent data to humans should be approached cautiously.

ACUTE EFFECTS

1 d

Freeland-Graves and Lin (1991) conducted a study with human subjects in which six young adults (18-26 y of age; gender not provided), were administered manganese as MnCl2 at 40 mg as a gelatin capsule, and plasma uptake of manganese was measured over 4 h. The peak concentration of manganese in plasma occurred between 1 and 3 h, and the maximum concentration was 2 nanomoles (nmoles) per liter or about 110 ng/L of plasma. This amount of manganese caused no discomfort to the GI systems of the subjects. In this study, no other clinical or neurologic parameters were measured. However, the blood manganese data can be compared with the data from a community study from Mergler et al. (1999), who studied neurologic parameters in subjects whose Mn-B ranged from 2.5 to 15.9 µg/L (median, 7.3 µg/L). Neurologic outcomes were examined with respect to Mn-B. The authors reported that subtle manganese-related neurologic outcomes were evident at Mn-B above 7.5 µg/L. Although in one case, total Mn-B was measured, in the other case, plasma manganese was measured. The concentration in the Freeland-Graves and Lin study was so low that it can be concluded that there would not have been any neurologic adverse effect from an acute single dose of 40 mg per subject.

A clinical case report of a patient who was on hemodialysis with a solution contaminated with manganese reported the patient had severe vomiting, abdominal pain, and increased heart rate and blood pressure. The dialysis was discontinued after 30 min. The dialysate contained MnSO4 at 120 mg/L, or manganese at 40 mg/L. The patient was diagnosed with an acute pancreatitis by day 2 (Taylor and Price 1982).

Several studies indicate that the dose lethal to 50% of test subjects (LD50) dose for MnCl2 or MnSO4, administered as a gavage, is in the range of manganese at 325 to 1,082 mg/kg/d. A summary of LD50 data is

Suggested Citation:"Appendix 9 Manganese (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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shown in Table 9-3 below. These LD50 values seem to be inconsistent with the data on survival rates observed in several subchronic and chronic studies in which manganese salts have been administered in the feed (see the discussion of the National Toxicology Program [NTP 1993] study below). In the NTP (1993) study, rats and mice have tolerated doses much higher than the LD50. Thus, use of these LD50 values for calculating acute risks for 1 d must be weighed carefully.

In an LD50 study (Singh and Junnarkar 1991), mice that received a single gavage dose of manganese as MnCl2 at 580 mg/kg body weight exhibited a decrease in spontaneous activity, alertness, muscle tone, and respiration.

Short-Term Toxicity (2-14 d)

No well-designed toxicity studies were conducted on the adverse effect of manganese ingestion, probably for ethical reasons. However, the literature is replete with human subject studies designed to evaluate manganese balance and absorption and the interaction of manganese with metals such as calcium and iron. Some of these studies included clinical observations, which can provide some insight into the adverse effects of supplemental manganese.

TABLE 9-3 Summary of LD50 Doses for Various Soluble Manganese Salts in Rats and Micea

Species

Manganese Salt

LD50 (mg/kg)

Reference

Rat

Acetate

1,082

Smyth et al. 1969

Wistar rat, male

Chloride

325

Kostial et al. 1989

Wistar rat, female

Chloride

331

Kostial et al. 1989

Rat, albino, male

Chloride

804b

Kostial et al. 1978

Sprague-Dawley rat, male

Chloride

412

Holbrook et al. 1975

Wistar rat, male

Chloride

642

Singh and Junnarkar 1991

Mouse, albino Swiss, male

Chloride

580

Singh and Junnarkar 1991

Wistar rat, male

Sulfate

782

Singh and Junnarkar 1991

Mouse, albino Swiss, male

Sulfate

848

Singh and Junnarkar 1991

aAll of these doses were administered one time as gavages.

bThe number of doses not specified.

Suggested Citation:"Appendix 9 Manganese (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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In a 124-d supplementation study in women (placebo, n = 13; manganese-supplemented, n = 11; supplements of manganese at 15 mg/d), measurements were made on days 1, 25, 60, 89, and 124. Davis and Greger (1992) did not observe any changes for up to 124 d in hematocrit, serum iron, serum copper, serum ferritin, or serum transferrin (the last two are indexes of iron status). Manganese status was indicated by measuring lymphocyte manganese-superoxide dismutase, and an increase was seen only after 89 d of administration of the supplement.

NTP (1993) conducted 14-d, 13-wk, and 2-y toxicology and carcinogenesis feed studies of MnSO4·H2O in F344/N rats and B6C3F1 mice. For the 14-d study, male and female rats and mice were exposed to 0, 3,130, 6,250, 12,500, 25,000, or 50,000 ppm of MnSO4·H2O in the diet. Assuming average food consumption, these correspond to dose rates of manganese at 0, 84, 165, 340, 665, and 1,265 mg/kg/d for both male and female rats. The doses varied for mice, with 0, 121, 262, 669, 1,603, and 2,500 mg/kg for male mice and 0, 240, 488, 1,068, 2,494, and 3,560 mg/kg for female mice. NTP measured hematology variables in addition to collecting body weight, food consumption, and tissue weight data 14 d after dosing.

In the NTP (1993) studies, no effect of manganese exposure on survival was observed in rats fed MnSO4 at up to 50,000 ppm for 14 d. However, decreases in body weight gain were observed in male rats (57%) and in female rats (20%) fed 50,000 ppm. Decreased body weight gain was also observed in male and female mice above 1,200 ppm. NTP (1993) reported that no conclusions could be made about the body weight data because of poor randomization at initiation of the study. Male rats exposed to 50,000 ppm and all exposed female rats had diarrhea during the second week, showing GI effects. The lowest dose that caused diarrhea was 25 mg/kg. Male and female mice did not show similar effects in spite of the fact that the doses for the mice were almost 2 to 3 times those for the rats. An evaluation of hematologic parameters indicated that total leukocyte and neutrophil counts were significantly increased, particularly in the group that received MnSO4 at 50,000 ppm.

A summary of results is listed below. In mice given MnSO4 in the feed for 14 d (NTP 1993), no effects on hematologic parameters were noted. At necropsy, the absolute and relative liver weights of 50,000 ppm dose rats were significantly lower than those of the controls, and this seemed to be chemical related. Even at this high dose, the liver manganese concentration was only twice that of control male and female rats. In male and female mice, the liver manganese concentration was 8 to 15 times that of controls (the dose was threefold greater in mice than in rats). In both male and female rats, the number of leukocytes and seg-

Suggested Citation:"Appendix 9 Manganese (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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mented neutrophils were increased, especially at the highest dose (5,000 ppm, or manganese at 1,270 mg/kg/d). The increased number of leukocytes was seen at doses as low as 340 mg/kg/d in male rats, who seemed to be more sensitive to this change.

Because of the implications of such research for growing children, the literature contains reports of several investigations focused on the adverse neurologic effects of manganese exposure on neonatal rodents (Kontur and Fechter 1988; Dorman et al. 2000). Because this is not directly relevant to the purpose of this document, these studies will not be discussed here.

Short-Term Toxicity (14-100 d)

No human studies have been specifically designed to evaluate the adverse effects of ingestion of manganese. However, nutrition studies of manganese balance provide some indication of the concentrations that do not lead to any observable deleterious effects. For example, as described above, Davis and Greger (1992) did not observe any changes in hematocrit, serum ferritin, serum transferrin, serum iron, or serum copper during a 124-d supplementation study in women taking supplements of manganese at 15 mg/d. These did not change over time for up to 124 d (measurements were made on days 1, 25, 60, 89, and 124). Even the manganese status, as measured by lymphocyte manganese-superoxide dismutase, increased only at 89 d of administration of the supplement.

In a study aimed to understand the interaction of iron and manganese, especially any interaction between the absorption and retention of manganese and serum ferritin concentration, Finley (1999) administered diets that contained manganese at 0.7 or 9.5 mg/d to healthy nonpregnant women. At the end of 60 d, the authors did not find any changes in hematocrit, hemoglobin (g/L), number of erythrocytes (cells/L), white cells, or platelets in women consuming either diet. This study indicated that a total intake of 9.5 mg/d was without any effects. Neurologic indices were not measured in this study (Finley 1999).

Recently, Finley et al. (2003) evaluated the effect of two doses of manganese supplementation in healthy nonsmoking premenopausal women (n = 17) with a mean age of 35.7 ± 8 y and a mean body weight of 72.9 ± 13 kg. The aim of the study was to find out whether there are significant changes in the manganese status in the range of manganese concentrations that are present in a mixed Western diet and also to determine whether the type of dietary fat has any effect on manganese

Suggested Citation:"Appendix 9 Manganese (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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status. The authors concluded that manganese intake in the range of 0.8-20 mg/d for 8 wk was efficiently managed in the human system by the manganese homeostasis mechanisms, because these doses did not affect any neurologic measures and had only minor effects on psychological variables. The lower dose did not result in manganese deficiency, and the high concentrations did not lead to signs of manganese toxicity. The details are as follows. The subjects were fed nutritionally adequate diets for 8 wk, but the diet was formulated to contribute manganese at 0.8 or 20 mg/d (which was supplemented in orange juice to the basal diet). The manganese-intake protocol was done in a randomized double-blinded crossover design. In this study, manganese absorption and retention in the body were estimated from the retention of a test dose of orally administered 54Mn. The authors conducted this study using two different types of fats, one enriched in saturated fatty acids (cocoa butter) and one enriched in unsaturated fatty acids (corn oil). Fat contributed 15% of the energy content of the diet. Neurologic and psychological tests were carried out to determine possible effects on psychomotor and behavioral variables. During the last week of the dietary exposure, to assess neurologic examination results and motor steadiness (tested using a steadiness tester in both dominant and nondominant hands), the subjects were examined by a board-certified clinical neurologist for the presence and severity of more than 75 neurologic signs and symptoms. These included measures used to determine manganese intoxication and measures used for PD (for details see Finley et al. 2003). Psychological assessment was done using three standardized self-report methods to evaluate broad-spectrum components related to hostility and anger. The Buss-Durke Hostility Inventory (BDHI), the State-Trait Anger Expression Inventory (STAXI), and the Interpersonal Behavior Survey (IBS) report measures were used (Finley et al. 2003). Psychological variables were converted to T-scores based on a gender- and age-appropriate normative database for evaluations. Clinical examination did not reveal any signs of neurologic impairment. No interaction was found between ingested manganese and any measure of point or line steadiness (steadiness assessment) within the same fat-type diet group. Differences in the point or line steadiness tests depended on the fat type, leading the authors to conclude that it was not the manganese in the range of concentrations used in this study, but rather the type of fat in the diet that accounted for the observed changes in neurologic and steadiness assessment.

In addition, data for several clinical parameters, such as activities of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, ammonia, concentrations of indicators of biliary function (bile

Suggested Citation:"Appendix 9 Manganese (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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acids and serum bilirubin), glucose, glucose tolerance tests, insulin, ironbinding capacity, and indicators of manganese and iron status were collected at the end of the dietary period. Manganese status was measured by lymphocyte manganese superoxide dismutase activity. Most indicators of manganese and iron status were not affected by dietary manganese. Biliary function was unaffected by diet and was normal in all subjects. Dietary manganese also did not affect the activities of antioxidant enzymes (glutathione peroxidase, catalase, and copper-zinc superoxide dismutase) in whole blood.

A case report described the symptoms of a man who mistakenly ingested low doses of potassium permanganate (manganese at about 1.8 mg/kg/d) for 4 wk and exhibited neurologic effects such as weakness and impaired mental capacity after this oral exposure (Holzgraefe et al. 1986). Although exposure was stopped after 4 wk, this subject developed a syndrome apparently similar to PD after about 9 months (mo).

Japanese Study

In a study by Kawamura et al. (1941), a group of six Japanese families (about 25 people) were exposed for approximately 2-3 mo to high concentrations of manganese in their drinking water, which came from a well. Manganese leached from an adjacent manganese battery storage area where about 300 batteries had been buried. A concentration of manganese at 14 mg/L was measured in the well water. Some of the exposed individuals exhibited muscle rigidity and tremors and mental disturbances similar to those seen in manganism. Not all members of the group were affected, but two individuals died. The actual concentration of manganese may have been 28 mg/L, as the initial well-water samples were taken 1 mo after the incident. The water also contained a high concentration of zinc. It must be pointed out that in spite of the small number of people affected, it was clear that the older individuals exhibited toxic symptoms to a greater degree than younger individuals did. The measurements were made several days after removal of the batteries. Several confounding factors, such as the potential presence of high concentrations of other metals associated with batteries, including nickel, could have caused the effects. Therefore, a LOAEL (lowest-observed-adverse-effect level) or NOAEL (no-observed-adverse-effect level) cannot be estimated from this study. The concentrations of manganese to which humans were exposed were much higher than reported in other epidemiologic studies described below.

Suggested Citation:"Appendix 9 Manganese (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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Animal Studies

There have been several reports on exposure through drinking water and consequent adverse effects from experiments on motor effects conducted mostly on rats. Several subchronic and chronic studies were conducted by Bonilla and coworkers on the behavioral effects and the concentrations and distribution of several biogenic amines (neurotransmitters) in rats treated with various concentrations of MnCl2 in drinking water (Bonilla and Diez-Ewald 1974; Bonilla 1978, 1980, 1984; Bonilla and Prasad 1984). In the 1978 study, Bonilla observed that in male Sprague-Dawley rats (200-300 g) administered MnCl2 in drinking water at 10 mg/mL for 2 mo a significant increase in GABA content of caudate nucleus (Bonilla 1978) resulted. GABA is a principal inhibitory neuro-transmitter in the cerebral cortex that counterbalances neuronal excitation. The increase is neither because of an increase in GABA synthesis, because there was no change in glutamic acid decarboxylase (an enzyme responsible for GABA synthesis), or because of its increased catabolism, because the activity of GABA-transminase (the enzyme that metabolizes GABA to succinic aldehyde) was unaltered. The author speculated that the increase may be because of the inhibition of GABA outflow. Spontaneous motor activity was not measured in this study, and hence, the direct relevance of observed changes could not be determined. In a later chronic manganese-drinking-water-exposure study in rats, the author measured motor activity at different times during the interim periods (Bonilla 1984). In this study, male Sprague-Dawley rats (150-250 g body weight) were given solutions of MnCl2 at concentrations of Mn+2 at 0.1 or 5 mg/mL in their drinking water for 8 mo. Spontaneous motor activity was measured using an optical digital animal activity monitor along with a vertical activity monitor. Various activity parameters measured indicated that at the end of the first month, the animals exhibited hyperactivity, which was seen in both groups of manganese-treated rats. However, the magnitude of the change was not a function of the dose. Furthermore, during months 2 through 5, the activities were comparable to controls. The reduced activity (hypoactivity) noted in the later months has been described under the “Exposure > 100 d” section of this chapter. The authors suspected that the initial increase in activity seen might be because of the decreased release of GABA from GABAergic neurons and the decrease in the inhibitory action on the neuronal excitation reported earlier (Bonilla 1978). The author also related that the noted hyperactivity was perhaps because of the overactivity of dopaminergic neurons, because in another study (Bonilla 1980), the author observed increased activity of tyrosine hydroxylase, an enzyme that converts tyrosine to levodopa, 3,4-

Suggested Citation:"Appendix 9 Manganese (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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dihydroxy-L-phenylalanine (L-DOPA) to DA, at least during the first 2 mo after manganese ingestion.

