Evm 9922 P

EVM/99/22.
REVISEDAUG2002
EXPERT GROUP ON VITAMINS AND MINERALS
REVIEW OF MANGANESE - REVISED VERSION
The attached review of manganese is a revised version of the paper presented to

the Expert Group at the meeting in October 2001. Some minor editorial changes
have been made and some of the paragraphs have been reordered for consistency
with other reviews.
The following annexes are included with this paper:
Annex 1 Intakes of manganese from food and supplements in the UK diet

Annex 2 Tables referred to in this review
Annex 3 Extract from TOX/94/58 (hard copy only)
Expert Group on Vitamins and Minerals Secretariat

August 2002
This paper has been prepared for discussion by the Expert group on Vitamins and Minerals and does
not necessarily represent the final views of the Group.
EVM/99/22.REVISEDAUG2002
MANGANESE
Chemistry and geochemistry
1. Manganese is a metallic Group VIIa element. It has an atomic weight of 64.9.

It can exist in valence states of 2, 3, 4, 6 and 7.
2. Manganese is usually associated with iron ores. Important ores of manganese

include pyrolusite (MnO2), manganite (Mn2O3 x H2O) psilomelane and rhodochrosite.
It represents 0.085% of the earth’s crust. Manganese has also been found in nodules
on the ocean floor at levels of up to 24%.
3. Manganese can exist in eleven oxidation states from -3 to +7 with the most
common valences being +2, +4 and +7. The +2 valence is the predominant form in
nature, with the +4 valence occurring in MnO2 and +7 in permanganate. However,
the Mn3+ state is critical in nature as this is the oxidative state of manganese in
superoxide dismutase, the form in which transferrin binds manganese and probably
the form which interacts with iron (ILSI, 1994).
Natural occurrence
4. Manganese occurs in soil, sediments and water both naturally and as a result
of environmental contamination.
Occurrence in food, food supplements and medicines.
Food
5. Manganese is present in a variety of foods including cereals and nuts. Data

from the UK TDA are provided in annex 1. Beverages are the largest source of dietary
manganese in the UK due to the high concentration of manganese in tea. The US
DHHS (1997) report manganese levels of 18.21- 46.83 mg/kg in nuts, 0.42-0.70
mg/kg in grains, 2.24-6.73 mg/kg in legumes, 0.2-10.28 mg/kg in fruits and 0.1-3.99
in meat, poultry fish and eggs.
6. A number of multi-vitamin and/or mineral food supplement preparations

include manganese, at levels of 0.25 to 5.0 mg per daily dose (OTC, 2001).
Drinking water
7. The levels of manganese in drinking water range from 1 to 100 µg/l with most
being in the region of 10 µg/l (ILSI, 1994).
8. EU Directive 80/778/EEC set a Maximum Admissible Concentration for

manganese of 50 µg/l, possibly on the basis of a 1984 WHO Guideline of 100 µg/l to
prevent staining. In the UK, 50 µg/l is the limit for manganese in the Water Supply
(Water Quality) Regulations 1989. However, manganese levels may be higher
because of the "nature and structure of ground" and, in accordance with the Directive,
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1
This paper has been prepared for discussion by the Expert group on Vitamins and Minerals and
does not necessarily represent the final views of the Group.
"relaxations" are permitted; for manganese the maximum relaxation is 2000 µg/l
(DOE, 1991). WHO (1993) Guidelines suggest a provisional health-based guideline
value of 500 µg/l, and reiterate the aesthetic guideline of 100 µg/l. EU Directive
98/83/EC includes manganese solely as an "indicator parameter" at 50 µg/l. This is
not an absolute maximum, but means that there is a requirement to monitor, to
consider whether non-compliance is a risk to human health, and to take remedial
action where this is necessary to protect human health. The Directive has not yet been
transposed into UK law. The EU Scientific Committee for Food recommended a
maximum level of 500 µg/l in drinking water (SCF, 1999).
Licensed medicinal products for oral use
9. Manganese (as the glycerophosphate or sulphate) may be included in products

sold in supermarkets and other retail outlets without the supervision of a pharmacist.
The maximum permitted daily dose is 1 mg elemental manganese. Five medicinal
products containing manganese (in addition to other nutrients) are licensed to be sold
in supermarkets and other retail outlets, whilst fifteen may only be sold under the
supervision of a pharmacist. The licensed uses include the prevention and treatment
of nutrient deficiencies, debility, supplementation of special diets and malabsorption.
The maximum daily doses specified in the licences for the general sales products are
up to 1 mg, and pharmacy products up to 5 mg, elemental manganese.
Other uses
10. Manganese additives are used in fuel.
Intake and Exposure
Food
11. The 1994 Total Diet Study showed that the estimated population average
intake of manganese in the UK in 1994 was 4.9 mg/day (MAFF, 1997). The COMA
report (1991) estimated the total manganese intake as 4.6 mg/person/day of which
half was derived from tea. Details of the estimated intake of manganese by specific
age groups in the UK, are given in Annex 1.
12. Diets high in unrefined cereals, nuts and leafy vegetables and tea have the
highest manganese content. The Indian diet is estimated to contain an average of 8.3
mg Mn/day compared to 0.36-1.78 mg/day in highly refined hospital diets in the US
(WHO, 1996). The US EPA has estimated manganese intake to be 0.008 and 3.8
mg/day from food and water respectively (US DHSS, 1997).
Recommended amounts
13. COMA (1991) was unable to set Reference Nutrient Intakes (RNIs) for
manganese. However, it was noted that population intakes appear to be adequate
since few cases of deficiency have been observed. From balance studies in human
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2
volunteers, Friedman et al (1987) calculated that the minimum requirement for

manganese in the normal diet was 2.5 mg/day.
14. WHO (1996) were unable to set a range of safe population intakes since low
manganese diets did not result in conclusive or marked effects on the health of adults
and the toxicity threshold was unknown.
15. The estimated safe and adequate daily dietary intakes (ESADDI) set by the US
National Research Council Food and Nutrition Board for manganese are 0.3-1.0
mg/day for infants, 1-3 mg/day for children, and 2-5 mg/day for adults. Insufficient
data were available to set a recommended dietary amount (RDA) (ILSI, 1994). In
2001, the Food and Nutrition Board of the Institute of Medicine published new
dietary reference intakes for manganese (Trumbo et al, 2001). Adequate intakes were
determined as there was insufficient information to set RDAs. They were:
0.003 mg/d (0-6 months) 0.6 mg/d (7-12 months)

1.2 mg/d (1-3 years) 1.5 mg/d (4-8 years)
1.9 mg/d (boys, 9-13 years) 2.2 (males 14-18 years)
2.3 for (males > 18 years)
1.6 mg/d (girls 9-18 years) 1.8 for (females > 18 years)
2.0 mg/d (pregnancy) 2.6 mg/d (lactation)
16. The EU Scientific Committee for Food (SCF) recommended a safe and
adequate dose of 1-10 mg/Mn/person/day (SCF 1993).
Analysis of tissue manganese levels and manganese status
17. The appropriate tissue measure of manganese exposure is uncertain. The dose-
response relationship between internal measures of manganese exposure (blood, hair
and urinary manganese) and external measures is stated to be inconsistent (Mergler
and Baldwin, 1997). However, in a study conducted by Kondakis et al., (1989)
separate populations in the Northwest Peloponnesus were exposed to different levels
of manganese in drinking water. Hair manganese levels were associated with
increasing manganese concentration and were higher in females. The relationship of
different tissue measures to each other is, however, unclear; since in the Kondakis
study, no relationship was found between hair and blood manganese levels.
18. The activity of manganese specific enzymes can be used to assess exposure.
For example, lymphocyte manganese-dependent superoxide dismutase (MnSOD)
activity and serum manganese levels, but not urinary manganese levels, increased
compared to controls following 124 days of daily supplementation of female
volunteers with 15 mg/day manganese (Davis and Greger, 1992). Similar increases
also occurred when 60 mg iron/day was co-administered with the manganese. The
authors concluded that the two measures could be used to monitor manganese status.
However, use of MnSOD (ILSI, 1994) as a measure is complicated by the number of
cytokines and disease states that increase MnSOD expression independently of
manganese status.
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3
19. WHO (1996) consider that whole blood and urinary manganese levels can be
used to assess exposure and that the activity of manganese superoxide dismutase and
the ratio of manganese superoxide dismutase to zinc-copper superoxide dismutase
activity could also be used as indicators. Rats deficient in manganese had lower heart
manganese superoxide dismutase activity, but experienced only two minor
compensatory changes in the activity of copper-zinc superoxide dismutase and
catalase (Malecki et al., 1994).
Function
20. Manganese is a component of enzymes such as pyruvate carboxylase,

mitochondrial superoxide dismutase and arginase. It also activates many other
enzymes including hydrolases, glycosyl transferases, kinases, prolinase and
phosphotransferases (COMA, 1991). A number of the enzymes activated by
manganese are non-specific and can be activated by other metal ions, particularly
Mg2+ and are not significantly affected during manganese deficiency (ILSI 1994).
Glycosyl transferases are specifically activated by manganese. Manganese is involved
in both carbohydrate and lipid metabolism (Leach and Lilburn, 1978).
Deficiency
21. Manganese deficiency has not been observed other than in two experimental
studies (COMA 1991). Miliaria crystallina, a fleeting dermatitis, was observed
following deliberate manganese depletion (Friedman, 1987). The condition
disappeared when manganese repletion began. Aberrations in the enzyme
glycosaminoglycan, which is activated by manganese, are thought to result in the
clinical symptoms of manganese deficiency.
22. Manganese deficiency was inadvertently induced in a participant in a study on