Behavioral and neurochemical changes were studied in ITRC albino rats (200-250 g) exposed daily to MnCl2 in drinking water for 14 and 30 d at 1 mg/mL, an estimated dose rate of manganese at 140 mg/kg/d (Chandra 1983). Spontaneous motor activity, the conditional avoidance response test, aggressive behavior, and learning ability were assessed at 14 and 30 d. In the treated rats, hyperactivity was seen after 14 and 30 d, with greater magnitude at 30 d. A reduction in the percentage of conditional avoidance responses and an increase in fighting score were also observed after 30 d. Additionally, increased concentrations of striatal DA and norepinephrine in rats exposed to manganese may be responsible for the increased motor activity (Chandra 1983). Measurement of turnover of corpus striatal DA measured at 30 d indicated a 30% increase. Only one dose was used in this study.

Senturk and Oner (1996) administered manganese as MnCl2·4H2O at 357 and 714 µg/kg in water intragastrically to 2-mo-old female albino rats for 30 d. Increased manganese concentrations in brain regions and slower learning, determined by the T-maze food retrieval method, were seen. Measurements were made after 15 and 30 d of manganese treatment. In addition, significant accumulation of cholesterol in the hippocampal region was seen. Normalization of hippocampal cholesterol using a cholesterol synthesis inhibitor significantly corrected this learning impairment, without any change in the increased brain concentrations of manganese that were observed. Therefore, the authors doubted that the slower learning was caused by manganese ingestion and that manganese-induced hippocampal hypercholesterolemia was involved in the process. It must be noted that neither the learning deficit nor the cholesterol increase was prevented by the drug in rats in the high-dose group (Senturk and Oner 1996).

Increased GABA content of caudate nucleus was reported in Sprague-Dawley male rats (200-300 g body weight) administered MnCl2 (10 mg/mL) in drinking water for 2 mo (Bonilla 1978). The increase did not result from an increase in GABA synthesis (as no change occurred in glutamic acid decarboxylase) nor from its increased catabolism (as the activity of GABA transminase was unaltered). The author speculated that it may have resulted from inhibition of GABA outflow. Spontaneous motor activity was not measured in this study.

In a drinking water study, male Sprague-Dawley rats were administered MnCl2·4H2O at a dose of 390 mg/kg/d for 60, 100, 165, or 265 d, and the concentrations of DA and its metabolite in the striatal regions of the brain (caudate nucleus and putamen) were measured (Eriksson et al.

Suggested Citation:"Appendix 9 Manganese (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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1987a). The rats were given manganese-containing water from 20 d of age. Rats exposed to manganese for 60 or 165 d had significantly increased concentrations of DA and its metabolites (dihydroxyphenylacetic acid [DOPAC]) in the discrete regions of the dorsal caudate-putamen. These alterations were not found in rats exposed for 100 or 265 d. The importance of the time factor has been shown in several investigations (Chandra and Shukla 1981; Eriksson et al. 1987a).

In a study by Subhash and Padmashree (1991), albino male rats were given a dose of manganese at 12 mg/kg in drinking water for 90 d, which resulted in a two- to threefold accumulation of manganese in all regions of the brain. Activities of DA β-hydroxylase and monoamine oxidase (MAO) were significantly inhibited in the striatum, hypothalamus, midbrain, and cortex (P ≤ 0.01). MAO activity was also significantly decreased in the cerebellum and cortex. DA concentration was lower (not statistically significant) in the striatum but significantly decreased in the hippocampus and significantly increased in the midbrain. No significant changes in 5-hydroxy tryptamine (5-HT) levels were observed in any region. No neuromotor activity was measured in the study to correlate with any of these changes, and the data were not found to be useful for the derivation of the acceptable concentration (AC).

A study by Dorman et al. (2000) included a comparative evaluation of the distribution of manganese in several regions of the brain and neurotoxicity of MnCl2 in neonatal (postnatal day 13, 17, and 21) and adult CD rats following subchronic high-dose oral exposure. Only data from adult rats will be described. Gavage doses of MnCl2·4H2O were administered to adult male CD rats at doses of MnCl2 at 0, 25, and 50 mg/kg for 21 d (dose rates of manganese at 0, 7, and 14 mg/kg/d). In this study, Dorman et al. (2000) measured spontaneous motor activity using an automated photo beam activity system and passive avoidance tests to assess learning and memory. Additionally, the investigators evaluated the pulse-elicited acoustic startling reflex, and numerous functional observations, such as observations of posture, tremors, spasms, convulsions, muscle tone, and the animals’ condition such as breathing pattern, ataxia, arousal, gait, and body position (see Dorman et al. 2000 for details). The authors reported that they found no statistically significant effects on motor activity that were related to manganese exposure. A significant decrease in the overall mean acoustic startle amplitude was elicited in the 25 mg/kg group but not in rats receiving manganese at 50 mg/kg, showing a lack of dose-related response.

Tissue manganese was determined in six brain regions, namely striatum, hypothalamus, hindbrain, cerebellum, hippocampus, and the rest of the brain (called “brain residue” by the authors). Increased striatal,

Suggested Citation:"Appendix 9 Manganese (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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cerebellar, and brain residue manganese concentrations were observed in adult rats from the 50 mg/kg group, but in the 25 mg/kg group, the increase was seen only in the “brain residue.” Similarly, measurement of neurochemistry variables indicated that only minor changes occurred in neurotransmitter levels, such as a small increase in cerebellar 5-hydroxyindoleacetic acid in the low-dose group and no significant changes in striatal DA and DOPAC. There were also no changes in homovanillic acid (HVA) or serotonin (Dorman et al. 2000).

Spadoni et al. (2000) reported some selective vulnerability of pallidal neurons in the early phases of manganese intoxication. In this study, 20-d-old male Wistar rats that were provided MnCl2 in drinking water at 20 mg/mL (about 550 mg/kg/d) for 3 mo accumulated manganese in liver and brain subregions. The authors did not conduct any behavioral tests in this study. Morphologic examination showed no neuronal loss or gliosis in the globus pallidus. However, when investigators attempted to isolate neurons from the globus pallidus, most neurons died, showing extreme sensitivity. The authors proposed that accumulation of Mn+2 in the brain mitochondria caused inhibition of mitochondrial superoxide dismutase, resulting in oxidative stress on the neurons, which led to vulnerability. The authors considered this an early phase of intoxication. Also, manganese-treated globus pallidus cells from these rats showed a peculiar response to glutamate, including irreversible cell damage. It must be noted that developing rats and not adults were used in this study. In a later study from the same laboratory, Calabresi et al. (2001) conducted biochemical, morphologic, and electrophysiologic experiments with 20-d-old male Wistar rats exposed to manganese as MnCl2 in drinking water for 10 wk at a concentration of 20 mg/mL (about 550 mg/kg). The rats were tested for locomotor activity, reactivity to object novelty in an open field, and radial maze performance. Exposed rats were hyperactive (compared to controls). However, no overt signs of brain damage, such as significant neuronal loss or gliosis, were observed. The concentration of manganese (nmole/mg protein) in basal ganglia, cortex, and cerebellum was threefold higher than in the same structures in control rats, and manganese in liver was 10-fold higher. The authors also reported that in spite of the rats’ hyperactive behavior, their ability to learn procedures and their spatial memory were not impaired. These results were consistent with the electrophysiologic measurements.

A variety of histologic changes in subcellular organelles (rough and smooth endoplasmic reticulum, Golgi apparatus) were observed in the livers of rats exposed to manganese as MnCl2 at 12 mg/kg/d for 10 wk in drinking water (Wassermann and Wassermann 1977). According to the authors, these were only adaptive, rather than adverse effects. NTP

Suggested Citation:"Appendix 9 Manganese (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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(1993) conducted a 90-d subchronic study in which male and female F344/N rats and male and female B6C3F1 mice were exposed to MnSO4·H2O in their feed (at the concentrations of MnSO4 at 0-25,000 ppm for rats and 0-50,000 ppm for mice). The estimated dose rates for the 13-wk experiment groups were 0-655 mg/kg/d for rats and 0-2,300 mg/kg/d for mice. The investigators observed few differences between the responses of male and female rats. Absolute and relative liver weights of all exposed males and females in the highest-dose group were significantly lower than those of controls. In the male rats, at concentrations above 65 mg/kg/d, a decrease in lymphocytes, an increase in segmented neutrophil counts, and increases in both hematocrit and erythrocyte counts were observed. An increase in erythrocytes in female rats was seen only at the highest dose. In the females, both lymphocytes and leukocytes were decreased. No clinical or abnormal histopathology findings were significant at 13 wk.

In the NTP (1993) subchronic study described above, at the end of the 13 wk, at the highest dose of 50,000 ppm (manganese at 2,300 mg/kg), significant reductions were found in body weight of both male and female mice and in relative and absolute liver weight of males. Hematocrit, hemoglobin levels, and mean erythrocyte volumes decreased in male and female mice receiving 50,000 ppm, suggesting that the animals had a microcytic anemia (probably because of sequestration or iron deficiency). Three male high-dose mice also had epithelial hyperplasia and hyperkeratosis of the forestomach (NTP 1993). Such observations were not seen in the interim evaluation period of 15 mo in the 2-y chronic study, making it difficult to interpret these changes as being related to treatment.

Komura and Sakamoto (1991, 1992) conducted two studies aimed at examining the effects on the CNS of rather large amounts of various chemical forms of manganese (two soluble and two insoluble) added to the diet of mice—effects including behavioral alterations and concentrations of biogenic amines. One of these (Komura and Sakamoto 1991) was a short-term (100-d) study and the other (Komura and Sakamoto 1992) was a long-term (12-mo) study. Six-week-old ddY mice were exposed to manganese via a diet containing one of two water-soluble (MnCl2·4H2O and manganese acetate) and two water-insoluble (manganese carbonate and manganese oxide) manganese compounds at a concentration of 2 g/kg or 200 mg/kg (calculated by the authors). Spontaneous motor activity was tested once in 30 d for 30 minutes (min) using an Animex activity meter. After 100 d, red blood cell count, hematocrit, hemoglobin, and white blood cell count were determined. The only hematologic effect seen with MnCl2 was a 42% decrease in white blood

Suggested Citation:"Appendix 9 Manganese (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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cell count. The group fed manganese acetate and MnCO3 had a significantly lower red blood cell count than controls. White cell count was decreased in the group fed manganese acetate, MnCl2, and MnO2. In the NTP (1993) 13-wk MnSO4 feed study in B6C3F1 mice, a decrease in white blood cell count was seen only in mice treated with more than 20 times the dose used by Komura and Sakamoto. Although one might argue that the salt (MnSO4 versus four other salts) and mouse strain (B6C3F1 versus ddY mice) were different in the two studies, such a difference in response is unexpected. Even with MnCl2 at 200 mg/kg, the authors did not find any change in motor activity compared to that of control mice, whereas in the manganese acetate group, it was lower at all three durations (30, 60, and 90 d). The difference between mice exposed to MnCl2·4H2O and manganese acetate cannot be explained. The dose used was very high and no dose-response data were reported. Because of the lack of consistent findings in hematology and low confidence in the spontaneous motor activity data, the data were not considered for AC calculation.

Chronic Toxicity (>100 d)
Human Exposure Data

Few reports exist about neurologic effects associated with human exposure to manganese from environmental sources such as drinking water. The neurotoxic effects on human populations of low-level exposure to manganese from environmental exposures have been reviewed by Mergler (1999). In this review, the authors drew attention to the progression of dysfunction leading to manganism after cessation of exposure.

In one epidemiologic study of an elderly population in Greece, Kondakis et al. (1989) evaluated an association between various concentrations of manganese and clinical symptoms akin to PD. Three areas in northwest Greece that had a range of manganese concentrations in drinking water were chosen for this study. The areas were categorized as areas A, B, and C. Manganese concentrations in natural well water were 3.6-14.6 µg/L in area A, 81.6-252.6 µg/L in area B, and 1,600-2,300 µg/L in area C. The total population of the three areas ranged from 3,200 to 4,350 people. The study included only individuals over 50 y of age, drawn from a random sample of 10% of all households. The number of subjects was 62, 49, and 77 for areas A, B, and C, respectively. The authors had stated that “all areas were similar with respect to social and dietary characteristics” and that it was improbable that dietary differ-

Suggested Citation:"Appendix 9 Manganese (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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ences existed, because food, fruits, and vegetables were traded among all these areas. A neurologist assigned a score value (from 0 [absent] to 3 [strong]) for each symptom for each subject based on its diagnostic value for PD. The mean combined scores for both sexes within an area were 2.7, 3.9, and 5.2 for regions A, B, and C, respectively. It must be pointed out that comparisons between sexes within an area and among areas were not very consistently significant. For example, the difference between region A and region C was statistically significant for men and not for women, even though in both genders combined, the difference in mean scores was highly significant. The data need to be interpreted cautiously. Only selected older populations were covered in this study. Although 33 symptoms were tested for presence and severity, the authors did not report which neurologic signs or symptoms increased. The investigators had assumed the symptoms of manganism are the same as those of PD. They did not measure sleep and emotional stability parameters, which were altered in miners exposed to manganese. The authors did correlate the prevalence of neurologic symptoms with the progressive concentration of manganese in the hair of the elderly subjects. Using hair manganese concentrations may have only a limited value as a measure of manganese body burden. Mn-B did not differ between areas A and C. There was no difference between genders for Mn-B or any correlation between Mn-B and hair manganese concentration. The authors did not report the general health status of this elderly population or whether subjects were taking any medications.

In a cohort study conducted in northern Germany, manganese burden from rural well water was studied cross-sectionally in two communities that had their own drinking-water wells (Vieregge et al. 1995). Study participants were randomly selected from right-handed residents over the age of 40 who had used their well as their principal source of drinking water for at least 10 y. Group A consisted of 41 subjects with a mean age of 57.5 y who were exposed to manganese at least 0.3 mg/L (range 0.3-2.16) in well water, and Group B consisted of 74 subjects with a mean age of 56.9 y who were exposed to concentrations of less than 0.05 mg/L. The authors stated that the groups were homogenous with regard to age, sex, nutritional habits, and drug intake. Structured questionnaires were used to gather data on medical and occupational history, habits, and medication use. Mean hemoglobin, ceruloplasmin, copper, and iron values, as well as results of liver function tests, were within the acceptable range in both groups. Each subject underwent a complete, standardized neurologic assessment by a neurologist who did not know the subject’s manganese exposure history. Data were collected by administering a symptom questionnaire, performing an assessment of possible PD signs

Suggested Citation:"Appendix 9 Manganese (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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by the Columbia University Rating Scale (CURS), and measuring the fine motor coordination of both hands using an instrument called MLS-22. MLS tests consisted of the following trials: 1) aiming, 2) steadiness, 3) line pursuit, and 4) tapping rate. No significant difference in any neurologic measure was found between groups, leading the authors to conclude that chronic exposure to drinking water containing manganese at concentrations of 0.3 mg/L will not result in detectable neurologic impairment. Several positive aspects of the quality of this study will be considered in conjunction with the study from rural Greece by Kondakis et al. (1989).

Several publications from the Ben-Gurion University of Israel discuss studies designed to evaluate the etiologic factor or factors responsible for the increased prevalence of PD in three adjacent clusters of kibbutzim (rural settlements) in southern Israel. In residents older than 40 in each of these three clusters, the prevalence of PD was 5 times greater than in residents in the remainder of the region (see Herishanu et al. 2001 and references cited therein, including Goldsmith et al. 1990). It was reported that well water and soils contained excess manganese and that Maneb (a manganese-containing fungicide) was commonly used in the area, but concentrations of these were not reported. In addition to the fact that both inorganic and organic manganese compounds were present, confounding factors such as an excess of aluminum and iron, as well as other heavy metals found in the water and soil in that region, make it difficult to use these data for quantitative risk assessment for inorganic manganese.

A few miscellaneous studies have associated environmental manganese exposures and adverse neurologic effects. Chinese children (11-13 y old) who were exposed to increased manganese concentrations (about 0.24 mg/L) in water and wheat irrigated with sewage for 3 y performed poorly in neurobehavioral tests and performed poorly at school compared to control children from a nearby village. Hair manganese concentrations reported in this study correlated negatively with performance scores (Zhang et al. 1995, based on the abstract from Medline for this Chinese paper). iron, copper, and zinc were measured in blood and hair; performance was inversely correlated only with hair manganese concentrations. Daily dietary intake of manganese was not provided. Gottschalk et al. (1991) reported significantly elevated manganese concentrations in the hair of populations of prisoners incarcerated for violent behavior compared with nonviolent subjects in the prison population. The source of exposure was not known.

Some case reports have associated adverse neurologic effects and exposure to manganese, sometimes apparently caused by the defective

Suggested Citation:"Appendix 9 Manganese (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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metabolism of manganese. One case history was that of a 62-y-old male who had been receiving parenteral nutrition that contained manganese (salt not known) at 2.2 mg/d for 23 mo (Ejima et al. 1992). He exhibited all of the symptoms of PD. An extrapolated oral amount of manganese was calculated as 40 mg/d. Another case was that of an 8-y-old girl who had end-stage liver disease with a block in biliary secretion and showed signs of manganism. Her intracranial T1 MRI scans indicated hyperintense globus pallidus and subthalamic nuclei. Biliary obstruction may have resulted in an increased uptake of circulating manganese by the brain (Ejima et al. 1992).

Animal Exposure Data

Considerably more data are available on the neurologic effects of manganese ingestion in animals. However, only a few studies have reported clinical signs such as weakness, ataxia, or altered gait following oral dosing. Gupta et al. (1980) conducted a study on adult male rhesus monkeys (5-6 kg) who were given MnCl2 at 25 mg/kg (6.9 mg/kg/d) orally by gavage for 18 mo. The monkeys developed weakness and muscular rigidity of the lower limbs. Histologic analysis also revealed scanty neuromelanin granules and degenerated neurons in the substantia nigra with gliosis and neuronal loss. This may be related to the fact that melanins are formed by the oxidation of DA, and DA depletion may be the reason for neuromelanin depletion, as noted by several investigators.

In male albino rats exposed to MnCl2 (manganese at 100 mg/kg/d) in drinking water for 360 d, catecholamines (norepinephrine [NE] and DA), HVA, MAO, and manganese were measured in the corpus striatum (Chandra and Shukla 1981) at different time intervals up to the full period of 360 d. Manganese treatment initially increased the concentrations of DA, NE, and HVA, but normal concentrations were seen from 120-240 d, and thereafter, the concentrations of these decreased significantly from 300 to 360 d. These concentrations could not be correlated with the concentration of tissue manganese in this region of the brain, which increased to a maximum at 240 d and remained at that concentration until the end of the study. In spite of the fact that the underlying cause (neuronal loss in the basal ganglia) of the psychiatric and neurologic phases of chronic manganese poisoning is known, it is difficult to determine a NOAEL for the interim duration of 100 d, because it is not clear that the early increase is an adverse effect.

Gianutsos and Murray (1982) observed that administration of manganese to mice in the form of MnCl2 (4%) in the diet for 6 mo (manga-

Suggested Citation:"Appendix 9 Manganese (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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nese at 2,300 mg/kg/d) resulted in a decrease in concentration of DA in the striatum and olfactory tubercles. The GABA content of the striatum was higher after treatment, whereas the cerebellar GABA content did not change. Choline acetyltransferase activity remained unchanged. Changes in neurotransmitter concentrations were observed after long-term manganese administration but were not seen in mice exposed to MnCl2 for 1-2 mo (Gianutsos and Murray 1982).

Similarly, in two studies by Bonilla and coworkers in which male rats were given manganese via drinking water (0.1 and 5 mg/mL) for 8 mo, an increase in motor activity during the first mo, normal activity during months 2-6, and then activity significantly lower than control after 6 months were observed (Bonilla 1984). A part of this study was described in the earlier section. Bonilla and Prasad (1984) conducted a study in male Sprague-Dawley rats on the effect of chronic intake (for 8 mo) of two concentrations (MnCl2 at 0.1 and 1 mg/mL) in drinking water on the concentrations of biogenic amines and their metabolites in several regions of the brain. One of the metabolites of DA, DOPAC, was found to be significantly reduced in both striatum and hypothalamus in both of the manganese-treated groups. There was no dose-consistent change in the other metabolite, homovanillic acid. A significant decrease in noradrenaline in the pons was also observed in both treated groups. The authors did not measure locomotor activities. The changes reported in the study do not appear to be dose related (Bonilla and Prasad 1984).

Nachtman et al. (1986) examined the effects of chronic manganese exposure on locomotor activity in rats maintained on MnCl2·4H2O at 0 or 1 mg/mL in drinking water for 65 wk. Locomotor activity was tested in 15-min sessions several times during the study. Manganese treatment produced a significant increase in activity in weeks 5-7, control values at 8 wk, and decreases from 14 to 29 wk. Manganese-exposed animals were found to be more responsive to the effects of d-amphetamine (1.25 mg/kg) than controls. This increased responsiveness to d-amphetamine found in earlier weeks was gone at weeks 41 and 65. The results were similar to those of the study described previously.

In addition to their 100-d study described earlier, Komura and Sakamoto (1992) also conducted a 12-mo study in which male ddY mice were chronically treated with four forms of manganese (MnCl2·4H2O, manganese acetate tetrahydrate, MnO2, and MnCO3) mixed in the diet at 2 g/kg. Biogenic amines in the brain and spontaneous motor activity were measured several times during the course of 12 mo. The manganese concentrations were higher in some parts of the brain after exposure to insoluble salts than after the soluble salts. A review of the data presented as a graph indicates that it is difficult to come to such a definite conclu-

Suggested Citation:"Appendix 9 Manganese (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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sion. The concentrations of hypothalamic DA correlated with the manganese concentrations, especially in the manganese acetate-exposed group. In addition, the amount of brain manganese correlated well with the extent of suppression of spontaneous motor activity measured using an Animex Activity Meter. Paradoxically, the largest manganese content was found in the cerebral cortex of mice treated with insoluble manganese compounds, MnCO3 and MnO2. In concordance with this, spontaneous motor activity was most affected in MnO2-fed mice. In the mice exposed to soluble manganese compounds, at the end of 12 mo, there was a significant decrease in DA and an increase in HVA, indicating that metabolism of DA increased.

In the 2-y NTP (1993) study, MnSO4·H2O was administered to rats (at doses of 0, 20, 65, and 200 mg/kg for males and 0, 23, 75, and 232 mg/kg for females) and mice (0, 52, 175, and 585 mg/kg for males and 0, 65, 228, and 731 mg/kg for females). Survival decreased in male rats fed the highest dose; however, females fed this amount of manganese were not affected. Several rats died in both the control and treated groups. But the cause of death in male rats was attributed to increased severity of nephropathy and renal failure. The survival of male and female mice that received MnSO4 at 15,000 ppm (manganese at about 600-750 mg/kg/d) for 2 y was not affected. Similarly, mice tolerated doses of MnCl2 as high as 2,270 mg/kg/d) in their diet for 6 mo without lethality (Gianutsos and Murray 1982). The authors did not observe any histologic changes in the lungs or cardiovascular system or any clinical signs of impaired function of these organs.

In rats fed MnSO4 at as much as 15,000 ppm (up to 232 mg/kg/d) for 2 y, no histologic effects on the GI system were observed. Mice in the highest-dose groups of this study (15,000 ppm for 730 mg/kg/d) had hyperplasia, erosion, and inflammation of the forestomach, but these effects were considered minor. Significant hepatic histologic changes were observed in neither mice nor rats exposed to MnSO4 in their diet for 2 y at various concentrations.

Genotoxicity

Studies of the genetic toxicology of manganese salts have been carried out using several methods, such as the Salmonella typhimurium/mammalian-microsome mutagenicity test (also in a preincubation-type assay), the rec assay with Bacillus subtilis for growth inhibition caused by DNA damage, the reversion assay with Escherichia coli, and many others. There appear to be some differences in results with differ-

Suggested Citation:"Appendix 9 Manganese (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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ent types of salt. MnCl2 was negative in S. typhimurium strains TA98, TA102, and TA1535 and weakly positive in TA1537 without activation (Wong 1988), whereas it was weakly positive in the preincubation protocol with TA102 but not with TA100 (De Meo et al. 1991). MnSO4 was negative in TA98, TA100, TA1535, TA1537, and TA97 (Mortelmans et al. 1986). MnCl2 was found to be positive in one E. coli strain (Zakour and Glickman 1984). In the NTP (1993) bioassay, using a preincubation, MnSO4 (100-10,000 µg/plate) was not mutagenic in S. typhimurium strains TA97, TA98, TA100, TA1535, or TA1537, with or without induced male Sprague-Dawley rat or Syrian hamster liver S9. MnSO4 was tested in two laboratories.

Several manganese salts (MnCl2, manganese nitrate, MnSO4, manganese acetate) were positive in the B. subtilis rec assay (Nishioka 1975), but were negative in the same system in a different study (Kanematsu et al. 1980).

Both MnSO4 and MnCl2 gave mutagenic dose-response relationships on tester strain TA102 without S9 mix. The mutagenic potencies were 2.8 and 2.4 revertant/nmole for MnSO4 and MnCl2, respectively. MnCl2 also induced DNA damage in human lymphocytes as determined by the “single cell gel assay.”

While Parry (1977), using the fluctuation test in yeast, found MnSO4 to be negative, Singh (1984) found MnSO4 to be positive in the yeast gene conversion and reversion assay. In mammalian cell tests, MnCl2 was positive for gene mutation in mouse lymphoma cells (Oberly et al. 1982), positive in the Syrian hamster ovary cells transformation assay (Casto et al. 1979), and positive in the DNA damage assay in human lymphocytes (De Meo et al. 1991). MnCl2 at high concentrations (10 mM) caused single-stranded DNA breaks in both Chinese hamster ovary (CHO) cells and human fibroblast cell cultures; the CHO cells seemed to be more sensitive (Hamilton-Koch et al. 1986).

Significant increases in chromosomal aberrations in CHO cells (Galloway et al. 1987) and in sister chromatid exchanges (SCE) in mouse fibroblasts and human lymphocytes (Andersen 1983) were reported. In cytogenetic tests with CHO cells, MnSO4 induced SCEs with and without S9 activation (NTP 1993).

In the in vivo genotoxicity tests, MnSO4 did not induce sex-linked recessive lethal mutations in germ cells of adult male Drosophila melanogaster treated with 12,500 ppm in feed or 1,000 ppm administered by injection. Similar results were obtained by Rasmuson (1985) with the somatic mutation system.

MnSO4 also induced chromosomal aberrations in CHO cells in the absence or presence of S9; in the presence of S-9, no significant increase

Suggested Citation:"Appendix 9 Manganese (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

in chromosomal aberrations compared with the results of tests without S9 was observed. A dose response was not clear.

Joardar and Sharma (1990) reported that when male Swiss albino mice were administered various concentrations of MnSO4 (MnSO4·H2O at 10.25, 20.5, and 61 mg/100 g body weight), it was clastogenic. For the chromosomal analysis, the animals were dosed daily for up to 21 d. The chromosomal aberrations in both bone marrow and micronuclei were significantly increased. In contrast, in earlier work in albino rats treated with oral doses of MnCl2, tests for induction of chromosomal aberrations in the bone marrow cells were negative. No induction of heritable translocations was observed in mice treated with MnSO4 in the feed for 7 wk, nor was induction of dominant lethal mutations observed in rats gavaged with MnSO4 for 1-5 d (Newell et al. 1974).

In spite of the fact that the results are mixed from both the in vivo and in vitro systems in prokaryotes, yeast, fungi, and mammalian systems, the positive results strongly indicate that excess manganese may be genotoxic.

Carcinogenicity

Manganese dusts, fumes, and soluble salts have not been recognized as possible human carcinogens by any of the regulatory and health organizations. Few animal studies have looked at the carcinogenic potency of manganese compounds. Stoner et al. (1976), using a strain A mouse lung tumor model, investigated the carcinogenic potency of MnSO4 in 6- to 8-wk-old mice after a total of 22 ip injections (3/wk) of MnSO4 at 132, 330, or 660 mg/kg of body weight (42.9, 107, or 214 mg/kg). The highest-dosed group had a slight increase in the number of pulmonary adenomas. Results for other groups were similar to those for the control group, which had been injected with vehicle solution. Because this strain A lung tumor model could detect only 5 of 18 known carcinogens, the validity of this result has been questioned. In an earlier study, DiPaolo (1964) injected DBA mice ip or sc with 0.1 mL of 1% MnSO4 solution (manganese at 200 mg/kg per injection) twice weekly for 6 mo (62.3 mg/kg/d). After 18 mo, 67% of mice treated via sc and 41% of ip-treated mice developed lymph sarcomas (24% of animals in the control group responded similarly). The study was reported only as an abstract.