vitamin K (Doisy, cited by US DHHS, 1997). Consumption of a diet low in
manganese (0.35 mg/day) and vitamin K resulted in a decreased level of clotting
proteins, decreased serum cholesterol, reddening of black hair and beard, slowed
growth of nails and scaly dermatitis. After vitamin K was returned to the diet, the
subject continued to exhibit the same symptoms. However when manganese was
returned to the diet the symptoms were eliminated.
23. A number of diseases have been partially characterised by low levels of blood
manganese, these include epilepsy, mseleni joint disease, maple syrup urine disease,
phenylketonurea, Down’s syndrome, osteoporosis and Perthe’s disease (reviewed
ILSI, 1994). The significance of such findings is uncertain.
24. In animal species, manganese deficiency is associated with growth retardation,

skeletal and cartilage malformations, impaired reproductive function, congenital
abnormalities and impaired glucose tolerance (reviewed Friedman, 1987). In
experimental animals, manganese deficiency has been associated with diabetic-like
symptoms (Leach and Lilburn, 1978).
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4
Overview of reported non-nutritional beneficial effects
25. Information obtained from the Internet (Health World Online) suggests that
manganese could be used as an anti-oxidant, and has been helpful in some cases of
fatigue, poor memory, nervousness, irritability or dizziness. It is further suggested
that by an unknown mechanism, manganese may help reduce some of the
parkinsonian symptoms such as muscle rigidity and twitching, secondary to
phenothiazone drug use. It has been reported that manganese supplementation may
be helpful in controlling both major and minor motor seizures (Pfeiffer and LaMola,
1983).
26. As manganese is a cofactor for many enzyme systems involved in the control
of blood sugar and because diabetics have low manganese levels, it is suggested that a
daily dose of 30 mg manganese might be beneficial for diabetics (Murray and
Pizzorno, 1998). Levels of manganese-containing superoxide dismutase (MnSOD) are
deficient in patients with rheumatoid arthritis (Pasquier et al., 1984). Manganese
supplementation has been shown to increase SOD activity and therefore it is
suggested as a treatment for rheumatoid arthritis (Rosa et al., 1980).
27. Based on the study by Reginster et al (1988), the Committee on Medical

Aspects of Food and Nutrition Policy (COMA) suggested there might be a plausible
biochemical basis for manganese influencing bone health (COMA, 1998). Strause et
al (1994) found a positive effect on spinal bone density with combined calcium, zinc,
manganese and copper supplementation. However, COMA concluded that there is
currently insufficient evidence to support dietary recommendations in relation to the
effect of manganese on bone health.
28. There is some evidence that manganese supplementation may improve the
clinical condition of schizophrenics (English 1929, Reed 1929) and manganese
chelate has been reported to cure some patients with tardive dyskinesia (Kunin 1976).
Interactions
Iron
29. There is a close relationship between iron and manganese absorption by the
intestinal mucosal cells with competition for the available binding sites (cited Carter,
1980). The affinity for manganese is lower than for iron.
30. Co-administration of 7.5 or 15 mg manganese (as manganese chloride) with 3

mg iron as ferrous sulphate reduced manganese absorption by 20 and 34%
respectively in human volunteers (Rossander-Hultén et al., 1991); when higher doses
of iron were given, manganese reduced absorption by a similar level. The fraction of
iron absorbed from a 3 mg dose was similar to that absorbed from a dose of 0.01 mg
iron + 2.99 mg manganese. The authors concluded that competitive inhibition was
occurring at the same step of mucosal absorption. When the iron was administered as
3 mg native non-haem iron in a hamburger meal, co-administration of 15 mg
manganese reduced iron absorption by 40 % suggesting that other dietary ligands did
not affect the iron-manganese interaction.
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5
31. Chua and Morgan (1996) conducted a number of isotope uptake studies to
determine whether manganese uptake and deposition in Wistar rats was affected by
iron. They concluded that manganese and iron interacted during transfer from the
plasma to the brain and other organs and that the interaction was synergistic rather
than competitive. This suggests that excessive intake of both metals may accentuate
the risk of tissue damage caused by one metal alone, particularly in the brain.
32. Iron-deficient rats absorbed more manganese (24.4 ± 6.6%) than control (12.5
± 4%) or iron loaded animals (5 ± 2.8%) when measured using an isolated intestinal
loop technique (Diez-Ewald et al., 1968). Iron deficiency was achieved by prior
removal of blood and iron overload by daily inter-muscular injections of iron dextran
(total dose 100 mg). However, manganese excretion was also increased in the
deficient rats and decreased in the iron-overload animals. It is suggested that this was
a compensatory mechanism for the altered absorption. Iron deficiency significantly
increased manganese levels in the brain, heart, spleen, kidney, testis, femoral muscle
and tibia of rats fed a depleted diet for 3 weeks (Yokoi, 1991). Iron deficiency
induced in rats for 8 weeks resulted in an increased in manganese levels in the
hypothalamus only (Shukla, 1989). The increase was not abolished by two weeks of
iron restoration.
33. From day 2 of gestation onwards, pregnant Long Evan rats were fed a low iron
(20 mg/kg) or high iron (240 mg/kg) diet (Rehnberg et al., 1982). In addition they
also received a basal diet containing 50 mg/kg manganese as manganese sulphate,
plus 0, 400, 1100 or 3550 mg Mn/kg as manganese oxide (Mn304). When calculated
on a body weight basis, this can be estimated to be equivalent to 2.5, 20, 55, 177.5
mg/Mn kg/bw day. The doses for weanling rats would be approximately six times
higher for the early part of the study. From weaning, the F1 offspring were given the
same diets as the dams. The animals were then mated at day 92-94. The F1 generation
was treated until 224 days of age and the F2 offspring until 24 days of age. A
manganese-related depression in F1 growth rates was apparent in the low iron groups
in the early part of the study. Beyond day 100, no body weight deficits were seen in
any group. Mortality was high in the low iron, 3550 mg/kg manganese group, with no
animals surviving beyond 50 days. Blood iron levels were severely depressed in these
animals. Liver iron levels were lower in the high iron, 3550 mg/kg manganese group
than in the low iron controls but this was not significant: liver manganese levels,
however, were significantly higher. In the high iron diet a general dose-related
increase in liver manganese was apparent. Tissue accumulation of manganese was
highest in the weanling rats (where biliary excretion is absent), lactating and term
dams and term pups in the iron deficient groups. The levels of manganese in milk and
placenta were largely unaffected by treatment. No information is provided on whether
manganese treatment affected reproductive or developmental parameters is provided.
The authors concluded that the most susceptible animals to tissue manganese
accumulation from chronic manganese exposure were those absorbing large amounts
of iron, the pre-weanling rat, the lactating dam and the iron deficient rat.
34. A study of iron status (as assessed by serum ferritin concentration) and effects
on manganese absorption and biological half-life was conducted in 26 women (Finley,
1999). Manganese absorption was highest in subjects on low manganese diets (0.7
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6
mg/day) with low iron status. Absorption was lowest in all subjects on high
manganese diets (9.5 mg/day). The half-life was longest in subjects on low
manganese diet and high iron status and shortest in all subjects on the high manganese
diet. As a result, manganese balance was not affected by iron status at the levels of
intake in this study.
35. The ability of manganese to interfere with iron absorption can result in
adverse physiological effects. This is described further in paragraphs 97-101.
Other dietary components
36. It has been reported that high levels of dietary fibre, calcium, phosphorus and
phytate increase the requirement for manganese possibly by the formation of
insoluble complexes (discussed ILSI, 1994). Low dietary phosphorus levels have
been shown to contribute to so called ‘manganese rickets’ (growth retardation and
impairment of bone mineralisation seen in deficiency studies in rodents) in
experiments in rats (Svensson et al., 1985). Protein does not appear to affect
manganese balance.
37. It was reported that calcium and copper may impair the plasma uptake of
manganese whilst zinc may increase plasma manganese levels (Freeland-Graves and
Lin, 1991). Davidsson and colleagues (1991) investigated the effects of different
dietary components on the absorption of 54Mn by adult volunteers. The addition of
calcium but not additional manganese reduced manganese absorption from human
milk. However, increasing calcium intake from 200-800 mg/day did not have any
effect on manganese balance in male volunteers (Spencer et al., 1979).
38. Manganese may decrease magnesium absorption and increase excretion,

though it can take the place of magnesium in some enzyme systems that require
magnesium (Watts, 1988). Miller et al., (2000) conducted a 5 week study of the
effects on differing levels of manganese in a magnesium-deficient diet in pigs. All 8
pigs on the high manganese diet (0.95 mmol/kg diet) died following convulsive
seizures, compared to 2 out of the 6 in the low manganese diet group (0.040 nmol/kg
diet). A subsequent study showed that the heart muscle of animals on the high
manganese diet contained significantly lower magnesium levels than that of animals
on the low manganese diet.
39. The addition of phytate, phosphate and ascorbic acid to infant formula and
iron or magnesium to wheat bread did not affect manganese absorption in adolescent
girls. Greger et al (1978) reported that substitution of meat with up to 30% soy did not
affect manganese retention. However, the level of dietary phytate achieved by the soy
was only 0.02%.
40. It has been reported (reviewed US DHHS, 1997) that ethanol increases the
susceptibility of humans to manganese toxicity. Exposure of rats to ethanol and
manganese chloride in drinking water led to increased levels of manganese in the
brain and liver compared to manganese chloride alone. The effects of the treatment on
liver and serum enzyme activities generally appear to be additive rather than
synergistic (Shukla et al., 1976, Shukla et al., 1978). Tissue MnSOD activity can be
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7
increased by stressors such as alcohol, ozone, interleukin-1 and tumour necrosis

factor-α (TNFα) This increase can be reduced in manganese deficient animals,
potentially increasing their sensitivity to these insults (ILSI, 1994).
41. Tea is a major contributor to the manganese intake in the British diet but there
is little data on the adverse effects, if any, of excessive tea drinking. It is possible that
the tannins present in tea bind manganese, reducing uptake.
Anti-psychotic drugs
42. It has been reported (discussed US DHHS, 1997) that chronic administration
of anti-psychotic drugs results in increased manganese levels in the brain.
Bioavailability
43. Few data are available on the bioavailability of manganese from the diet.
Bioavailability of manganese appears to be generally fairly low because of the low
solubility; it is, however, higher for some food types. In a study by Knudsen et al
(1995) samples of human breast milk and formula milk were labelled with 54Mn as
manganese chloride (MnCl2) and left for 24 hours to allow exchange to take place.
Using the rat pup model, it was determined that manganese absorption was 83-88%
from human milk and premature infant formula after 6 hours. Retention (by organs
and carcass) was 85-95%. Pasteurisation did not have any significant effect on
manganese absorption or retention. Similar findings were reported by Keen et al
(1986).
Absorption
44. Absorption of manganese occurs in the small intestine. The efficiency of

absorption is thought to be low (10.1-13.9%) due to the low solubility of manganese
in digestive fluids (Bencko and Cikrt, 1984) and it is uncertain how this is affected by
conditions of deficiency or excess (COMA, 1991). Manganese is probably absorbed
as Mn2+ in quantities proportional to those in the diet (Leach and Lilburn, 1978).
45. Manganese absorption is thought to have the characteristics of a carrier-

mediated mechanism (Leach and Lilburn, 1978). Some studies indicate that the
binding site for uptake into the mucosae may be different from the binding sites for
transfer of the metal from the mucosae to the body. A second non-saturable process
occurring by diffusion has also been proposed (Garcia-Aranda et al., 1983).
46. Variation in the excretion, rather than absorption was thought to maintain
manganese homeostasis (Leach and Lilburn, 1978). However work in rats suggests
that control of absorption is the main way of maintaining manganese homeostasis. In
a study by Davis et al (1992) endogenous losses of manganese were about 8% of the
amount of manganese actually absorbed regardless of intake. Absorption was
increased in manganese deficient diets and tended to be higher where manganese was
adequate rather than high. A number of cases of manganese toxicity and high serum
manganese levels in patients receiving home parenteral nutrition have been reported.
Although macro- and micro-nutrient status needs to be carefully monitored in such
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8
patients, it has been suggested that the by-passing of a regulatory step in manganese
homeostasis, regulation of intestinal absorption, may contribute to such patients being
vulnerable to manganese toxicity (Reynolds et al., 1998).
47. It has been suggested that absorption of manganese is higher in infants.

Studies in animal models and preliminary work in human infants indicate that in the
early post-natal period intestinal uptake and whole body retention is increased
(COMA, 1991).
Human
48. Absorption of 54Mn from a juice drink was significantly higher in women than
in men, but the half-life of the labelled manganese was longer in men compared to
women (Finley et al., 1994). Half-life and absorption were determined from whole
body counts. A significant association was found between manganese absorption and
plasma ferritin levels and between manganese absorption and biological half-life. The
authors concluded that the differences between men and women might be related to
iron status.
Laboratory animals
49. In the rat, manganese absorption is thought to be a rapidly saturable process

probably mediated by a high-affinity low capacity transport system (Garcia-Aranda et
al., 1983). Following single oral doses of manganese, little tissue accumulation
occurs. However, in animal studies where there is prolonged exposure to manganese,
increased tissue levels are found but the magnitude of the increase diminishes over
time (US DHHS, 1997).
50. The chemical form of the manganese compound may also influence its
absorption. Administration of 24.3 mg Mn/kg manganese chloride by oral gavage to
rats once a week for 4 weeks resulted in a 68% increase in blood manganese levels
(Roels et al., 1997) and a 22% increase in the level of manganese in the cortex but not
the cerebellum and striatum. In contrast the same dose of manganese dioxide given
orally did not increase the levels of manganese in blood or cerebral tissue. Hepatic
manganese levels were not affected by either form of manganese. Manganese chloride
is more soluble in aqueous media than the oxide.
51. Manganese absorption and retention are higher in neonatal rats than in adults
(Keen et al., 1986), up to 80-90% retention of manganese from human and cows’ milk
taking place in 14 day rat pups, decreasing to 60% in older pups. Retention of
manganese from soya infant formula was lower, being about 60%. Developmental
changes in the permeability of the brush border membrane may also contribute
towards the higher absorption in young animals (discussed ILSI, 1994).
Distribution and metabolism
52. In the portal blood manganese may become bound to α2-macroglobulin (Leach
and Lilburn, 1978). When either free or in the divalent state, or if bound to the α2-
macroglobulin, manganese is efficiently removed from the blood by the liver. A small
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9
proportion of manganese is oxidised to Mn3+, becomes bound to transferrin and enters

the systemic circulation, for transport to the tissues. The oxidation step may be
performed by caeruloplasmin since Mn+2 will not bind to transferrin in the absence of
an oxidising agent (Leach and Lilburn, 1978). The manganese in blood plasma is
believed to be bound to albumin as well as transferrin and α2-macroglobulin
(discussed Chua and Morgan, 1996). It has been suggested (Schroeder et al., 1966,
Bencko and Cikrt, 1984) that manganese in the blood is transferred by the protein
transmanganin, a β1 globulin. Transmanganin is not identical with transferrin (Bencko
and Cikrt, 1984). The authors add that transmanganin-bound manganese is readily
substituted for manganese in the body tissues. No other references to this protein
have been found.
53. Once manganese enters the liver it can enter one of five metabolic pools;
lysozymes (by which the manganese is taken up into the liver), mitochondria, the
nuclear fraction of the cell, newly synthesised manganese proteins, and the free
manganese pool (ILSI, 1994). Manganese uptake by hepatic tissue does not appear to
increase in conditions of deficiency, suggesting a lack of inducible manganese
transport proteins (noted ILSI, 1994).
54. Within the cell, manganese is sequestered in the mitochondria. It thus,

preferentially accumulates in tissues that are rich in mitochondria (Bencko and Cikrt,
1984). The highest concentrations of manganese are found in the pancreas and the
liver (COMA, 1991). Uptake and release of manganese by mitochondria is thought to
be linked to calcium flux (ILSI, 1994). Release of glucocorticoid hormones or
adrenocorticotrophic hormone (ACTH) leads to a shift of manganese from the liver to
other parts of the body (Leach and Lilburn, 1978). Following an intra-venous
injection of manganese, maximal tissue uptake occurred within 2 hours ever; maximal
uptake in the liver occurred within 0.5 hours (Chua and Morgan, 1996). This was
followed by a 30% decrease within 2 hours.
55. The distribution of different forms of manganese compounds can vary

(Komura and Sakamuto, 1992). Groups of six male ddY mice were fed a diet
containing 2000 mg/kg manganese as manganese dioxide, or, one of the divalent
manganese compounds manganese chloride, manganese carbonate, or manganese
acetate for 1 year (the latter two compounds are the more water soluble ones). On a
body weight basis the dose can be estimated to be 300 mg/kg bw/day (WHO 1987).
Manganese chloride treatment significantly increased blood manganese levels,
however, this was not apparent following treatment with the other manganese
compounds. The levels of manganese in the liver were elevated in all treatment
groups but this was only significant in the manganese carbonate treated group. In
contrast, manganese levels in the kidney were similar to or lower than the levels in the
controls. This was significant only in the manganese chloride treated group.
Manganese levels were elevated in the spleen in all but the manganese acetate treated
animals; this was significant in the manganese dioxide and manganese carbonate
groups.
56. Manganese also accumulates in the brain. Magnetic resonance imaging of

manganese intoxicated humans and primates indicates that manganese is located
preferentially in the globus pallidus, striatum and the substantia nigra (Mergler,
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10
1996). It has been suggested that either the free Mn2+ ion or Mn3+ is tightly bound to
transferrin and is transported across the blood-brain barrier (reviewed Roels et al.,
1997). However, several studies have shown no effect of co-administration of Mn2+
with transferrin on manganese uptake into the brain (discussed Malecki, 2001). It is
possible that another iron transporter, DMT-1, which is localised in the brain, is
involved in manganese uptake to the brain.
57. Chronic ingestion of manganese in drinking water alters regional brain