In the NTP (1993) 2-y feeding study with MnSO4, when rats ingested MnSO4 at 0, 1,500, 5,000, or 15,000 ppm in the diet (see

Suggested Citation:"Appendix 9 Manganese (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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TABLE 9-4 Incidence of Nonneoplastic Lesions of the Pancreas in Male Rats in the 2-y MnSO4 Feed Study

Dose in food (ppm)

Dose (mg/kg/d)

Hyperplasia

Adenoma

0

0

0/52

0/52

1,500

20

2/50

3/50

5,000

65

2/51

4/51

15,000

200

3/51

3/51

Source: Data from NTP 1993.

Table 9-4 for estimated average doses), hyperplasia or adenomas of the pancreatic islets occurred in a few males of all the treated groups, but none were found in the controls. In addition, carcinoma of the pancreas was seen in one male rat of the highest-dose group (NTP 1993). Adenomas and carcinomas were within the NTP (1993) historical controls, even though the study controls had none.

Chronic oral exposure of mice and rats to MnSO4 in the feed resulted in a marginally increased incidence of thyroidal follicular cell adenomas. From the results of this 2-y study, NTP (1993) concluded that there was no evidence of carcinogenic activity in male or female rats fed MnSO4 at 1,500 or 15,000 ppm in their diet for 2 y. But there was equivocal evidence of carcinogenic activity in male and female B6C3F1 mice based on the marginally increased incidence of thyroid gland follicular cell adenoma and the significantly increased incidence of follicular cell hyperplasia.

Biologically significant changes did occur in the incidences of neoplasms and/or non-neoplastic lesions in the thyroid gland, forestomach, and liver of male and female mice.

In the thyroid glands, at the end of the 2-y study in mice, the incidence of follicular dilatation increased significantly in males exposed to MnSO4·H2O at 15,000 ppm and females exposed to 5,000 or 15,000 ppm (see Table 9-5). A significantly increased incidence of focal hyperplasia of follicular epithelium also occurred in males dosed with 15,000 ppm and in all manganese-fed females. Follicular cell adenomas were found in some males and females fed manganese at 15,000 ppm, but the incidence of adenomas was not considered significantly different from that of controls (NTP 1993). However, an increased incidence of follicular cell hyperplasia with adenoma leads one to conclude that there is equivocal evidence of carcinogenicity in mice.

In the forestomach in male and female mice exposed to MnSO4 at 15,000 ppm, a statistically significant increased incidence of focal

Suggested Citation:"Appendix 9 Manganese (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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TABLE 9-5 Thyroid Lesions in Mice That Received MnSO4 in the Diet for 2 Years

Sex

Lesions

Concentration of MnSO4 in the Feed

Control

1,500 ppm

5,000 ppm

15,000 ppm

Male

Follicular dilatation

2

2

5

23a

 

Follicular cell hyperplasia

5

2

8

27a

 

Follicular cell adenoma

0/50

0/49

0/51

3/50

Female

Follicular dilatation

1

5

11a

24a

 

Follicular cell hyperplasia

3

15a

27a

43a

 

Follicular cell adenoma

2/50

1/50

0/49

5/51

aSignificantly different (p 0.05) from the control group by logistic regression test.

Note: The follicular cell adenomas were only slightly increased above the historical controls.

Source: Modified from NTP 1993.

hyperplasia of the forestomach squamous epithelium occurred, accompanied by ulceration or erosion and by inflammation with focal occurrence of infiltrating neutrophils and mononuclear leukocytes at various sites on the forestomach mucosa.

In mice at the 9-mo interim evaluation, absolute liver weights of males exposed to 15,000 ppm and females exposed to 5,000 or 15,000 ppm were significantly lower than those of controls. Because these groups also had lower mean body weights and relative liver weights were similar to those of controls, the lower absolute liver weights cannot be considered an adverse effect of the manganese dose.

Reproductive Toxicity

Few reports exist on the reproductive toxicity of manganese compounds in humans or experimental animals. All of the human data are from an occupational setting where workers were exposed to manganese dust or manganese oxide, and all pertain to long-term exposure to manganese (Baranski 1993). Manifested symptoms included loss of libido and impotence (Rodier 1955; Mena et al. 1967; Kilburn 1987) and a decrease in the number of children born to the workers exposed to manganese dust (Lauwerys et al. 1985). Gennart et al. (1992) did not find any

Suggested Citation:"Appendix 9 Manganese (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

difference in the reproductive rate of dry-battery plant workers exposed to 0.71 mg/m3 of manganese dust for 6.2 y. No reports of any adverse reproductive effects in humans from the ingestion of manganese by the oral route could be located.

There are several studies that had looked at the reproductive effects of manganese after injection of the solution (ip or sc). These studies will not be discussed here. Several rodent studies have reported that ingestion of manganese in the diet or drinking water leads to adverse reproductive parameters. Laskey and coworkers conducted several experiments in mice and rats administered Mn3O4 in the diet (Gray and Laskey 1980; Laskey et al. 1982). This insoluble form of manganese is not relevant for determining AC for drinking water. When weanling mice were fed a diet containing Mn3O4 at 1,050 mg/kg/d and were sacrificed on days 58, 73, or 90, significant decreases in the growth of preputial gland, seminal vesicle, and testes were observed (Gray and Laskey 1980). In Long-Evans rats chronically exposed to dietary Mn3O4 (concentrations of manganese as Mn3O4 at 350, 1,050, and 3,500 ppm) beginning on day 1 of gestation and continuing through 224 d of age, male reproductive development was delayed by manganese treatment as indicated by testes weight, sperm count, and serum follicle-stimulating hormone and testosterone concentrations. After receiving the manganese-containing diet for 100 d, the rats were mated. When male and female rats were fed a diet containing Mn3O4 at 3,500 ppm/kg/d for about 100 d before breeding, male fertility was reduced; female reproductive parameters were unaffected (Laskey et al. 1982). MnCl2 administered to pregnant rats in drinking water (manganese at up to 620 mg/kg/d during the gestation period) did not adversely affect litter size or the sex ratio of the pups (Pappas et al. 1997). Similarly, Kontur and Fechter (1985) did not find any effect on litter size when dams were exposed to concentrations of MnCl2 as high as 1,240 mg/kg/d in drinking water. NTP (1993) did not find changes in testicular weight even at the highest concentration of MnSO4 (50,000 ppm).

In a study by Joardar and Sharma (1990), gavage solutions containing MnSO4·2H2O) at 10.25, 20.5, or 61 mg per 100 g body weight (equivalent to manganese at 33, 66, or 198 mg/kg/d) were administered to mice for 5 d. The percent of sperm with abnormal heads increased with the dose. However, studies in which a dietary regimen of MnSO4 was given to rats and mice for 13 wk or 2 y revealed no gross or abnormal histopathology lesions or changes in reproductive organ weights. No other reproductive parameters were evaluated (NTP 1993).

In a study of male rats exposed to MnSO4 at a concentration of 1,000 ppm (manganese at 30 mg/kg/d in drinking water) for 12 wk,

Suggested Citation:"Appendix 9 Manganese (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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Bataineh et al. (1998) suggested that subchronic exposure to MnSO4 has adverse effects on sexual behavior, territorial aggression, and the reproductive system of the adult male rat. Although ingestion of MnSO4·2H2O in drinking water for 12 wk did not affect male rat fertility, the total number of resorptions increased in female rats impregnated by treated males. Only one dose was used. Confidence in these data is low because other metals tested as a part of this study, such as aluminum chloride, lead acetate, and copper chloride, produced very similar results. Such effects have not been previously reported for these metals. The concentration of MnSO4·2H2O used in this study (1 g/L) is rather high. Elbetieha et al. (2001), from the same laboratory, reported that when sexually mature male and female Swiss mice were exposed to MnCl2·4H2O for 12 wk at 1, 2, 4, and 8 g/L in drinking water, fertility was significantly reduced in males of the high-dose group. The average daily doses, calculated from the water consumption data provided by the authors, were 30, 48, 98, 196 mg/kg/d for males and 28, 52, 100, and 176 mg/kg/d for females. Ingestion of MnCl2·4H2O at 8,000 mg/L significantly reduced the fertility of male rats. There were no effects on the number of implantations, viable fetuses, or resorptions in untreated females impregnated by treated males. Fertility was not significantly affected in treated female mice, but the number of implantations and viable fetuses in the highest dose group (MnCl2 at 8 g or 176 mg/kg/d) was reduced. A LOAEL of 196 mg/kg/d and a NOAEL of 98 mg/kg/d for adverse effects on male fertility was identified. Water consumption decreased in all dosed groups, without a clear dose-response effect. It must be noted that the dosage concentrations used were much higher than one would encounter from sources of water.

Szakmary et al. (1995) observed adverse effects of manganese on reproduction parameters of rats but not rabbits. Administering MnCl2 to pregnant rabbits and rats, by gavage at doses of 0, 11, 22, and 33 mg/kg/d resulted in an increase in the postimplantation loss in the rat but not in the rabbit (as cited in ATSDR 2000).

Recently, Ponnapakkam et al. (2003) assessed organ weights and histopathology of male reproductive organs and sperm parameters in 6-wk-old male CD-1 mice (n = 12/group) that received manganese acetate at 7.5, 15, and 30 mg/kg/d as gavage doses for 43 d. The dose rates were calculated as 1.65, 3.3, and 6.6 mg/kg/d. In mice of the 15 and 30 mg/kg/d groups, cauda epididymis and testis sperm counts and sperm motility showed significant reductions. No alterations were found in male fertility (examined only in the 30 mg/kg group) based on the number of implantations, corpus lutea, number of resorption sites, and num-

Suggested Citation:"Appendix 9 Manganese (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

ber of live and dead fetuses, or histopathology of right testis, epididymis, seminal vesicle, or accessory glands.

Developmental Effects

There have not been many conclusive studies of the teratogenic effects of manganese exposure in humans. The incidences of neurologic disorders, birth defects, and stillbirths were elevated in a small population of people living on an island having rich manganese deposits (Kilburn 1987), but no reliable association with manganese exposure could be made.

Animal studies indicate that manganese salts can cross the placental barrier to fetuses. The FDA carried out a teratologic evaluation of MnSO4 in rats, mice, hamsters, and rabbits. The compound was gavaged at different doses in each of these species (0.783-78.3 mg/kg for rats, 1.25-125 mg/kg for mice, 1.36-136 mg/kg for hamsters, and 1.12-112 mg/kg for rabbits). No significant effects were seen on maternal or fetal survival, nor were any abnormalities found in the soft or skeletal tissues of the test groups (NTIS 1973). Studies in which manganese compounds were injected ip, iv, or sc have documented fetal deaths and skeletal malformations when the compound was injected during the gestation period. These studies are not relevant to setting oral exposure guidelines for spacecraft and will not be described here.

Pappas et al. (1997) reported that when MnCl2 in drinking water at 0, 2, or 10 mg/mL was provided to rat dams and their litters from conception until postnatal day 30 (PND-30), no physical abnormalities were observed in the offspring. The rats exposed to MnCl2 at 10 mg/mL had increased cortical manganese concentrations and were hyperactive at PND-17.

A summary of manganese toxicity studies described in the above paragraphs is listed in Table 9-6.

LIMITS SET BY OTHER ORGANIZATIONS FOR SOLUBLE MANGANESE

Table 9-7 provides a list of the current standards and recommendations by other organizations. The EPA SMCL is 50 µg/L based on taste and discoloration. The World Health Organization’s (WHO’s) guideline value in drinking water for aesthetic quality is 100 µg/L.

Suggested Citation:"Appendix 9 Manganese (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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TABLE 9-6 Manganese Toxicity Summary

Chemical Form

Species and Gender

Mode of Dosing and Duration

Dose

Effects

LOAEL/ NOAEL (mg/kg/d)

Reference

MnSO4

Human case report

Hemodialysis solution (iv)

40 mg/L; 30 min

Severe vomiting, abdominal pain, increased heart rate and blood pressure; acute pancreatitis on day 2

Serious effect; not calculated

Taylor and Price 1982

MnCl2

Women

Capsule, single dose

40 mg

No adverse effect reported

NOAEL = 0.57

Freeland- Graves and Lin 1991

Manganese supplement aminoacid chelated

Women (60 kg)

Oral, 1, 25, 60, 89, and 124 d

15 mg

No adverse effects on hematocrit, serum iron, zinc and copper, or indexes of iron status; lymphocyte manganese superoxide dismutase (manganese status) did not change until day 89

NOAEL = 15 mg/d for up to 89 d; or 0.25 mg/d as supplement

Davis and Greger 1992

MnSO4 supplemented in diet

Women

Oral; diet (60 d)

0.7 or 9.5 mg/d supplement

No changes in hematocrit, hemoglobin, erythrocyte count, white cells, or platelets

NOAEL = 0.15 mg/kg/d (body weight assumed to be 60 kg)

Finley 1999

Dietary intake

Women

Diet (56 d)

0.8 or 20 mg/d; 8 wk

No signs of adverse symptoms of neurologic and motor steadiness or psychological assessments attributed to Mn

NOAEL = 20 mg/d or 0.33 mg/kg/d

Finley et al. 2003

Suggested Citation:"Appendix 9 Manganese (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

MnSO4·H2O

Swiss albino mouse, male

Gavage, 2 doses

33, 66, and 198 mg/kg/d

Increased frequency of micronucleated polychromatic and normochromatic erythrocytes as a function of dose

LOAEL = 33

Joardar and Sharma 1990

MnSO4·H2O

Swiss albino mouse, male

Gavage, 5 doses

33, 66, and 198 mg/kg/d

Increased sperm head abnormalities as a function of dose

LOAEL = 33

Joardar and Sharma 1990

MnSO4

F344/N rat, male

In feed, 14 d

0, 84, 165, 340, 665, and 1,264 mg/kg/d

Decreased neutrophils and leukocyte counts; reduced liver weight; decreased body weight

LOAEL = 1,264; NOAEL = 665

NTP 1993

MnSO4

F344/N rat, female

In feed, 14 d

0, 84, 159, 340, 675, and 1,275 mg/kg/d

Decreased body weight; No hematolog , neurologic, reproductive, hepatic, or renal system effects

LOAEL=1275; NOAEL = 675

NTP 1993

MnSO4

B6C3F1 mouse, male

In feed, 14 d

0,121, 262, 669, 1,603, and 3,212 mg/kg/d

No effect on body weight, hematologic , respiratory, hepatic, renal, reproductive, or cardiovascular systems

LOAEL = none; NOAEL = 3,200

NTP 1993

MnSO4

B6C3F1 mouse, female

In feed, 14 d

0, 240, 488, 1,068, 2,494, and 3,560 mg/kg/d

No changes in body weight; no effect on hematologic , respiratory, hepatic, renal, reproductive. or cardiovascular system.