manganese levels (Chan et al., 1991). After 10 days of exposure, the highest levels
were found in the pons and medulla and the lowest in the hypothalamus. High levels
of manganese are found in the olfactory bulb in the nose (Mergler and Baldwin,
1997).
58. The manganese concentration in human milk is low, but does not decline post-
partum (Knudsen et al., 1995). The manganese concentration of infant formula is
often higher. Hair manganese increased after birth but this was significant only in
those infants fed formula milk (Collipp et al., 1983).
Excretion
59. Systemic manganese homeostasis is achieved through hepato-biliary and

intestinal secretion (COMA, 1991) although as noted previously, it has also been
argued that variation in absorption of manganese may be involved.
60. Manganese is excreted largely through the bile and thus the faeces; urinary
excretion is much lower (Benkco and Cikrt, 1984). In addition to the manganese
excreted into the gut via the bile, a small fraction may be directly transported from
blood across the intestinal wall (US DHHS, 1997). Spencer et al (1979) reported
average urinary excretion by human volunteers of 0.03 mg Mn/day and faecal
excretion of 2.3 mg Mn/day compared to consumption of approximately 2.1 mg/day
during the same period.
Human
61. Humans who ingested trace levels of manganese, excreted the manganese with
whole body retention times of 13-37 days (reviewed, US DHHS, 1997). Elimination
of intra-venous 54Mn was slower in patients suffering from manganese toxicity
compared to the two control groups (Mena et al., 1967). The authors concluded that
the results indicated a large, actively exchanging tissue manganese store in the
controls in contrast to the patients with manganese toxicity. No evidence of hepatic
disorders, and thus reduced biliary clearance, was apparent.
Laboratory animals
62. Manganese-deficient rats conserved manganese through a 70-fold reduction in

endogenous faecal losses of manganese (Malecki et al., 1994).
63. Approximately 3.4% of a single gavage dose of 0.2, 1 or 10 mg Mn/kg bw (as

manganese chloride and containing 54 Mn) was excreted in the bile of rats in the 0.5 to
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11
6.5 hours after dosing regardless of the initial dose administered (Malecki et al.,
1996). A dose-related increase in biliary manganese excretion occurred. The rats had
previously had bile duct catheters fitted and were conscious during the post dose
period. Diets with high or low fat content did not affect manganese excretion. In rats
given a low (0.49 mg Mn/kg) or adequate (72 mg Mn/kg) diet for 8 weeks, biliary
manganese excretion was only 0.7% of that in the manganese replete animals during
the 4 hour collection period (Malecki et al., 1996). Despite this reduction, tissue
manganese levels in the deficient rats were still 50-80% lower than in the manganese-
replete rats. The rats had previously had bile duct catheters fitted were conscious
during the post dose period. The fat content of the diet did not affect manganese
excretion. Information on food consumption is not provided but the reduction in
biliary manganese appears to reflect the dietary manganese content. It is however
noted that the deficient and replete rats excreted 0.18 and 0.16% respectively of the
previous day’s manganese intake.
64. Excretion of manganese may be reduced in neonatal animals, possibly due to

immaturity of biliary excretion or the low tissue manganese concentrations dictating
positive uptake of manganese metalloenzymes (reviewed ILSI ,1994).
Toxicity
65. The 1994 COT review of manganese is attached at Annex 2. This should be
read in conjunction with the review below which considers additional data on
manganese toxicity. The data have generally been considered in terms of
toxicological endpoint rather than duration of study. Additional data on respiratory
exposure have not been considered as this is not relevant to manganese in foods.
Human toxicity
Acute toxicity
66. Following acute ingestion of potassium permanganate, local corrosion but no

systemic toxicity was observed (Southwood et al., 1987).
Neurotoxicity
67. As noted in paragraphs 27-42 of Annex 2, excessive manganese exposure is

associated with neurotoxic symptoms. This is particularly apparent in miners,
smelters and workers involved in the manufacturers of dry batteries (Calne et al.,
1994) and is often termed manganism. It is noted that the most severe neurological
symptoms are those involving the extra-pyrimidal system which resemble those seen
in Parkinson’s disease and Wilson’s disease. Manganese toxicity and idiopathic
Parkinsonism are reviewed by Calne et al (1994). The authors conclude that the
similarities between the two conditions are the presence of generalised bradykinesia
and widespread rigidity. In manganese toxicity, however, there is less frequent resting
tremor; more frequent dystonia; a particular propensity to fall backwards; failure to
achieve sustained therapeutic response to levodopa and failure to detect a reduction in
fluoradopa uptake in Positron Emission Tomography (PET) scanning. The disease of
manganese toxicity progresses even after exposure to manganese stops (Mergler and
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12
Baldwin, 1997). Full regression is thought to be possible only in the early stages of
manganese poisoning. The available human data are summarised in Table 1, Annex 2.
68. The early signs of neurotoxic dysfunction are reviewed by Mergler and
Baldwin (1997). In the absence of clinical manifestations, neurophysiological and
neurobehavioral tests can be used. The results of individual studies varies, but a
pattern of slowing motor function, increased tremor, reduced response speed,
enhanced olfactory sense, possible memory and intellectual deficits and mood
changes is apparent. The dose-response relationship is uncertain.
69. An episode of 15 cases of manganese poisoning was reported in a study of six

Japanese families exposed to high levels of manganese (20-30 mg/l) in contaminated
well water (Kawamura et al., 1941). This resulted from leaching of manganese from
batteries buried near the well. Ten exposed subjects were not affected. Two fatalities
occurred. Symptoms included a mask-like face, muscle rigidity and tremors, and
mental disturbance. The actual exposure to manganese is uncertain but if it is assumed
that 2 l of water is consumed per day this would represent exposure of 40-60 mg/day
(0.67 to 1 mg/kg bw/day for a 60 kg adult). Elderly people appeared to be more
susceptible to the poisoning than children. However, certain features of the episode
are not consistent with classic manganese toxicity (ILSI, 1994). For example, there
was much less of a latent period, and the course of the disease was more rapid than is
generally the case for manganese toxicity. In addition those subjects that survived
recovered. It is possible that the differences were partly due to the differences in the
pharmacokinetics of inhaled versus ingested manganese. Exposure to other toxic
substances may also have occurred. ILSI estimated the manganese intake to be 58
mg/day in this study and noted that this was comparable with the 2.2 mg/day i.v. dose
associated with parkinsonian symptoms through parenteral nutrition, taking the
reduced absorption from oral exposure into account.
70. In a study conducted by Kondakis et al (1989), populations in the Northwest

Peloponnesus exposed to different levels of manganese in well water were
investigated. The manganese concentrations were 0.0036-0.0146 mg/l in area A, 0.08-
0.25 mg/l in area B and 1.8-2.3 mg/l in area C. The study focused on adults aged over
50 who had lived in the area for 10 or more years. No data on water consumption are
provided but if 2 l/person/day was assumed then this would represent intakes of
0.007-0.03, 0.16-0.5 and 3.6-4.6, mg Mn/day in areas A, B and C respectively. Data
on manganese intake from food are not provided, but analysis of samples of common
foods from households in areas A and C were comparable. Clinical examination was
undertaken using a standard neurological rating scale by a neurologist unaware of the
manganese concentrations. Progressive increases in the manganese concentration of
drinking were associated with increased neurological scores and hair manganese
concentrations. The differences were significant between areas A and C. No
relationship was found between hair and blood manganese levels or between blood
manganese and neurological score. The authors note that the subjects were older than
those that would be found in the workplace and that older people might be more
susceptible to manganese poisoning.
71. In a study by He et al (1994) children aged 11-13 from an area where there
was a high level of sewage irrigation had significantly lower scores on tests of short-
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13
term memory, manual dexterity and visuo-perceptive speed than paired controls. The
levels of manganese in drinking water were 0.241 - 0.346 mg/l in the test area and
0.030-0.040 in the control area. Hair manganese levels from children in the area with
the sewage irrigation were significantly higher than the controls and correlated
negatively with most of these scores. Only an abstract of this study is available in
English and this does not provide data on consumption. If it were assumed that each
child drank 2 l/day, manganese exposure would be approximately 0.48-0.69 in the test
group and 0.06-0.08 mg/day in the controls. Data on the manganese content of the
diet were not provided.
72. The effects of exposure to manganese in well water were investigated in a

retrospective study (Vieregge et al., 1995). Two cohorts living in rural northern
Germany, exposed to manganese in water from separate wells for up to 40 years
(range 10- 40 years) were investigated. Group A contained 41 subjects, mean age
57.5 years, who had consumed water containing at least 0.300 mg Mn/l (range 0.300 –
2.160 mg/l). Group B consisted of 74 subjects, mean age 56.9 years and consumed
water containing less than 0.05 mg Mn/l. The groups were stated to be homogenous
with regard to age, sex, nutritional habits and drug intakes. Neurological assessments
were made by investigators blinded to exposure status. These assessments included
structured questionnaires, standard neurological examinations with assessment of
possible Parkinsonian signs using the Columbia University rating scale and
instrumental tests of fine motor co-ordination. No neurological impairments were
detected and non-significant differences were found between the groups in any
neurological measure. Blood manganese concentrations were 8.5 ± 2.3 µg/l and 7.7 ±
2.0 µg/l respectively. This was not significantly different. Data on manganese intake
from the diet and estimates of the amount of water consumed were not provided.
However, if the standard default value of 2 l water consumption/adult day is used,
manganese exposure from water could be estimated to be 0.6 to 4.3 mg/day in Group
A and < 0.1 mg/l in Group B.
73. A cluster of Parkinson’s disease cases in Israel was investigated by Goldsmith