LOAEL = none; NOAEL = 3,500

NTP 1993

Suggested Citation:"Appendix 9 Manganese (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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Chemical Form

Species and Gender

Mode of Dosing and Duration

Dose

Effects

LOAEL/ NOAEL (mg/kg/d)

Reference

MnSO4

Swiss albino mouse, male

Gavage, 7, 14, 21 d

33, 66, 198

Increased chromosomal aberrations and breaks

LOAEL=33

Joardar and Sharma 1990

MnCl2·4H2O

CD rat, male

Gavages, 21 d at 0, 25, and 50 mg/kg

7 and 14 mg/kg

No changes in clinical observations; no change in striatal DA or DOPAC; no changes in spontaneous motor activity; decreased acoustic startle reflex was noted only in low-dose group

LOAEL = 14

Dorman et al. 2000

MnCl2

ITRC rats, male

Drinking water, 30 d

140 mg/kg/d

Hyperactivity, aggression, altered neurotransmitter levels, increased turnover of striatal DA

LOAEL = 140; only dose (serious effects)

Chandra et al. 1983

Manganese acetate

CD-1 mouse, male (6 wk old)

Gavages, (43 d) at 7.5, 15, and 30 mg/kg/d

1.65, 3.3, and 6.6 mg/kg/d

Significant decrease in caudal epididymal and testicular sperm counts, and sperm motility of two high-dose groups; no changes in mating behavior or fertility of male mice and no abnormal histopathol- ogy of testicular tissues (testis and epididymis) in mice treated at the highest dose; no manganese-related changes in the fetuses delivered on gestation day 18

NOAEL = 1.65

Ponnapakkam et al. 2003

Suggested Citation:"Appendix 9 Manganese (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

MnCl2

Sprague- Dawley rat, male

Drinking water, 2 mo at 10 mg/mL

400 mg/kg/d

Decreased water consumption; increased GABA in caudate nucleus; motor activity not assessed

LOAEL = 600

Bonilla 1978

MnCl2

Albino rat, male

Drinking water, 90 d

12 mg/kg/d

Altered DA, serotonin, and MAO

LOAEL = 12

Subhash and Padmashree 1991

MnCl2

Rat, male (20 d old)

Drinking water, 13 wk at 20 mg/L

550 mg/kg/d

No neuronal loss or gliosis in GP, but GP neurons were vulnerable to death; peculiar response to glutamate; behavioral tests not done

LOAEL = 550

Spadoni et al. 2000

MnCl2

Rat, male (20 d old)

Drinking water, 10 wk at 20 mg/L

550 mg/kg/d

Rats were hyperactive in the open field tests; manganese concentrations in brain regions, morphologic assessments and electrophysiologic tests done; no overt signs of brain damage; no obvious morphologic or cytologic or cytochemic characteristics of striatum or substantia nigra

LOAEL = 550

Calabresi et al. 2001

Manganese- contaminated water

Human, male and female

Drinking water, 2-3 mo

28 mg/L estimated

Lethargy, increased muscle tonus, tremor; children not affected; microscopic changes in globus pallidus of the dead subject

LOAEL = 28 mg/L

Kawamura et al. 1941

Suggested Citation:"Appendix 9 Manganese (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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Chemical Form

Species and Gender

Mode of Dosing and Duration

Dose

Effects

LOAEL/NOAEL (mg/kg/d)

Reference

MnSO4 dihydrate

Sprague-Dawley rat, male

Drinking water, 12 wk

30 mg/kg/d

Suppressed sexual behavior in males and aggression; number of resorptions increased in females impregnated by exposed males

LOAEL = 30; NOAEL not known.

Bataineh et al. 1998

MnCl2·4H2O

Swiss mice, male and female

Drinking water, 12 wk

0, 38, 76, and 152 mg/kg/d

Reduced male fertility, but no effect on implantations or fetus viability or resorptions; reduced sexual activity

LOAEL = 152; NOAEL = 76

Elbetieha et al. 2001

MnSO4

F344/N rat, male

In feed, 13 wk

0, 33, 66, 113, 275, and 546 mg/kg/d

Increased neutrophil counts; decreased liver weight; no changes in respiratory, cardio, renal, endocrine, neurologic, reproductive, or immunologic systems

LOAEL = none; NOAEL = 275

NTP 1993

MnSO4

F344/N rat, female

In feed, 13 wk

0, 37, 74, 183, 303, and 655 mg/kg/d

Reduced lung weight; no hematologic , respiratory, cardio, renal, hepatic, endocrine, reproductive, or immunologic effects

LOAEL = 655; NOAEL=303

NTP 1993

Suggested Citation:"Appendix 9 Manganese (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

MnSO4

B6C3F1 mouse, male

In feed, 13 wk

0, 135, 260, 530, 1,075, and 2,300 mg/kg/d

Reduced body and liver weights; increased neutrophil; no effect on respiratory, renal, reproductive, or cardiologic systems

LOAEL = 135; NOAEL = not known for hematology /immunology

NTP 1993

MnSO4

B6C3F1 mouse, female

In feed, 13 wk

0, 170, 340, 660, 1,350, and 2,800 mg/kg/d

Reduced body weight and reduced liver weight; increased neutrophil; no effect on respiratory, renal, reproductive, or cardiovascular systems

LOAEL = 170; NOAEL = not known for hematology effects

NTP 1993

MnCl2, manganese acetate, MnCO3, MnO2

ddY mouse, male (6 wk old)

In feed, 100 d

200 mg/kg/d

Decreased hematocrit; erythrocytes, white blood cells; decreased spontaneous motor activity in manganese acetate group; none in MnCl2 group

LOAEL = 200 (only one dose)

Komura and Sakamoto 1991

MnCl2

CD-1 mouse, male

In feed, 180 d

2,300 mg/kg/d

Decreased levels of DA; increased GABA in striatum

LOAEL = 2,300 (one dose only)

Gianutsos and Murray 1982

MnCl2

Sprague- Dawley, rat, male

Drinking water, 8 mo at 0.1 and 1 mg/mL

4 and 40 mg/kg/d

Decrease neurotransmitter norepinephrine in striatum and pons; significant decreases in DOPAC in striatum and hypothalamus at both doses; magnitude of decrease was not dose related

LOAEL = 4

Bonilla and Prasad 1984

Suggested Citation:"Appendix 9 Manganese (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

Chemical Form

Species and Gender

Mode of Dosing and Duration

Dose

Effects

LOAEL/NOAEL (mg/kg/d)

Reference

MnCl2

Sprague-Dawley, rat, male

Drinking water, 8 mo at 0.1 and 5 mg/mL

4,200 mg/kg/d

Increased spontaneous motor activity during the first mo; decreased activity after 6 mo; extent of change same for both doses

LOAEL = 10

Bonilla 1984

MnCl2, manganese- acetate, MnO2, MnCO3

ddY mouse, male

In feed, 12 mo at 2 g/kg diet

200 mg/kg/d

Reduced spontaneous motor activity; reduction in DA and increase in HVA; changes in biogenic amines

LOAEL = 200; (only one dose)

Komura and Sakamoto 1992

MnCl2·4H2O

Sprague-Dawley, rat, male

Drinking water, 65 wk

40 mg/kg/d

Hyperactivity at week 5 to 7; control values at 8 wk; decreased at 14 to 29 wk; increased response to d-Amphetamine seen in earlier week not seen at 41and 65 wk

LOAEL = 40 (only one dose)

Nachtman et al. 1986

MnCl2·4H2O

Rhesus monkey, male

Gavage, 18 mo

6.9 mg/kg/d

Muscular weakness; rigidity of lower limbs; histopathology confirmation

LOAEL = 6.9 (only one dose)

Gupta et al. 1980

MnSO4

F344/N rat, male

In feed, 2 y

0, 20, 65, and 200 mg/kg/d

Chronic progressive nephropathy; reduced body weight; no changes in lung weight; no hematologic , GI, cardiovascular, hepatic, endocrine, reproductive, or immunologic effects

LOAEL = 200; NOAEL = 65

NTP 1993

Suggested Citation:"Appendix 9 Manganese (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

MnSO4

F344/N rat, female

In feed, 2 y

0, 23, 75, and 232 mg/kg/d

No changes in lung weight; no hematologic , respiratory, cardiovascular, renal, hepatic, endocrine, reproductive, or immunologic effects

NOAEL = 232

NTP 1993

MnSO4

B6C3F1 mouse, male

In feed, 2 y

0, 52, 175, and 585 mg/kg/d

Hyperplasia and erosion of GI tract; forestomach ulceration and inflammation; increased hematocrit, hemoglobin, and erythrocyte count; follicular hyperplasia of thyroid and dilation; no effect on body weight or respiratory, renal, reproductive, or cardiovascular systems

LOAEL =175; NOAEL = 52 for renal and body weight

NTP 1993

MnSO4

B6C3F1 mouse, female

In feed, 2 y

0, 65, 228, and 731 mg/kg/d

Ulceration and inflammation of forestomach; thyroid follicular hyperplasia; 13% decrease in body weight; no significant changes in liver weight; no hematologic effects; no effect on respiratory, renal, reproductive, or cardiovascular systems

LOAEL = 65 for thyroid effect; NOAEL = not known

NTP 1993

Suggested Citation:"Appendix 9 Manganese (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

Chemical Form

Species and Gender

Mode of Dosing and Duration

Dose

Effects

LOAEL/NOAEL (mg/kg/d)

Reference

MnCl2·4H2O

Wistar rat, male and female

Drinking water, 2 y

40 mg/kg/d

A developmental rat model: expo- sure initiated in utero; measure-ments made at 2 and 24 mo after manganese exposure; altered uptake of neurotransmitters such as DA and choline in brain regions

LOAEL = 40 (only one dose)

Lai et al. 1984

MnCl2·4H2O

Wistar rat, male and female

Drinking water, 2 y

1, 10, 20 mg/mL

Developmental model: exposure from in utero to 2 y; brain regional distribution of manganese and other metals studied; increase in manganese accumulation caused region-specific changes in the brain iron, copper, selenium, zinc, calcium, and magnesium concentrations; subcellular fractionation indicates selective enhancement of manganese accumulates in brain mitochondria

No adverse end point studied

Lai et al. 1999

Manganese salt form not specified

Human case report

Parenteral nutrition (iv)

2.2 mg/d, 23 mo (690 d)

Developed symptoms characteristic of Parkinson’s disease

Serious effect; LOAEL not estimated

Ejima et al. 1992

Suggested Citation:"Appendix 9 Manganese (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

Salts not specified; well water

Human, male and female; a Greek study

Drinking water, 50 y

3.6 µg/L to 2.3 mg/L

Weakness, fatigue, gait disturbances, tremors, and dystonia; increase in manganese concentrations in water correlated with higher prevalence of neurologic signs of chronic manganese poisoning based on neurologic scores (diagnostic value for Parkinson’s disease)

NOAEL = 167 µg/L or 0.005 mg/kg/d

Kondakis et al. 1989

Salt form not known; well water

Human, male and female

Drinking water, 10-40 y

<0.05 mg/L or 0.3 to 2.16 mg/L

A German cohort study: no detectable neurologic impairment as determined by structured questionnaire, standardized neurologic examinations, and fine motor coordination measurements

NOAEL = 0.3-2.16 mg/L

Vieregge et al. 1995

Abbreviations: DA, dopamine; DOPAC, dihydroxyphenylacetic acid; GABA, gamma-aminobutyric acid; GI, gastrointestinal; GP, globus pallidus; HVA, homovanillic acid; LOAEL, lowest- observed-adverse-effect level; MAO, monoamine oxidase; NOAEL, no-observed-adverse-effect level.

Suggested Citation:"Appendix 9 Manganese (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

TABLE 9-7 Current Regulatory and Guideline Concentrations from Other Organizations

Standard

Value

Reference

EPA

 

 

MCLG

None established

 

MCL

None Established

 

SMCL

0.05 mg/L (for aesthetic quality)

40 CFR 1991

1-d HA

None derived

 

10-d HA

None derived

 

Longer-term HA

None derived

 

RfD

0.142 mg/kg/d (for food)

IRIS 1996

RfDa

0.050 mg/kg/d (for water)

IRIS 1996

Lifetime HA

None derived

 

Cancer grouping

Group Db

 

ATSDR (Agency for Toxic Substances and Disease Registry

Acute MRL

None Derived

 

Intermediate MRL

None Derived

 

Chronic MRL

None Derived

 

Other Agencies

 

 

FDA

0.05 mg/L for bottled water

21 CFR 1993

WHO

0.1 mg/L for water aesthetic quality

WHO 1984

aA factor of 3 is used to account for increased absorption from water.

bGroup D: Not classifiable as a carcinogen; inadequate or no human and animal evidence of carcinogenicity.

Abbreviations: HA, Health Advisory; MCL, maximum contaminant level; MCLG, maximum contaminant level goal; MRL, minimal risk level; RfD, reference dose, an estimate of a daily oral exposure to the human population (including sensitive subgroups) that is likely to be without an appreciable risk of deleterious effects during a lifetime; SMCL, secondary maximum contaminant level.

The Institute of Medicine (IOM) recently determined a tolerable upper intake level (UL) of 11 mg/d (IOM 2001), which was set for adults based on a NOAEL for Western diets using data from Greger (1999). UL is defined as “the highest level of daily nutrient intake that is likely to pose no risk of adverse effects in almost all individuals.” IOM (2001) also recommended an AI (acceptable intake) of 2.3 mg/d for men and 1.8 mg/d for women of 19+ y of age.

RATIONALE

The following paragraphs provide a rationale for proposing guideline limit values for manganese in spacecraft drinking water for 1 d, 10 d,

Suggested Citation:"Appendix 9 Manganese (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

100 d, and 1,000 d. The values listed were based on ACs for each duration according to Methods for Developing Spacecraft Water Exposure Guidelines (NRC 2000). Usually, an intraspecies factor is not used because astronauts, composed of men and nonpregnant women, come from a healthy population, and there is no evidence of a group of healthy persons having excess susceptibility to Mn+2. However, while considering some adverse effects, consideration has to be given to the physiologic changes that occur in microgravity that could make the astronauts more susceptible to some chemicals. Our search of the literature indicates that no hypersensitivity factors are known to be related to manganese, except in neonates and those with liver disease, who are susceptible to increased toxicity from manganese ingestion. This is not an issue here. A summary of SWEGs derived for various durations is listed in Table 9-8.

A review of the manganese-ingestion studies indicates that there are two key toxicity end points: neurotoxicity and reproductive organ toxicity. The neurotoxicity literature indicates strongly that rodents may not be appropriate models for human neurotoxicity because manganese neurotoxicity often results in a behavioral syndrome and motor disturbances in humans, and the brain organization of rodents is different from that of humans. It should be pointed out that recently, Brenneman et al. (1999) concluded that the rat may be a poor model for human manganese-induced neurotoxicity because selective regional brain distribution of manganese was not observed in CD rats administered manganese as MnCl2, in contrast to what has been reported to occur in humans and primates. Several studies have shown that DA levels of rodents are

TABLE 9-8 Spacecraft Water Exposure Guidelines for Soluble Manganese (Salts)

Duration

SWEG (mg/L)

Toxicity End Point

Reference

1 d

14

No adverse effects (human subject data)

Freeland-Graves and Lin 1991

10 d

5.4

No adverse effect (human subject data)

Davis and Greger 1992

100 d

1.8

No abnormal neurologic effects or clinical parameters

Davis and Greger 1992 and Finley et al. 2003

1,000 d

0.3

No neurotoxicity (human population)

Vieregge et al. 1995

Note: The 1,000-d SWEG is higher than EPA’s SMCL value of 0.05 mg/L. The EPA’s SMCL is based on taste and discoloration.