et al., (1990). A water source was common to the cluster and both water and soil
contained high levels of manganese; a fungicide containing the element was used in
the area. However, data on intakes and water concentrations of manganese were not
reported and paraquat structurally similar to the neurotoxin MPTP was also used in
the area.
74. A case of possible manganese toxicity as a result of dietary supplement

consumption has been reported (Banta and Markesbery, 1977). A 59 year old male
had taken a vitamin and mineral preparation for 4-5 years. He was admitted to
hospital with complaints of confusion, aggression inability to continue working and
Parkinsonian-like motor symptoms. At autopsy highly elevated levels of manganese
were found in serum, hair and brain samples. This was presumed but not proven to
have come from self-medication.
75. Manganese was found to have deposited in the brain of a 5 year old Japanese
boy who had been given total patenteral nutrition with trace element supplements for
over 2 years (Ono et al., 1995). The dose given was 10 µM (1.98 mg as manganese
chloride tetrahydrate, 54.9 mg as manganese). Severe headache and amnesia was
______________________________________________________________________________
14
apparent but the neurologic findings were not specific. An MRI examination indicated
hyperintense lesions in the basal ganglia, especially the globus pallidus, tectum,
tegmentum of mid-brain and pons, superior cerebellar peduncle and deep white
matter. After withdrawal of the manganese supplementation for 5 months, a second
MRI examination showed a considerable improvement with only a hyperintense
lesion in the globus pallidus being apparent. Blood manganese levels decreased from
135 to 20 µg/l over the period of withdrawal (the normal range quoted is 14.6 ± 4.7
µg/l). Nagamoto (1999) reported two cases of manganese toxicity as a result of total
pareneteral nutrition in adults. A 68 year old woman and a 70 year old man received
20 µmol (approximately 1.1 mg) manganese per day for 3 and 4 months respectively.
The manganese concentration was above recommended guidelines. Parkinsonian
symptoms were observed and hyper intense lesions were found in the globus pallidus
on MRI examination. On cessation of trace element treatment, the symptoms
improved. Nagamoto and colleagues also reviewed the literature and noted a further 3
cases in adults with manganese treatment lasting from 56 days to 2 years.
76. A statistically significant increase in the level of hair manganese in learning

disabled children has been reported (Collipp et al.,, 1983). It is possible that other
factors such as lead could be involved, so it is not possible to establish a cause and
effect relationship from this study. It has also been reported that the concentration of
manganese in the hair of jail inmates convicted of violent felonies was higher than
controls (Gottschalk et al., 1991). The authors suggest that mild manganese toxicity
could be one of a combination of factors promoting violent behaviours.
77. Manganese has also been associated with amylotrophic lateral sclerosis (ALS)
(Kihira et al., 1990). In a human study, spinal cords from ALS patients were found to
have higher manganese concentrations in the lateral fasciculus and anterior horn than
in the posterior horn. ALS patients had a positive correlation between manganese and
calcium spinal cord content, whilst controls had a negative correlation. It was
suggested that an imbalance between the two elements was involved in functional
disability and neuronal death. It was suggested that previous studies had indicated that
excess manganese intake from drinking water caused the imbalance. However no
supporting data are provided.
Liver disease and Cholestasis
78. The normal homeostatic mechanism in the gut and the liver is bypassed in
patients receiving long-term parenteral nutrition, and it is uncertain whether
cholestasis causes manganesaemia or vice versa. Manganese is thought to be one of
the factors contributing to the cholestatic disease occurring in such patients,
particularly in young children (Fell et al., 1996). However, the significance of
manganese toxicity in these patients, is disputed by other authors (Beath et al., 1996).
79. Work by Hauser (1994) indicates that manganese homeostasis fails in certain
forms of liver dysfunction, leading to high blood manganese levels. The excess
manganese is taken up by the basal ganglia of the brain and the increased levels are
monitored as abnormalities observed by MRI.
______________________________________________________________________________
15
80. However, in a study by Mena et al (1967) a group of miners suffering from

manganese toxicity, were compared to two control groups (healthy working miners
and a normal population). Low plasma protein concentrations were apparent in both
the healthy miners and patients, but otherwise there were no abnormalities. No
haematological or significant hepatic disorders was evident in any of the groups.
Immune function
81. It has been reported that male welders exposed to manganese by inhalation
exhibited suppression of T and B lymphocytes (Boshnakova et al., 1989).
Carcinogenicity.
82. No carcinogenicity studies have been identified.
Genotoxicity
83. Chromosomal aberrations have been reported in workers occupationally

exposed to manganese However, simultaneous exposure to other toxic substances
such as nickel, which is known to cause such abnormalities, means that no
conclusions can be drawn (Elias et al., 1989).
Human supplementation studies
84. Patients given a supplement of 30 mg manganese citrate in a mildly alcoholic

tonic in addition to their normal diet did not show any signs of toxicity after many
months (Schroeder et al., 1966). No further details are provided. Supplementation of
female volunteers with placebo, 15 mg/day manganese or 60 mg/day iron for 124
days did not result in any apparent adverse effects (Davis and Greger, 1992) though it
is unclear whether participants were asked about them.
Adverse drug reactions
85. Suspected adverse reactions to medicinal products are reported to the

Committee on Safety of Medicines/Medicines Control Agency. Many factors
influence the number of reports received, and in most situations there is considerable
"under-reporting" of reactions. The small number of reactions reported related to
multiconstituent products and may not, therefore, be attributable to manganese.
Vulnerable groups
86. Iron deficient individuals may be at risk of manganese toxicity (ILSI, 1994).
87. Subjects with impaired biliary excretion may be vulnerable to manganese

accumulation and toxicity. These would include patients with liver disease and elderly
people. Similarly, Knudsen et al (1995) noted that bile acid secretion is also
suppressed in infants making them potentially vulnerable to manganese toxicity.
______________________________________________________________________________
16
88. In addition, Cawte (1985) argues that fetal and neonatal animals and humans
might be at increased risk of manganese toxicity due to the increased absorption of
trace elements that occurs during pregnancy and lactation.
Genetic variants
89. No data have been identified.
Toxicity in laboratory animals – see Table 2, Annex 2
90. Manganese compounds have relatively low acute toxicity (reviewed, US

DHHS, 1997). The survival of rats was not affected by 1300 mg Mn/kg day in feed
for 14 days. Similarly, male and female mice that received 722 or 905 mg/kg day
respectively.
Acute toxicity
91. Groups of 5 male or female F344 rats were fed diet containing 0, 3, 130, 6,250,
12,500, 25,000 or 50,000 mg/kg manganese sulphate monohydrate for 14 days (NTP
1993). Survival was not affected by treatment. Body weights were reduced in the top
dose groups. The level of manganese in the control diet was approximately 92 mg/kg.
On a body weight basis, the manganese doses were 25-370 mg/kg. During the second
week of the study, the top dose males and all females exhibited diarrhoea. Total
leukocyte and neutrophil counts were significantly increased in the top dose groups;
this was particularly marked in the males. Absolute and relative liver weights of the
top dose males were significantly reduced. Liver manganese levels in the top dose
groups were over twice the levels of the controls. No other treatment-related changes
were apparent.
92. Groups of 5 male or female B6C3F1 mice were fed diet containing 0, 3,130,
6,250, 12,500, 25,000 or 50,000 mg/kg manganese sulphate monohydrate for 14 days
(NTP, 1993). The level of manganese in the control diet was approximately 92 mg/kg.
Survival was unaffected by treatment. Conclusions could not be drawn regarding
body weights due to poor randomisation at the start of the study. Liver manganese
levels in the top dose groups were 8 to 15 times those in the controls. No other
treatment-related effects were apparent.
Sub-chronic toxicity
93. Albino rabbits were given oral doses of 60 mg/kg body weight Mn2+ for 6
months (Khandelwal and Tandon, 1981). A variety of blood parameters were
measured to identify an early marker of manganese poisoning. Significant increases in
blood (but not plasma) manganese, plasma copper and serum total cholesterol were
observed compared to the controls throughout the study. A transient increase in
glutathione and a transient decrease in glutathione peroxidase also occurred. Alkaline
phosphatase levels were significantly decreased from 2 months onwards.
Haemoglobin concentrations were significantly decreased in the first few months of
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17
the experiment. The authors concluded that the measurement of erythrocyte

manganese and serum cholesterols could be the most useful indicators of manganese
toxicity.
Neurotoxicity
94. Rodents are considered to be of limited value in assessing the neurobehavioral