Suggested Citation:"Appendix 9 Manganese (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

affected by manganese exposure. Various indications of an initial increase in DA are followed by a normal response, which is followed by a significant decline (Cotzias et al. 1976; Gupta et al. 1980; Chandra and Shukla 1981; Barbeau 1984). Rodents have very low levels of pigment (neuromelanin) in the substantia nigra compared to those found in humans and monkeys. The argument that favors comparison between rodents and humans is that, in both cases, oral bioavailability is only 3-5%, and the clearance pathway is essentially biliary. Furthermore, rodents and humans respond to nutritional change very similarly; for example, an iron-deficient diet increases manganese absorption. Nevertheless, nonhuman animals require much more manganese than humans do. Rodents seem to tolerate much higher supplemental doses than humans, and thus, caution must be exercised when using species factors to extrapolate rodent data to humans. Rodents, like primates including humans, exhibit neurobehavioral effects attributed to manganese poisoning, but the neurologic symptoms seem to be different (McMillan 1999).

Manganese is essential for normal physiologic function because it is a cofactor for several enzymes involved in energy metabolism. In addition, it is an integral part of superoxide dismutase and pyruvate carboxylase. It seems to play a key role in the production of superoxide anions in the mitochondria of many mitochondria-rich organs, including the brain. Yet there is no RDA for manganese because it is available in numerous food sources to various degrees and no natural deficiency of manganese in humans has been encountered. In 1973, after evaluations of standard diets in the United States, England, and Holland, WHO concluded that manganese at 2-3 mg/d for adults is adequate and 8-9 mg/d is safe. The Food and Nutritional Board of the National Research Council (NRC) of the National Academy of Sciences (NAS) determined an estimated safe and adequate daily dietary intake (ESADDI), which is 2-5 mg/d for adults (NRC 1989).

NRC (1989) based this ESADDI on the metabolic study by McLeod and Robinson (1972). Four women aged 19-22 y old were fed various foods as a source of manganese for 27 d. A positive balance (of 0.32 mg) was obtained after an intake of 2.78 mg/d. Several metabolic studies conducted after this work obtained results close to this value. Also, The Total Diet Study (Pennington et al. 1989) conducted in the United States between 1982 and 1986 showed that the average of the intake of manganese was 2.7 mg/d for men and 2.2 mg/d for women. On the basis of the report by WHO (1973) that stated that adverse effects were seen in people consuming 8-9 mg/d, NRC suggested that the occasional intake of about 10 mg/d will not cause any adverse effects. Also,

Suggested Citation:"Appendix 9 Manganese (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

because of the efficiency with which humans exert homeostatic control over manganese concentrations, NRC rationalized the extra margin in the ESADDI of 10 mg/d for occasional intakes but recommended a concentration of 2-5 mg/d to provide a margin of safety on the 10 mg/d.

The ESADDI is also consistent with the U.S. Total Diet Study (Pennington and Young 1991), which summarizes the average daily dietary intakes of nutritional elements from 1982 to 1989. Furthermore, studies by Greger (1999) on differences in manganese status between individuals consuming a Western diet and a vegetarian diet indicated that there were no adverse effects in subjects consuming a diet containing manganese at 10.9 mg/d. This somewhat supports the extra allowance in the NRC’s ESADDI. Freeland-Graves (1994) suggested a concentration of 3.5-7 mg/d.

EPA has determined an oral reference dose (RfD), that was not based on an observable toxicity end point. EPA based the values on the NRC (1989) recommendations and used the safe dose of 10 mg/d. Thus, an RfD for food of 0.14 mg/kg/d based on a nominal adult weight of 70 kg (10 mg/70 kg = 0.14 mg/kg/d) was derived. In determining the concentration for drinking water, EPA recommended the use of a factor of 3 to account for differences in exposure from food compared to water, assuming that absorption of manganese would be more from water than from food. Also considered is the exposure of neonates, who can absorb more manganese from formula milk. In spite of the very well known adverse neurologic effects of manganese exposure, EPA did not arrive at a regulatory enforceable value (MCL) for manganese in drinking water. Only a SMCL of 0.05 mg/L was issued for “discoloration.” manganese was not on the list of drinking water priority pollutants because it is abundant in natural food and there have not been a considerable number of documented cases of high manganese concentrations in distributed water. Also, there was no convincing evidence of the prevalence of manganese-induced toxicity from drinking water in the general population. EPA derived an oral RfD only as a health advisory.

As stated earlier, the Food and Nutrition Board of the National Academy of Sciences (IOM 2001) recommended an AI of 2.3 mg/d for men 19+ y of age and 1.8 mg/d for women 19+ y of age. IOM (2001) also recommended a UL of 11 mg for both men and women 19+ y of age.

ATSDR, while recognizing that manganese is beneficial and essential at low concentrations and could be toxic to neurologic systems at high concentrations, did not derive a minimal risk level (MRL) for acute-, intermediate-, or chronic-duration exposure. Quantitative data

Suggested Citation:"Appendix 9 Manganese (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

were not available to derive an acute-duration oral MRL. Because no threshold levels were identifiable in the intermediate-duration experiments, no intermediate MRL was set. A chronic MRL was not derived, because the human epidemiologic studies leave a significant amount of uncertainty regarding exposure levels.

For NASA’s AC calculations, it was decided not to use studies with manganese dioxide. It lacks relevance in drinking water because of its extremely poor solubility in water. The results from animal studies that used these oxides in the feed indicate that manganese from this source is systemically absorbed and stored in tissues. Secondly, it was decided not to use data from neonates because it is clear that neonates absorb manganese to a much greater extent than adults and lack development of the blood-brain barrier. Therefore, in infants, higher concentrations will be found in the brain, one of the target organs. Although several changes in neurotransmitters (an initial increase in DA followed by a longer-term decrease) in response to manganese ingestion are very similar in rodents and humans, there have been reservations about the validity of extrapolating rodent neurotoxicity data to humans. As stated earlier, rodents have very low levels of neuromelanin in the highly pigmented regions of the brain.

A survey of literature of manganese toxicity strongly indicates increased absorption of inhaled manganese compared with ingested manganese, hypersusceptibility of infants and neonates (from the lack of development of the blood-brain barrier, resulting in higher uptake of manganese by the brain) and elderly persons, and increased absorption associated with iron deficiency. These exposure scenarios will not be applicable to spaceflight crew exposure; data from them will not be useful for deriving a SWEG. Data from studies that used Mn2O3 or MnO2 will not be useful, because of their low solubility in water. For example, as described earlier, Roels et al. (1997), using MnO2 and MnCl2 and orally administering these manganese compounds to adult rats, observed significant differences in manganese concentrations in blood, liver, and cerebral tissues such as cortex, cerebellum, and striatum. In contrast to MnCl2 given orally, MnO2 did not increase blood and cerebral manganese concentration to a significant extent, perhaps because of low bioavailability from the lack of intestinal absorption. Thus, pharmacokinetic considerations favor the use of data from studies that used soluble manganese salts (Roels et al. 1997). However, a major issue is deciding the appropriateness of using or extrapolating manganese toxicity data from rodents to humans. According to McMillan (1999), rats can be used as the model because a) the largest database on manganese-induced neu-

Suggested Citation:"Appendix 9 Manganese (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

rotoxicity (neurobehavioral effects) is available for rodents, especially the rat; b) in spite of the fact that gross neurologic syndromes are not seen (extrapyramidal syndromes) in rats after manganese administration and the fact that rats do not have pigmentation in the substantia nigra, manganese compounds produce behavioral effects and neurochemical (neurotransmitter) alterations in rats that are similar to those seen in subhuman primates and in humans. For example, the biphasic response reported in monkeys with respect to locomotor activities is similar to those reported in rats. But according to Newland (1999), the effects are not consistent and are influenced greatly by dose and duration. NASA’s reservation of using the rat neurotoxic effects data comes mainly from the vast difference in the responses between rodents and primates as excellently summarized by Newland (1999) in a comparative chart depicting various changes in neurotransmitter levels and neurobehavioral effects in rodents and primates as a function of cumulative doses of manganese. This makes it difficult to derive a human equivalent dose. The monkey data can be useful because the nonhuman primates exhibit very similar effects (neurologic symptoms and disorders) seen in humans exposed to high doses of manganese. Rodent studies will still be included in the following discussions.

1-d AC for Ingestion

The human study in which one individual developed pancreatitis after being exposed for 30 min to a hemodialysis solution contaminated with manganese could not be used because it had only one subject, the dose was not known, and the effects were very serious. Also, the individual’s health was already compromised, and exposure was via the iv route (Taylor and Price 1982). Other case reports cited in this document on manganese intoxication during total parenteral nutrition also can not be used, not only because of the route of administration, but also because the subjects’ health status was compromised.

No acute toxicity data are available from which to derive a 1-d AC. The LD50 values cannot be used, because the doses are not concordant with the survival data from the 14-d, 13-wk, and 2-y NTP MnSO4 feed study (1993). It is difficult to determine if the mode of administration (delivery by diet or by gavage) could explain the differences in the LD50 and the survival of animals exposed through the diet. Comparing the mortality data from the LD50 dosage studies and the long-term NTP diet

Suggested Citation:"Appendix 9 Manganese (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

study (1993), it seems the availability of manganese from a single bolus and from small doses may be very different.

It was decided to use the observations from human subject manganese nutrition balance studies to derive ACs for acute and short durations.

Freeland-Graves and Lin (1991) conducted a human subject study in which six young adults were administered manganese as MnCl2 at 40 mg as a supplement in a gelatin capsule, and plasma uptake of manganese was measured over 4 h. The peak concentration of manganese in plasma was about 110 ng/L. This amount of manganese was without any discomfort to the GI system of the subjects. In this study, no other clinical or neurologic parameters were measured. The Mn-B data from this study was compared with data reported from a community study by Mergler et al. (1999), who determined neurologic parameters in subjects whose Mn-B ranged from 2.5-15.9 µg/L (median: 7.3 µg/L). Neurologic outcomes were examined with respect to Mn-B. The authors reported that subtle manganese-related neurologic outcomes were evident at MnB concentrations above 7.5 µg/L. In one case, total Mn-B was measured, whereas in the other case, plasma manganese was measured. The concentration in the Freeland-Graves and Lin study was so low that one can conclude that there would not have been any neurologic adverse effect attributed to an acute single dose of 40 mg per subject. Therefore, using 40 mg/d as the NOAEL and 2.8 L/d as the nominal water consumption, a 1-d AC can be calculated as follows:


10-d AC for Ingestion

Human subject studies designed to study manganese absorption and retention were evaluated to derive an AC for 10 d. In a study by Davis and Greger (1992) during a 124-d supplementation study in women (placebo, n = 13; manganese supplemented, n = 11), supplements of manganese at 15 mg/d did not affect levels of hematocrit, serum ferritin, serum transferrin (both indexes of iron status), serum iron, or serum copper. These did not change over time for up to 124 d when measurements were made on days 1, 25, 60, 89, and 124. Even in the manganese status, as measured by the lymphocyte manganese-superoxide dismutase, an increase was seen only after 89 d of administration of the supplement. Thus, an amount of 15 mg/d can be identified as a NOAEL. Even though

Suggested Citation:"Appendix 9 Manganese (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

the total numbers of subjects are ≤100 and NASA usually applies a “low n” factor if a human study indicates only a NOAEL and not a LOAEL (NRC 2000), we decided not to use the factor, because the results show that there is enough margin of safety between 10 and 89 d. Thus, a 10-d NOAEL will be 15 mg/d.

A 10-d AC for hematology and iron and copper status end points can be derived as follows:



A second study that was considered for deriving the 10-d AC is that of Finley and co-workers (Finley 1999). In the first study designed for evaluating the interaction of iron and manganese, Finley did not find any changes at the end of 60 d in nonpregnant women consuming a diet containing manganese at either 0.7 or 9.5 mg/d. Hematocrit, hemoglobin (g/L), number of erythrocytes (cells/L), white blood cells, and platelets were measured. This study indicated that a total intake of 9.5 mg/d was without any effects, a NOAEL for 60 d. However, neurologic indices were not measured in this study.

In another study conducted recently, Finley et al. (2003) evaluated the effect of two concentrations (0.8 and 20 mg/d) of manganese supplementation on manganese status in healthy nonsmoking premenopausal women (n = 17).1 These manganese concentrations are usually present in a mixed Western diet. They also studied the influence of type of dietary fat on manganese status. In addition, data for several clinical parameters such as activities of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, concentrations of ammonia, bile acids, and serum bilirubin—indicators of biliary function—glucose, glucose tolerance tests, insulin, iron-binding capacity, and indicators of manganese and iron status were collected at the end of the dietary period. Manganese status was measured by lymphocyte manganese superoxide dismutase activity. Most indicators of manganese and iron status were not affected by dietary manganese. Biliary function was unaffected by diet and was normal in all subjects. Additionally, dietary manganese did not affect the activities of antioxidant enzymes (glutathione peroxidase, cata-

1

The 17 women made up two study populations. The first (n = 11) included women who ate all meals and participated in testing procedures in the metabolic ward. The second (n = 6) included women who lived in the metabolic ward for the duration of the study.

Suggested Citation:"Appendix 9 Manganese (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

lase, and copper-zinc superoxide dismutase in whole blood) (Finley et al. 2003).

Neurologic and psychological tests were carried out to determine possible effects on psychomotor and behavioral function during the last week of the dietary exposure. The authors concluded that manganese intake in the range of 0.8-20 mg/d for 8 wk was efficiently managed in the human system by the manganese homeostasis mechanisms, because these doses did not affect any neurologic measures and had only minor effects on psychological variables. Clinical examination did not reveal any signs of neurologic impairment. No interaction was found between ingested manganese and any measure of point or line steadiness (steadiness assessment) within the same-type-fat-diet group (Finley et al. 2003). Thus, the highest amount of manganese at 20 mg Mn/d can be identified as a NOAEL for 10-d.