effects of manganese compared to primates (ILSI, 1994). Early neurological effects
seen in primates are often preceded by psychological symptoms. This is thought to be
due to neuroanatomical differences and the relative lack of neuromelanin in rodents.
The dietary manganese requirements for rodents are also higher.
95. Biochemical changes have been demonstrated in the brains of rats treated with
approximately 39 mg/kg bw/day manganese (ILSI, 1994).
96. The toxicity of different forms of manganese was compared by Komura and
Sakamoto (1992). Groups of six male ddY mice were fed diet containing 2000 mg/kg
manganese as manganese dioxide, or one of the divalent manganese compounds
manganese chloride, manganese carbonate, or manganese acetate for 1 year (the latter
two compounds are the more water soluble ones). On a body weight basis the dose
can be estimated to be 300 mg/kg bw/day (WHO, 1987). Although food consumption
was similar, manganese treatment reduced body weight gain compared to the controls.
The levels of a range of biogenic amines in different regions of the brain were
measured. In some parts of the brain, manganese levels were higher after feeding
insoluble salts than after feeding soluble salts. Treatment with manganese dioxide
lowered dopamine but increased homovanilic acid levels. The authors concluded that
manganese dioxide could be increasing oxidative metabolism of dopamine.
Accumulation of manganese in the brain correlated with reduced hypothalamic
dopamine levels in the manganese acetate group; the amount of manganese correlated
with the intensity of suppression of motor activity. The authors concluded that
manganese dioxide was more toxic than the divalent manganese compounds, and of
these, manganese acetate had the greatest toxic effect. Comparable, though more
marked, effects on tissue manganese levels were observed following a 3 month study
by the same authors (Komura and Sakamoto, 1991). The authors considered this
difference to be due to the effects of homeostasis in the longer study.
Haematology
97. A number of effects on haematological parameters have been reported

following administration of manganese compounds, probably as result of interference
with iron. Additional work has been conducted using diets with variable iron levels in
addition to the manganese.
98. Groups of 10 male or female F344 rats were fed diet containing control (92
mg/kg manganese), 1,600, 3,130. 6,250, 12,500 or 25,000 mg/kg manganese sulphate
(NTP, 1993) for 13 weeks. Mean daily intake ranged from 110 to 1700 mg/kg bw in
the males and 115 to 2000 mg/kg bw in the females. Food consumption and body
weights were not significantly affected by treatment. Absolute and relative liver
weights were reduced in all treated males and the top dose females. Absolute and
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18
relative lung weights were also reduced in all treated females. Neutrophil counts were
significantly higher in treated males, but lymphocyte counts significantly lower in the
males receiving 6,250 mg/kg or above manganese sulphate. In the females the total
leukocyte was significantly reduced in the 6,250 mg/kg or above groups, largely as a
result of reduced lymphocyte numbers. A small but significant increase in haematocrit
and erythrocyte count was measured in the 6,250 mg/kg or above males. No clinical
or histopathological findings were attributed to treatment.
99. Groups of 10 male or female B6C3F1 mice were fed a diet containing control
(92 mg/kg manganese), 3,130. 6,250, 12,500, 25,000 or 50,000 mg/kg manganese
sulphate (NTP, 1993) for 13 weeks. Mean daily intake ranged from 330 to 7400
mg/kg bw in the males and 390 to 6900 mg/kg bw in the females. Absolute and
relative liver weights were reduced in the top dose males only. Haematocrit,
haemoglobin concentrations and mean erythrocyte volume were reduced in the top
dose groups compared to the controls. The findings were thought to suggest
microcytic anaemia possibly related to sequestration or deficiency of iron. Total
leukocyte counts in the males of the top two dose groups were reduced but it was
uncertain whether this was due to treatment. It was reported that a few animals in the
treated groups had fight wounds and that mild epithelial hyperplasia was observed in
3 of the 10 males in the top does group. No other treatment related effects were
reported.
100. Long Evans rats were exposed in utero to normal or iron deficient (240 and 20
mg/kg respectively) diet, which was supplemented with manganese oxide (Carter et
al., 1980). The males of the F1 generation were then exposed to the same diet until
day 224. Both types of diet contained 50 mg/kg manganese sulphate initially and
after supplementation contained a total of 50, 400, 1100 or 3550 mg/kg manganese.
Due to excessive mortality, the animals in the low iron/3550 mg/kg manganese group
were killed at day 40. The achieved doses are not given. However, these can be
estimated from control data, to be approximately 2.3, 18.4 or 50.6 mg Mn /kg bw/day
for the control, 400 and 1100 mg/kg and normal iron groups and 2.7, 21.6 and 63.8
mg Mn /kg bw/day in the control, 400 and 1100 mg/kg and low iron groups.
Differences in red cell count and mean cell volume (MCV) were apparent between the
low and normal iron groups. In the normal iron group, a slight manganese dose-
related increase in RBC count was apparent at days 60 and 224 but this was not
significant. No effects due to manganese were apparent on MCV or, on the level of
serum proteins (albumin and globulins), glucose or enzymes (alkaline phosphatase,
lactate dehydrogenase or glutamic-oxaloacetic transaminase). In the low iron group,
manganese treatment was associated with a dose-related decrease in RBC count and
MCV; the differences lessened during the study and had disappeared by the end of the
study (day 100 for MCV). Treatment with 400 and 1100 mg/kg manganese reduced
serum creatinine levels and treatment with 1100 mg/kg manganese increased serum
phosphate and calcium levels at day 100 in both iron groups.
101. In a second study conducted by the same authors, the dams received the
normal iron diet. From day 10 after gestation, groups of 9-11 male offspring received
low or high iron diet, or low iron diet with 400 or 1100 mg/kg manganese for a further
30 days. While RBC count, MCV, haematocrit and haemoglobins were reduced in the
low iron groups compared to the controls, there was no additional effect attributable
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19
to manganese. The authors concluded that the rats given normal iron diets were
largely unaffected by manganese treatment, but those on the low iron diet in the pre
and post natal period developed microcytic anaemia. The young animals were
considered to be more sensitive to manganese treatment.
Liver toxicity
102. High doses (50-60 mg/kg bw) of intravenous manganese have been reported to
result in reduced bile flow in the first 4 hours after treatment and a reduction in the
ability of the liver to excrete bilirubin (Witzleben, 1969). At 24 hours after treatment,
bile flow was increased in the manganese-treated animals compared to the sham
treated controls. Histological changes characteristic of cholestasis were apparent at
both 4 and 24 hours post treatment. The decreased initial bile flow rate was not
apparent at lower doses (0.03-0.04 mg/kg) (Cikrt, 1972).
Immune system
103. Immune effects reported (US DHHS, 1997) following manganese exposure
include stimulation of macrophage and natural killer cell activity by increased levels
of interferon, altered responsiveness of lymphoid cells to mitogens and inhibition of
antibody production in response to T-dependent antigens. It is uncertain whether these
immune parameters would result in clinically significant impairment of immune
function.
Reproductive toxicity
104. The reproductive effects of in utero followed by lifetime manganese exposure

were described by Laskey et al (1982); other aspects of this study are reported by
Carter et al, 1980 (see paragraph 100). As described, the rats were exposed to a diet
supplemented with 350, 1050 and 3500 mg/kg manganese (as Mn3O4). The basal
manganese concentration was 50 mg/kg manganese. Manganese consumption was
estimated to be 16-32, 44-48 and 158-316 mg/kg respectively. General toxicity was
apparent in the young animals receiving 3500 mg/kg Mn in the diet; this was
accentuated by low iron levels. Breeding took place at 90-100 days of age. Fertility
was significantly reduced in the 3500 mg/kg group in the presence of adequate iron
concentrations; 63% of the treated females became pregnant compared to 84% in the
controls. Litter size, ovulation, resorptions, pre-implantation deaths and fetal weights
were not affected by treatment. A number of effects were seen in the males fed 1050
mg/kg manganese, these included a decrease in sperm count at day 100 and the
abolition of the usual decrease in serum FSH levels between days 60 and 100. Male
reproductive development as measured by testes weight, sperm counts and serum
follicle stimulating hormone and testosterone levels was delayed by manganese
treatment.
105. No effects on litter size or weight were found in female rats exposed to
manganese chloride in drinking water (Kontur and Fechter, 1985) except where the
concentrations were so high that water intake by the dams was severely reduced.
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20
Carcinogenicity
106. In a chronic (2 year) feeding study carried out by the NTP (1993) manganese
sulphate was administered to groups of 50 male or female F344 rats in the diet at
control (92 mg/kg Mn) or levels of 1,500, 5000 or 15,000 mg/kg. The daily doses
were 60, 200 or 615 mg/kg bw in the males and 70, 230 or 715 mg/kg in the females.
Survival was reduced in the top dose males as a result of increased severity of
nephropathy and renal failure in this group. This was not evident until week 93 of the
study. The body weights of the top dose males began to decline compared to the
controls towards the end of the study. Food consumption was similar in all groups. No
changes in haematology or clinical chemistry parameters related to treatment were
apparent. A small increase in the incidence of pancreatic hyperplasia and tumours
was found in treated males. This was not dose related, but did not occur in the
controls. Lesions associated with nephropathy such as mineralisation of the blood
vessels, mineralization of the glandular stomach, fibrous osteodystrophy of the femur
and parathyroid gland hyperplasia were increased in the top dose males. It was
concluded by NTP that there was no evidence of carcinogenicity in male or female
rats. It has been suggested (discussed, US DHHS 1997) that the evidence was
equivocal since the increase in lesions in the pancreas while slight, was not apparent
in the controls.
107. In a chronic (2 year) feeding study carried out by NTP (1993) manganese
sulphate was administered to groups of 50 male or female B6C3F1 mice in the diet at
control (92 mg/kg Mn) or levels of 1,500, 5000 or 15,000 mg/kg. The daily doses
were 160, 540 or 1800 mg/kg bw in the males and 200, 700 or 2250 mg/kg in the
females. Survival was similar in the control and treatment groups. The body weights
of the treated males were similar to the controls but the body weights of all treated
females were lower than the controls. Food consumption was similar in all groups.
Haematocrit, haemoglobin concentration and erythrocyte count were slightly
increased in the top dose males at the 15 month evaluation. This was not consistent
with the findings of the 13 week study (see paragraph 99) and the significance of the
finding was uncertain. Hepatic iron levels were lower in exposed females at 9 and 15
months and in the 5,000 and 15,000 males at 15 months. Thyroid follicle dilatation
was present in the top dose animals at 9 and 15 months but not in the controls. At the
end of the study the incidence of thyroid follicle dilatation was significantly increased
in the top dose animals and the 5000 mg/kg females. A significantly increased
incidence of thyroid gland follicular cell hyperplasia was found in all the exposed
females and the top dose males. A marginally higher incidence of thyroid gland
follicular cell adenomas was found in the top dose mice. The incidence was not
significantly different from the controls but was slightly higher than the average
historical incidence although just within the range. A significant increase in the
incidence of focal squamous hyperplasia in the forestomach occurred in the top dose
mice. This was accompanied by ulceration/erosion and inflammation. The NTP
considered that there was equivocal evidence for the carcinogenicity of manganese
sulphate in B6C3F1 mice.
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21
Genotoxicity
108. The available mutagenicity data have been summarised by US DHHS (1997)
in the attached tables. The results of the studies are conflicting. Tables 1 and 2
adapted from US DHHS (1997) summarise the available information. Some of the
studies are considered below.
In vitro
109. High levels of manganese have been shown to be mutagenic in bacteriophage,

yeast and animal cells in vitro.
110. Manganese sulphate was not mutagenic in Salmonella typhimurium strains

TA97, TA98, TA100, TA 1535 or TA1537 with or without metabolic activation from
hamster or rat S9 (Mortelmans, 1986, NTP, 1993). The assay was conducted to a
standard protocol and the positive controls produced the anticipated response.
However, Wong (1988) reported that manganese chloride at doses of 20-120 mg/kg
were negative in strains TA98, TA 102 and TA1353 in the presence and absence of
metabolic activation using the standard plate incorporation method of the Ames assay.
A positive result was recorded in strain TA1537 in absence of activation only. Data
on positive controls are not provided. The mutagenicity of divalent manganous
sulphate in Salmonella strain TA97 was reduced by addition of the chelating agent
diethyldithiocarbamate (Pagano and Zeiger, 1992).
111. Manganese sulphate induced sister chromatid exchange in cultured CHO cells
in the presence and absence of metabolic activation (NTP, 1993). In the absence of S9
a delayed harvest was used to offset cytotoxicity, whereas in the presence of S9 all
positive responses were achieved with normal harvest times. Chromosome aberrations
were also induced in the absence of S9; a delayed harvest time was also used in this
experiment. The dose response relationship was less marked and chromosome
aberrations were not found in the presence of S9 activation.
112. Manganese chloride was found to be strongly positive in the L5178 mouse
lymphoma assay (Oberley et al 1982) over a dose range of 5-100 µg/ml. The increase
in mutant frequency over the solvent control was up to 6.9 fold and a dose response
relationship was apparent. The method used was a standard procedure and the positive
controls produced the anticipated response.
113. De Méo et al (1991) investigated the mutagenicity of a range of manganese

compounds in different in vitro conditions and concluded that Mn2+ was the major
mutagenic species. The manganese ion, Mn2+ can substitute for Mg (II) in DNA
polymerase in vitro leading to errors in the fidelity of DNA replication (El Deiry et
al., 1984).
In vivo
114. Manganese sulphate did not induce sex-linked recessive lethal mutations in
the germ cells of adult Drosophila melanogaster treated with feeding at 12,500 mg/kg
______________________________________________________________________________
22
manganese sulphate in feed or by injection of 1000 mg/kg. Manganese chloride has

also been reported to be negative in this assay (Rasmuson, 1985).
115. In vivo mutagenicity has not been demonstrated in mammals (Joarder and
Sharma, cited by ILSI 1994). In this study (described in US DHHS 1997) Swiss
albino mice were fed MnSO4 or KMnO4 at varying doses over 3 weeks. The doses
were 10.25, 20.25, and 61 mg/100 g for MnSO4 and 6.5, 13 and 38 mg/100g for
KMnO4. Sperm head abnormalities and the frequency of chromosomal abnormalities
in bone marrow cells and micronuclei were significantly increased. In a study by
Dikshith and Chandra (cited, US DHSS 1997) repeated oral doses of 0.04 Mn/day as
manganese chloride did not produce any significant damage in bone marrow
spermatogonial cells.
Mechanisms of toxicity
116. Different hypotheses have been put forward to explain how manganese affects
dopaminergic neurotransmission. These include, the formation of free radicals
through glutathione reduction, decreased glutathione peroxidase activity, irreversible
auto-oxidation of dopamine via the transformation of Mn3+ to Mn2+, inhibition of
mitochondrial respiration, abnormal hydrocarbon metabolism and excitotoxic
processes through NDMA receptors. Mn2+ may also be involved in manganese
neurotoxicity since this can substitute for Ca (II) under physiological conditions (US
DHHS, 1997). Other theories regarding the mechanism of manganese neurotoxicity
include damage following the formation of hydroxyl radicals during the manganese
catalysed auto-oxidation of hydrazines. A recent study (Malecki, 2001b) of exposure
of rat primary neurone cultures to Mn2+ suggests that manganese causes
mitochondrial dysfunction, and as a result triggers apoptosis. Exposure to Mn2+ for 48
hours at concentrations of 5, 50 and 500 µM caused dose dependent decreases in
mitochondrial membrane potential and complex II activity. The specific effects of
manganese in different regions of the brain are thought to be due to the affinity of
manganese for neuromelanin (Mergler 1996).
117. Mn2+is also thought to be the active mutagenic species in vitro.
Regulatory considerations
118. There are no maximum levels of manganese specified for food in the UK.
However, the maximum levels of manganese specified for drinking water, spring
water and bottled water is 50 µg/l (The Natural Mineral Water, Spring Water and
Bottled Drinking Water Regulations, 1999 and The Private Water Supplies
Regulations 1991).
Existing recommendations on maximum intake levels
119. COMA (1991) note the low toxicity of manganese and state that safe intakes
are believed to lie above 1.4 mg/day for adults and 16 µg/kg/day for children.
______________________________________________________________________________
23
120. The US EPA set a reference dose (RfD) of 0.14 mg/kg day based on a
statement by the NRC FNB that 10 mg/day should not present a toxicity problem.
The available epidemiological data was considered to be too limited to use to set the
RfD. A separate water RfD was derived using the NOAEL of 0.2 mg/l identified by
Kondakis et al (1989). An uncertainty factor of 1 was used since the study considered
large numbers of people that had been chronically exposed. The individuals were all
aged over 50 and were considered to represent a sensitive sub-group.
121. The US DHHS (1997) considered that there were insufficient data available to
establish a Minimal Risk Level (MRL). The upper range of the ESADDI (5 mg/day)
(see paragraph 14) was used to derive an interim guidance value of 0.07 mg/kg/day
for Agency for Toxic Substances and Disease Registry (ATSDR) human health
assessment.
122. Hambidge and Krebs (1989) recommended an upper limit for infant formulae
of 50 µg manganese/100kcal though it is noted that this is considerable excess of the
intake from human milk (0.5 µg manganese/100 kcal) even taking the reduced
bioavailability from formulae into account. It was considered that an intake of >8.5
µg/kg/day was necessary to achieve positive manganese balance. Manganese levels in
infant formula have been reported to be up to 5000 µg/100 kcal (cited in, ILSI 1994).
123. The EU Scientific Committee for Food could not establish a tolerable upper
intake level for manganese (SCF, 2000).
124. The US Food and Nutrition Board derived an upper level of 11 mg/day based
on the observation that adverse effects from dietary manganese intake have not been
observed (IOM, 2001).
Existing recommendations on maximum supplementation levels
125. The UK trade association, the Council for Responsible Nutrition (CRN, 1999)
recommends a maximum upper safe level for manganese supplementation of 15
mg/day long term and 20 mg/day short term.
Summary
126. Manganese is an abundant element occurring in soil, sediments and water. It is

present in foods, particularly nuts, legumes and cereals. The average population
intake of manganese from food in the UK is 4.9 mg/day.
127. Manganese is an essential element being a component and activator of a

number of enzymes and thus involved in carbohydrate and lipid metabolism.
Manganese deficiency has not been described in the general population but has been
induced experimentally. Manganese deficiency is known in animal species.
128. Manganese absorption occurs in the small intestine. It is relatively low but is
dependent on the chemical form of the element. Absorption is thought to be higher in
infants or young animals. It has been suggested that variable manganese absorption
______________________________________________________________________________
24
helps to maintain homeostasis. Iron and manganese compete for binding site and thus
can interfere with each others’ absorption. This can result in adverse effects in
laboratory animals.
129. In the portal blood, manganese may become bound to α2-macroglobulin,

albumin and transferrin. Transport to the tissues occurs following oxidation and
binding by transferrin. Manganese particularly accumulates in mitochondria-rich
tissue such as the liver and the pancreas. It also accumulates in other metabolic pools.
Manganese accumulates in brain tissue. Low levels of manganese are found in human
milk. Manganese is largely excreted through the bile, though direct excretion through
the intestine into the gut may also occur. Urinary excretion of manganese also occurs
but to a much lesser extent.
130. Manganese has low acute toxicity.
131. In humans, chronic oral exposure to high doses of manganese is associated