A 10-d AC for no liver, hematologic, or neurotoxic effects can be calculated as follows:



A Japanese study by Kawamura et al. (1941) was also considered for deriving a 10-d AC. A group of six Japanese families (about 25 people) was exposed for approximately 2-3 mo to high concentrations of manganese that leached into their drinking water from an adjacent manganese battery storage area where about 300 batteries had been buried. Manganese at a concentration of 14 mg/L was measured in the well water when the subjects became sick. Because the initial well-water samples were taken 1 mo after the incident, the concentration of manganese to which the subjects were exposed was estimated to be 28 mg/L. Some of the exposed individuals exhibited muscle rigidity and tremors and mental disturbances similar to those seen in manganism. Not all in the group were affected, but two individuals died. These data could not be used because of several confounding factors such as the presence of high concentrations of other metals associated with batteries, including nickel. Effects were seen only in older individuals.

Some rodent studies were evaluated but were not used for deriving the 10-d AC in preference to available data from human studies.

In the 14-d NTP (1993) study in which male and female rats and mice ingested MnSO4 in the diet (0-1,275 mg/kg/d for rats and 0-3,560 mg/kg/d for mice), the number of leukocytes and segmented neutrophils increased in male rats and in female rats only at the highest dose. Male rats seemed to be more sensitive, and a NOAEL of 84 mg/kg/d for an

Suggested Citation:"Appendix 9 Manganese (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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increase in leukocytes and a NOAEL of 665 mg/kg/d for an increase in neutrophils can be identified. A gross comparison of such changes with the changes noted at 13 wk in the 13-wk study and at the 9-mo interim evaluation point of the 2-y study at similar doses indicates that the changes in hematologic parameters are transient or adaptive. In addition, the increases in leukocytes and segmented neutrophils may be too nonspecific as toxicologic indicators to be considered for AC derivation. Thus, the data were not used for deriving the 10-d AC. Mice did not show any notable changes in hematology.

In this study, the authors reported that female rats of all treated groups had diarrhea during the second wk. This may have been because of some GI disturbances. The lowest dose for this effect was manganese at 84 mg/kg/d. Male rats were not as sensitive in that only the 50,000 ppm group exhibited this effect. Because a similar effect was not reported in the 13-wk study in which rats were exposed to some similar doses (0, 1,600, 3,130, 6,250, 12,500, and 25,000 ppm), using diarrhea as an end point for 10-d AC derivation was not justified.

Behavioral and neurochemical changes were studied in ITRC albino rats exposed daily to MnCl2 for 14 and 30 d at 1 mg/mL in drinking water—at an estimated dose of 140 mg/kg/d (Chandra 1983). In the treated rats, hyperactivity was seen after 14 and 30 d, with greater magnitude of alteration in the latter period. Only one dose was used in this study. In preference to the human subject data, these rodent data were not used for AC derivation.

Bonilla (1984), using two different doses of manganese, reported similar results that male Sprague-Dawley rats (150-250 g body weight) given manganese as MnCl2 at 0.1 or 5 mg/mL (about 10 and 500 mg/kg/d, respectively) in drinking water for 8 mo showed a significant increase in spontaneous motor activity in the first mo at both doses. Thereafter, from months 2-7, the activity returned to normal. However, during the eighth mo, the rats exhibited hypoactivity. Both hypo- and hyperactivity were not dose-dependent. The later changes in activity were consistent with the marked decrease in DA (Bonilla and Diez-Ewald 1974). The total activity also changed in a similar manner. In another study that measured motor activity, Nachtman et al. (1986) exposed rats to MnCl2 at 1 mg/mL in drinking water (estimated dose of manganese at 30 mg/kg/d) for 65 wk, and locomotor activity was tested at weekly intervals from week 1 to week 13. Locomotor activity was increased during weeks 5-7 and returned to normal at 8 wk. Only one dose was used. These studies and studies reported by others indicate that the earliest effect of manganese ingestion is the hyper motor activity. All

Suggested Citation:"Appendix 9 Manganese (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

these studies reported early hyperactivity at low doses of Mn; however, two of the studies, those of Chandra (1983) and Nachtman et al. (1986), used only one dose. Bonilla’s 1984 study showed that although two doses were used, the magnitude of the changes were not dose dependent (dose rate was not proportional to dose). Similar results for the concentration of some neurochemicals in the brain have been described earlier in this document. Therefore, NASA decided not to use these data for deriving a 10-d AC.

Another rodent study that was evaluated for 10-d AC derivation was that of Dorman et al. (2000). In this study, the authors evaluated changes in the distribution of manganese in several regions of the brain and neurotoxicity in adult CD rats after gavage doses of MnCl2·4H2O at 0, 25, and 50 mg/kg body weight for 21 d. In this study, Dorman et al. (2000) measured spontaneous motor activity, using an automated photo beam activity system and used passive avoidance tests to assess learning and memory. Additionally, observations of the pulse-elicited acoustic startling reflex and numerous other functions were made (see Dorman et al. 2000 for details). There were no statistically significant effects related to manganese exposure on motor activity. A significant decrease, observed in the overall mean acoustic startle amplitude elicited in the 25 mg/kg group, was not seen in rats of 50 mg/kg, thus showing a lack of dose-related response. Therefore, for motor activity, a calculated dose rate of manganese at 14 mg/kg/d seems to be a NOAEL. Similarly, there were no significant changes in striatal DA and DOPAC or in the concentrations of HVA or serotonin (Dorman et al. 2000) in any of the dosed groups compared to controls. A 10-d AC can be calculated using a NOAEL of 14 mg/kg/d for neurotoxicity and a species factor of 10 and 2.8 L/d as daily water consumption:



Although the authors had performed extensive evaluations and more than one dose had been used in contrast to many previous studies, the AC derived will not be used, because of uncertainties associated with deriving human equivalent concentrations.

The other study that was considered for setting a 10-d AC was that of Joardar and Sharma (1990). Male Swiss albino mice were administered MnSO4 by oral bolus for 3 wk at doses of 33, 66, and 198 mg/kg. Total chromosomal aberrations (CA) and breaks per cell (BC) in bone marrow of mice (n = 5) showed significant increases at 7, 14, and 21 d. An evaluation of micronucleus (MN) formation in bone marrow erythro-

Suggested Citation:"Appendix 9 Manganese (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

cytes showed that MN percent was significantly elevated in both polychromatic and normochromatic erythrocytes. The animals received only two doses within an interval of 24 h, and the slides were prepared 6 h after the second dose. The committee had concerns that the authors had only presented the total chromosomal aberrations without including the specific nature of the aberrations, such as chromatid gaps, breaks, fragments, isochromatid gaps, chromatid exchanges, and double minutes. Also, there was no change as a function of duration of a particular dosing. Because of limited confidence in the data, it was not considered for calculating AC.

The changes in reproduction toxicity parameters observed in this study were also evaluated for 10-d AC derivation (Joardar and Sharma 1990). Male adult Swiss mice received doses of manganese (as MnSO4·H2O) as a gavage for 5 d, and the animals were killed 35 d after treatment to remove the caudate epididymis. The dose rates were 33, 66, and 198 mg/kg/d. The percentage of abnormal sperms increased in all treated groups as a function of dose. A NOAEL could not be identified for sperm head abnormalities.

The NTP (1993) study in which both male rats and male mice were fed diets containing manganese as MnSO4 at much higher doses than used in the Joardar and Sharma study (about 1,300 mg/kg for 14 d) did not find any change in weight, gross morphology, or histology in the reproductive organs at the end of 14 d or at the end of 13 wk. NTP (1993) did not measure sperm head abnormalities; the rodents were exposed to manganese via the diet; and the mouse species studied were different from that used in the Joardar and Sharma study. The magnitude of the effects is questionable. In the Joardar study, MnSO4 was given orally as a single bolus. Several articles in the literature report that inhalation exposure to high concentrations of manganese oxide produced decreased fertility, sperm counts, and testosterone in young animals. although some results cannot be directly compared, the effects reported by Joardar and Sharma were too pronounced after just five doses of MnSO4 administered to adult mice. Also, the percent of abnormal sperm in the untreated control mice seems to be low for mice. The dose-response curve is also quite steep. Because of limited confidence in the data, the study could not be used for deriving 10-d AC.

100-d AC for Ingestion

There are no human studies designed directly to evaluate the toxicity of ingested manganese. However, there are data from human-subject

Suggested Citation:"Appendix 9 Manganese (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

manganese balance studies that can be evaluated for a 100-d AC. Numerous rodent studies have been conducted to assess manganese toxicity by the oral route (drinking water, diet, and gavages), several of which had used developing animals.

First, the 13-wk data from the NTP (1993) study, which used MnSO4 at 0-25,000 ppm in the diet, were evaluated for deriving a 100-day AC. The decreased body weights and significantly lowered absolute and relative liver weights could not be used for AC derivation without an abnormal histology being reported. The increased hematocrit and erythrocytes seen in male rats at the end of 13 wk were not seen in the 9-mo interim evaluation, so the effect seems somewhat transient. Significant increases in neutrophils and decreases in lymphocytes were not seen at 9 mo. Similarly, changes seen in the female rats at 13 wk were not seen at later times. Because of the transient nature of these changes, the data were not used for AC derivation.

Inhibition of DA hydroxylase and MAO, and altered DA and serotonin concentrations in certain regions of the brain were reported by Subhash and Padmashree (1991) for albino male rats exposed to MnCl2 at 12 mg/kg/d in drinking water for 90 d. A significant decrease in the hippocampus but a significant increase in midbrain DA levels indicates that the effect of manganese is region-specific in the brain. However, these neurochemical changes by themselves could not be used as specific functional deficiencies in the treated rats. The profile of changes attributed to manganese in neurotransmitters is quite complex and depends on duration and dose rate. Because of the biphasic nature of these changes and their direct relation to motor activity, this study, which lacks a dose and duration response, was not used for calculating an AC for 100 d.

The other study that was considered for the 100-d AC was the study by Wassermann and Wassermann (1977), in which rats received MnCl2 at 200 ppm in drinking water for 10 wk (12 mg/kg/d). The investigators reported ultrastructural changes in liver morphology that included an increased amount of rough endoplasmic reticulum, a proliferated smooth endoplasmic reticulum, and prominent golgi apparatuses in the biliary area. These data were not considered for AC derivation because of the very low sample size (n = 3) of the treated group.

The following human data were evaluated. Kawamura and co-workers (1941) reported a study of members of five Japanese families who were exposed to high concentrations of manganese in drinking water from wells contaminated with materials from several hundred dry batteries buried nearby. Twenty-five cases of manganese poisoning were reported, with symptoms of lethargy, increased muscle tonus, tremor,

Suggested Citation:"Appendix 9 Manganese (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

and other symptoms. Three individuals died. The concentration of manganese in water samples was estimated retrospectively to be 28 mg/L at the time of exposure. Analysis of the severity of symptoms with respect to the age of the exposed subjects indicated that the older the individual, the more severe the symptoms were. Children were not affected. Autopsy results from one subject who died indicated high concentrations of brain manganese and microscopic changes in the globus pallidus. The length of exposure to manganese was estimated to be 2-3 mo. The neurologic symptoms of manganism or PD develop over a longer period (long latency period), so that in spite of the autopsy findings, it is questionable if the effects seen in this case are entirely because of manganese in the water. They may have been caused by other contaminants leaching from the batteries. At least one of the contaminants was zinc, which seemed not to be related to the symptoms seen. Thus, this study could not be used for 100-d AC calculations.

In order to derive a 100-d AC for manganese, the doses used in the nutrition balance and excretion studies that employed moderate durations were used. For example, Davis and Greger (1992), in their studies to identify indexes for manganese status, carried out a study in 47 nonsmoking young women (aged about 25 y and weighing about 60 kg) supplemented with manganese at 15 mg/d for 124 d. The authors did not observe any changes over time for up to 124 d when measurements were made on days 1, 25, 60, 89, and 124 of hematocrit, serum ferritin, serum transferrin (both indexes of iron status), serum iron, or serum copper. Even for the manganese status as measured by the lymphocyte manganese-superoxide dismutase, an increase was seen only after 89 d of administration of the supplement. Davis and Greger (1992) did not report any toxic symptoms or any obvious neurobehavioral changes. It must be noted that no neurologic tests were done in this study. Therefore, manganese at 15 mg/d can be considered a NOAEL for 100 d. Because observations for critical parameters were made at 124 d, no time extrapolation factor is needed. However, the number of subjects who were given manganese supplements was only 11, and thus, a factor for uncertainty may be required on the NOAEL. This factor will be equal to 1011, which is 3.02. An additional consideration is that the investigators used subjects of 60 kg body weight. So in terms of dose, the actual NOAEL will be 15 mg/d divided by 60 = 0.25 mg/kg/d, which will be used in the calculation.

Thus, the 100-d AC for no adverse effects on critical hematology variables and also on iron status can be derived using a NOAEL of

Suggested Citation:"Appendix 9 Manganese (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

0.25 mg/kg/d, 70 kg as the nominal body weight, 2.8 L/d as the nominal water consumption, and 3.02 as the NOAEL uncertainty factor:



In a study on the interaction of iron and manganese, Finley (1999) administered diets that contained manganese at 0.7 or 9.5 mg/d to healthy nonpregnant women. The authors did not find any changes in hematocrit, hemoglobin (g/L), number of erythrocytes (cells/L), white blood cells, and platelets at the end of 60 d in women consuming either diet. This study indicated that a total intake of 9.5 mg/d was without any effect. Neurologic indices were not measured in this study (Finley 1999). A NOAEL of 9.5 mg/d for at least 60 d can be identified. As the Davis and Greger study indicated, a higher NOAEL for a longer time would be preferred.

Recently, Finley et al. (2003) evaluated the effect of two concentrations (0.8 and 20 mg/d) of manganese supplementation in healthy nonsmoking premenopausal women (n = 17) with a mean age of 35.7 ± 8 y and a mean body weight of 72.9 ± 13 kg. This study has been discussed in detail earlier in the section on a 10-d AC for ingestion. The authors concluded that manganese intake in the range of 0.8-20 mg/d for 60 d was efficiently managed by the body’s homeostatic control mechanism for manganese. Neurologic and psychological tests were carried out to determine possible effects on psychomotor and behavioral effects. Measurements of the severity of more than 75 neurologic signs and symptoms included measures used for manganese intoxication and for PD (for details see Finley et al. 2003). Clinical examination did not reveal any signs of neurologic impairment. No interaction was found between ingested manganese and any measure of point or line steadiness (steadiness assessment) within the diet group ingesting the same type of fat.

In addition, data for several clinical parameters (activities of alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase; ammonia, bile acids, and serum bilirubin concentrations (indicators of biliary function); glucose, glucose tolerance tests, insulin, iron binding capacity, and indicators of manganese and iron status) were collected at the end of the dietary period. Manganese status was measured by lymphocyte-manganese superoxide dismutase activity. Most indicators of manganese and iron status were not affected by dietary manganese. Biliary function was unaffected by diet and was normal in all subjects. Dietary manganese also did not affect the activities of antioxidant enzymes (glutathione peroxidase, catalase, and copper-zinc superoxide dismutase)

Suggested Citation:"Appendix 9 Manganese (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

in whole blood. This study indicated that manganese at 20 mg/d could be identified as a NOAEL for at least 60 d. The strength of this study is that extensive adverse health-related indices were measured, including the psychological parameters. However, for this subchronic study, it may be necessary to apply a “low n” factor for uncertainty to the NOAEL, because this study did not identify a LOAEL (NRC 2000). Thus, a factor for uncertainty on the NOAEL will be equal to (10/√6), which is about 4, where 6 is the number of subjects used for this particular protocol. This study was carried on for up to 60 d, and one might need a time extrapolation factor of 100 d/60 d, which is 1.67. In this case, the uncertainty factor of 4 can be used as a combined factor, because it will be protective of the time extrapolation factor of 1.67.

Thus, using a NOAEL of 20 mg/d, 2.8 L/d as the nominal drinking water volume, and a combined factor of 4 for duration and uncertainty on NOAEL, a 100-d AC can be calculated as follows:



Mean age and body weight of women used in the Finley study were 35 y old and 70 kg, respectively; therefore, there is no need to use any adjustment factor for body weight.

1,000-d AC for Ingestion

A few human studies were considered for AC derivation for 1,000 d. Ejima et al. (1992) reported a case study of manganese intoxication in a 62-y-old man who received total parenteral nutrition that provided manganese at 2.2 mg/d for 23 mo (690 d). He developed symptoms characteristic of PD. This study could not be used for deriving the 1,000-d AC, because it involved only one subject, the subject’s health was already compromised, and the dose was given intravenously. Extrapolation to an oral dose cannot be done with enough certainty, taking into account only the mean human absorption of manganese by the oral route.

The second study considered was the Kondakis study, which was based on epidemiologic studies in northwest Greece (Kondakis et al. 1989). Three different ranges of manganese concentration were found in the drinking water of three areas, called areas A, B, and C in order of increasing concentration of manganese (see Table 9-9).

Suggested Citation:"Appendix 9 Manganese (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

TABLE 9-9 Summary of Manganese Concentrations in Water from Different Areas

Area

Number of Samples

Range of Manganese Concentration (µg/L)

Mean Manganese Concentration (µg/L)

A

62

3.6-4.6

9

B

49

81.6-252.5

167

C

77

1,800-2,300

1,950

Source: Data from Kondakis et al. 1989.

The presence and intensity scores for 33 neurologic symptoms indicated that the manganese-W in area C could be considered a LOAEL and manganese-W in area B a NOAEL. The duration of exposure is assumed to be 10-50 y, because the individuals selected for this study were over 50 y old (both sexes were included). The authors communicated to EPA that the median concentration of manganese in the water of Area B was 167 µg/L. Assuming that this is a NOAEL, the AC will be 0.167 mg/L. The mean manganese concentrations in hair were 3.51, 4.49, and 10.99 µg/g dry weight of hair for areas A, B, and C, respectively. According to the authors, there was a good correlation of manganese concentrations in hair with manganese concentrations in the water of the corresponding area. The age range of subjects was narrow.

There are, however, some drawbacks to the way the data were collected, and much uncertainty existed. The dietary manganese status of the selected population is not known. The effects may have been because of consumption of water over several years, and there is no history of how the concentrations changed with time. The neurologist was not blinded, because the sequence of data collection was not randomized. The exposure time varied widely, from 10-50 y. Neurologic signs of aging may have significantly confounded the study. The data collection was done only once. Some of the neurologic symptom variables included in the data collection usually vary with the time of day and probably biased the results. The neurologic scores had a wide range, with considerable overlapping among the groups. For example, for both sexes, the ranges of values were 0-21 for area A, 0-43 for area B, and 0-29 for area C. A nonparametric statistical analysis using Mann-Whitney, Kruskal-Wallis, and Jonckheere tests was used. No data on medical history or the use of medications were collected in this study.

The third set of data considered for the 1,000-d AC is that of Vieregge et al. (1995) who conducted a neurologic assessment of two

Suggested Citation:"Appendix 9 Manganese (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

TABLE 9-10 Summary of Manganese Concentrations in Water in Two Areas in Vieregge et al. (1995) Study

Group Area

Number of Subjects

Sex

Mean Age ± SD (Years)

Age Range

Manganese Concentrations in Water

A

41

Male (21)

57.5 ± 10.3

41-84

<0.05 mg/L

 

 

Female (20)

 

 

 

B

74

Male (41)

56.9 ± 11.8

41-86

0.3 to 2.16 mg/L

 

 

Female (33)

 

 

 

Note: In the Kondakis et al. (1989) study, the mean ages ranged from 65.4 ± 6.3 to 67.6 ± 8.4 for areas A, B, and C.

Source: Data from Vieregge et al. (1995).

communities in northern Germany, in which manganese in drinking water water was 0.05 mg/L and 0.3-2.16 mg/L. A brief summary of the details are in Table 9-10.

The mean age of subjects in the Vieregge et al. (1995) study is at least 10 y younger than in the Kondakis et al. (1989) study. In this study, during the neurologic evaluation, the clinical investigator was blinded to the manganese exposure concentration. The study used not only a structured questionnaire but also a validated neurologic examination, tests using instrumentation for fine motor performance, and a CURS for signs of PD. The authors reported that there were no neurologic effects of exposure, even when the manganese concentrations in the well water were in the range of 0.3-2.1 mg/L for up to 40 y. Because it has the strength of presenting human population data that assessed a critical toxicologic end point, this study was chosen for deriving a 1,000-d AC.

Because we do not back-extrapolate from 40 y to 1,000 d, the AC represents a significant safety margin of 40 y over 1,000 d. Choosing the lowest exposure level of the high-concentration community water, that is, 0.3 mg/L (over the dietary contributions), should eliminate a risk of neurologic effects from manganese. The maximum concentrations of manganese observed in the water samples collected from the previous U.S.-Mir missions did not exceed 0.15 mg/L.

A 1,000-d AC based on a NOAEL for neurologic effects in humans is 0.3 mg/L.

Some observations from the chronic animal manganese-exposure studies on the effect of manganese ingestion were also considered. First, the 2-y NTP (1993) study was evaluated for deriving the 1,000-d AC. The dietary concentrations of MnSO4 were 0, 1,500, 5,000, and 15,000 ppm. The estimated dose rates were manganese at 65, 200, and 615

Suggested Citation:"Appendix 9 Manganese (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

mg/kg for male rats and 70, 230, and 715 mg/kg for female rats. There was an increased severity of nephropathy and renal failure in male rats that were exposed to the highest dose (615 mg/kg/d) and died during the course of the study. NTP (1993) did not report whether the lower-dose groups had the same effects. For nephropathy and renal failure, manganese at 65 mg/kg/d can be considered a NOAEL for renal effects. The adenomas and carcinomas were within NTP (1993) historical controls for rats of this age and thus were not taken into consideration.

A 1,000-d AC for renal effects can be calculated as follows:



where

65 mg/kg/d = NOAEL;

70 kg= nominal body weight;

10 = species extrapolation factor; and

2.8 L/d = nominal water consumption.


In both male and female mice in the 2-y NTP (1993) study, significant increases in focal hyperplasia of the forestomach and ulceration and inflammation were reported in the highest-dose group (15,000 ppm, corresponding to a maximum of manganese at 731 mg/kg/d). No such changes were reported in the lower-dose groups. A NOAEL of manganese at 175 mg/kg/d, based on the lowest dose for male mice, was identified.

A 1,000-d AC for GI-system effects can be calculated as follows:



where

175 mg/kg/d = NOAEL;

70 kg = nominal human body weight;

10 = species extrapolation factor; and

2.8 L/d = nominal water consumption.


An AC was also calculated based on the adverse effect on the thyroid glands of manganese-exposed animals. In mice, at the end of the 2 y of exposure to MnSO4 in the diet, the incidence of follicular dilatation increased significantly in 15,000 ppm dosed males (manganese at 585 mg/kg) and in 5,000 ppm (228 mg/kg/d as manganese) and 15,000 ppm (731 mg/kg/d manganese) females (NTP 1993). A significantly increased

Suggested Citation:"Appendix 9 Manganese (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

incidence of focal hyperplasia of follicular epithelium also occurred in the 15,000 ppm dosed males and in all manganese-fed females. The number of follicular cell adenomas found in some males and females fed manganese at 15,000 ppm was not considered significantly different from that of controls (NTP 1993). This is shown in Table 9-11.

Female mice seem to be sensitive to thyroid lesions from manganese exposure. Thus, the calculation of the AC for 1,000 d was based on data from female mice only. Factors of 70 kg for nominal body weight, 10 for species extrapolation, and 2.8 L/d for nominal water consumptions were used. A time factor to extrapolate to 1,000 d was not used.

A 1,000-d AC for follicular dilatation based on a BMDL01 of manganese at 8.4 mg/kg/d is derived as follows:



A 1,000-d AC for follicular hyperplasia using a BMDL01 of manganese at 17.5 mg/kg/d is derived as follows:



A manganese toxicity study with nonhuman primates was also considered for the 1,000-d AC (Gupta et al. 1980). A group of four monkeys administered manganese at 6.9 mg/kg/d as an oral bolus for 18 mo

TABLE 9-11 Thyroid Lesions in Mice in 2-y NTP Study

Lesion

LOAEL (mg/kg)

NOAEL (mg/kg)

BMDL01 (mg/kg)

Male Mice

Follicular dilatation

585

175

12

Follicular cell hyperplasia

585

175

18.5

Female Mice

Follicular dilatation

228

65

8.4

Follicular cell hyperplasia

65

Not known

17.5

Note: The response data were also processed using the benchmark dose (BMD) approach using the EPA BMD software. BMDL01, the effective dose or the benchmark dose corresponding to the 95% lower confidence limit of 1% response (benchmark response level = 1%), was used. The LOAEL and NOAEL are included for informational purposes only.

Source: Data from NTP 1993.

Suggested Citation:"Appendix 9 Manganese (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

developed muscular weakness and rigidity of the lower limbs. Histologic analysis showed degenerated neurons in the substantia nigra and scanty neuromelanin granules. Because this study was done in primates, who are the best available models for humans, especially for neurotoxic outcomes of manganese, these data may be quite suitable. The confirmation by histology is strength. The biggest drawback is that only one dose and only four monkeys per group were used. A survey of literature strongly indicates that neurologic effects and all characteristics of neurotoxicity typically seen in manganese-exposed workers have been documented in primate models, in spite of the fact that most of the primate model studies involved administration of the dose via iv or sc (Olanow et al. 1996; Newland 1999). Additionally, the use of primate data is well justified because Eriksson et al. (1987b), who studied the effects of manganese dioxide (long-term sc injections) on monkeys, concluded that manganese-exposed monkeys revealed a response pattern very similar to humans, as judged by a combined eurochemical, histologic, and neurophysiologic evaluation. Also, Eriksson et al. (1992) observed that manganese-induced brain lesions, as measured by PET scans and MRIs, in Macaca fascicularis monkeys were very similar to those reported in humans exposed to excess manganese via occupational exposures, total parenteral nutrition with excessive or contaminated with manganese, and hepatobiliary disease (see Lucchini et al. 2000).

1,000-d AC based on neurotoxicity is equated as follows:



where

6.9 mg/kg/d = LOAEL;

10 = LOAEL to NOAEL;

70 kg = nominal body weight;

3 = species extrapolation factor;

2.8 L/d = nominal water consumption; and

1,000 d/540 d = time extrapolation factor from 18 mo to 1,000 d.


A summary of ACs and SWEGs for various durations is listed in Table 9-12.

Suggested Citation:"Appendix 9 Manganese (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

TABLE 9-12 Acceptable Concentration (ACs) and SWEGs for Manganese

Toxicity End Point

Exposure

Species

Modificaton Factors

AC (mg/L)

Primary Study

To NOAEL

Species Factor

Time Factor

Spaceflight Factor

1 d

10 d

100 d

1,000 d

No adverse effects (human subjects)

NOAEL= 40 mg/d

Human

1

1

1

1

14

Freeland-Graves and Lin 1991

No adverse effect on hematologic parameters or iron or copper status

NOAEL = 15 mg/d

Human

1

1

1

1

5.4

Davis and Greger 1992

No adverse effect on neurologic parameters or serum clinical chemistry

NOAEL = 20 mg/d

Human

1

1

1

1

7.0

Finley et al.2003

No abnormal hematologic parameters or iron or copper status

NOAEL = 0.25 mg/kg/d

Human

3.02 for low n

1

1

1

2

Davis and Greger 1992

No adverse neurologic effects or serum clinical chemistry

NOAEL = 20 mg/d

Human

4 for low n

1

1

1

1.8

Finley et al. 2003

Nephropathy and renal failure

NOAEL = 65 mg/kg

Rats

1

10

1

1

163

NTP 1993

Forestomach hyperplasia and inflammation

NOAEL = 175 mg/kg

Rats

1

10

1

1

437

NTP 1993

Thyroid lesions: follicular dilatation

BMDL01 = 8.4 mg/kg

Mice

1

10

1

1

21

NTP 1993

Suggested Citation:"Appendix 9 Manganese (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

Toxicity End Point

Exposure

Species

Modificaton Factors

AC (mg/L)

Primary Study

To NOAEL

Species Factor

Time Factor

Spaceflight Factor

1 d

10 d

100 d

1,000 d

Thyroid lesions: follicular cell hyperplasia

BMDL01 = 17.5 mg/kg

Mice

1

10

1

1

44

NTP 1993

Neurotoxicity (histopathologic lesions, muscular weakness, rigidity of lower limbs)

LOAEL = 6.9 mg/kg

Primates

10

3

1,000 d/ 540 d

1

3.0

Gupta et al. 1980

Neurotoxicity (absence of adverse neurotoxic indices)

NOAEL = 0.3 mg/L

Human

1

1

1

1

0.3

Vieregge et al. 1995

SWEG

 

 

 

 

 

 

14

5.4

1.8

0.3

 

Suggested Citation:"Appendix 9 Manganese (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

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Suggested Citation:"Appendix 9 Manganese (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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Suggested Citation:"Appendix 9 Manganese (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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Suggested Citation:"Appendix 9 Manganese (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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Suggested Citation:"Appendix 9 Manganese (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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Suggested Citation:"Appendix 9 Manganese (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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Suggested Citation:"Appendix 9 Manganese (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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Suggested Citation:"Appendix 9 Manganese (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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Suggested Citation:"Appendix 9 Manganese (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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Suggested Citation:"Appendix 9 Manganese (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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Suggested Citation:"Appendix 9 Manganese (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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Page 448
Suggested Citation:"Appendix 9 Manganese (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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Page 449
Suggested Citation:"Appendix 9 Manganese (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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Page 450
Suggested Citation:"Appendix 9 Manganese (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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Page 451
Suggested Citation:"Appendix 9 Manganese (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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Page 452
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