with neurotoxic effects. There are some reports that manganese may be involved in
liver disease but since the majority of manganese is excreted via the bile, it may be
that the accumulation of manganese in such cases is secondary to the impairment of
biliary function. Adverse effects on the immune system have also been reported.
132. No genetic variants with increased susceptibility to manganese toxicity have

been identified. It has been suggested that elderly people, infants, individuals with
liver disease and individuals that are iron deficient may be vulnerable to manganese
accumulation and toxicity.
133. Neurotoxic effects have also been observed in laboratory animals. Other
adverse effects attributable to manganese include anaemia and other alterations to
haematological parameters. Some adverse effects on reproduction have been reported
in particular reduced fertility. It is uncertain whether this is a specific effect or is
secondary to behavioural changes resulting from neurotoxicity.
134. Conflicting results are obtained in genotoxicity studies in vitro. However

genotoxic effects have not been reported in vivo. Chronic carcinogenicity studies of
manganese sulphate in mice and rats were essentially negative, with equivocal
evidence of carcinogenicity being observed in mice only.
______________________________________________________________________________
25
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______________________________________________________________________________
33
ANNEX 1
FOR COMMITTEE USE ONLY
INTAKES OF MANGANESE FROM FOOD AND SUPPLEMENTS
The data presented on manganese intakes are obtained from two sources, i) the UK
Total Diet Study, which gives population average intakes, and ii) dietary surveys of
specific population age groups in Britain carried out over the last 15 years1234. In
each survey food consumption data were collected by means of a dietary record
(usually weighed) kept for 4 or 7 consecutive days. Nutrient intakes were calculated
using a set of nutrient composition data contemporaneous with the time of the survey.
Therefore some apparent differences in intakes between population age groups may
be due to changes in the nutrient composition data and reflect changes in the nutrient
composition of foods over time.
Population average intake of manganese from food sources
The 1994 Total Diet Study5 showed that estimated population average intake of
manganese in 1994 was 4.9mg/day. Table 1 shows the concentration of manganese in
each of the TDS food groups and the intake from each food group. This intake is
comparable with manganese intakes estimated from previous TDS but is rather higher
than intakes from dietary surveys of specific age groups as presented in Table 2. The
highest concentration of manganese was found in the nuts group, followed by bread
and miscellaneous cereals. The main contributor to intakes was beverages (due to
high concentrations in tea), followed by bread, miscellaneous cereals and potatoes.
Intakes of manganese from food and supplements for specific age groups
Table 2 provides information on the median intake and the upper and lower end of the
intake distribution (defined as the upper and lower 2.5 percentiles, respectively), of
manganese by the British population, classified by age and sex. No information is
available on manganese intakes of adults aged 16-64 years.
Median intakes of manganese were higher for males than for females, increased with
age for young people, and decreased with age for people aged 65 years and over.
Body weight adjusted intakes showed an age related decrease. No RNI has been set
for manganese. Average intakes for all groups exceeded the minimum thresholds set
for safe intakes of manganese for adults and children. In the 65 years and over group
6% of men and 11% of women free-living in the community and 8% of men and 12%
of women living in institutions had intakes below the minimum safe intake for adults
of 1.4mg/day.
1
Food and nutrient intakes of British infants. 1986
2
National Diet and Nutrition Survey of children aged 1½-4½ years. 1992/3
3
National Diet and Nutrition Survey of young people aged 4-18 years. 1997/8
4
National Diet and Nutrition Survey of people aged 65 years and over. 1994/5
5
MAFF (1997) 1994 Total Diet Study: Metals and other elements. Food Surveillance Information
Sheet No. 131.
______________________________________________________________________________
34
Sources of manganese in the diet
Table 3 indicates the contribution made by different types of food to average intakes
of manganese by young people aged 15-18 years. This dataset was collected in 1997
and so most closely reflects current eating habits and fortification practices. The main
source of manganese in this group was cereals and cereal products which contributed
over 50% of total intake, followed by vegetables, potatoes and savoury snacks.
Manganese is not commonly used as a fortificant and fortificant manganese is
therefore likely to make a negligible contribution to total intakes. Other age groups
had similar patterns of intake, except that for people aged 65 years and over, tea
contributed about a fifth of total intake.
Manganese intake from supplements
Table 4 shows the number of consumers of manganese supplements for each age
group, together with the median and range of intakes for each group. Only a very
small proportion of participants took manganese supplements. The contribution of
manganese supplements to average intakes for the total sample was negligible for all
age groups. For those few users of manganese supplements median intakes from
supplements were <0.1-1.0 mg / day and the maximum intake was 2.8 mg/day.
Nutrition Unit A
JFSSG MAFF
August 1999
______________________________________________________________________________
35
Table 1 Concentrations of manganese in 1994 Total Diet samples6 and estimated

average intake
Food group (TDS) Mean Mn concentrations Intake of Mn

(mg/kg fresh weight) Mg/day
Bread 8.0 0.880
Miscellaneous cereals 6.81 0.681
Carcase meat 0.14 0.0036
Offal 2.8 0.0028
Meat products 1.39 0.061
Poultry 0.17 0.0031
Fish 1.14 0.015
Oils & fats 0.02 0.00058
Eggs 0.31 0.0050
Sugars & preserves 1.52 0.102
Green vegetables 2.01 0.074
Potatoes 1.94 0.258
Other vegetables 1.6 0.117
Canned vegetables 1.84 0.064
Fresh fruit 1.99 0.129
Fruit products 2.25 0.097
Beverages 2.71 2.339
Milk 0.03 0.0085
Dairy produce 0.27 0.015
Nuts 14.9 0.030
Total intake (mg/day) 4.9mg/day
6
The Total Diet Study is a model of the average domestic diet in the UK. A total of 119 categories of
food and drink are specified for inclusion in the Total Diet. These are assigned to one of twenty broad
food groups. The quantities and relative proportions of each food that make up the Total Diet are
largely based on data from the National Food Survey (NFS) and are updated annually. Food samples
are purchased fortnightly from different locations representative of the UK as a whole and prepared
and cooked according to normal consumer practice. The constituents of each group are then
homogenised and frozen. Samples can be analysed for a range of food constituents. The population
average intake of a particular food constituent can be estimated from its concentration in each food
group and consumption of each group as determined by the NFS.
______________________________________________________________________________
36
Table 2: Total intakes of manganese
Absolute manganese intake Bodyweight adjusted manganese

(mg/day) intake (mg/kg bwt /day)7
Age/sex8 intakes from food and supplements9
2.5%ile Median 97.5%ile 2.5%ile Median 97.5%ile
Infants (1986) 10
6-12mths/M&F 0.4 1.1 2.4 0.04 0.10 0.23
Pre-school children
(1992/3)
1½-2½ yrs/M&F 0.4 1.0 2.5 0.033 0.086 0.201
2½-3½ yrs/M&F 0.5 1.1 2.4 0.035 0.078 0.170
3½-4½ yrs/M 0.6 1.3 2.7 0.033 0.080 0.158
3½-4½ yrs/F 0.5 1.1 2.7 0.033 0.072 0.165
Young people (1997/8)
4-6 yrs/M 0.67 1.68 3.17 0.034 0.080 0.140
4-6 yrs/F 0.82 1.44 2.92 0.041 0.072 0.149
7-10 yrs/M 1.08 1.92 4.22 0.028 0.068 0.128
7-10 yrs/F 0.86 1.70 4.19 0.029 0.056 0.121
11-14 yrs/M 1.01 2.10 4.79 0.019 0.049 0.098
11-14 yrs/F 0.89 1.81 4.21 0.016 0.039 0.082
15-18 yrs/M 1.21 2.40 4.98 0.014 0.037 0.082
15-18 yrs/F 0.74 1.92 4.19 0.012 0.032 0.081
Older people free-living in the community
(1994/5)
65-74 yrs/M 1.06 3.23 6.20 0.015 0.042 0.084
65-74 yrs/F 0.93 2.60 4.99 0.016 0.040 0.087
75-84 yrs/M 1.13 2.94 6.59 0.017 0.040 0.093
75-84 yrs/F 0.90 2.24 4.60 0.014 0.036 0.082
85 and over/M 0.85 2.70 5.80 0.013 0.040 0.084
85 and over/F 0.81 2.19 4.52 0.015 0.037 0.091
Older people living in institutions (1994/5)
65-84 yrs/M 1.01 2.45 5.00 0.017 0.037 0.089
65-84 yrs/F 1.13 2.32 3.60 0.017 0.039 0.073
85 and over/M 0.97 2.62 5.02 0.013 0.040 0.076
85 and over/F 1.11 2.03 3.77 0.017 0.033 0.087
7
Body weights measured for each subject for all age groups except infants aged 6-12 months where
reported body weights were used.
8
No information on manganese intakes is available from the 1986/87 survey of adults aged 16-64
years.
9
Absolute intakes presented for pre-school children, young people and older people are from food
sources only as the contribution of supplements was negligible.
10
Intakes for infants aged 6-12 months are from food only.
______________________________________________________________________________
37
Table 311: Sources of manganese in the diet
Contribution of food types to average

daily intake of manganese
Food Type mg/day % of total
Cereal and cereal products 1.22 53

- of which white bread 0.35 15
high fibre and whole grain breakfast cereals 0.18 8
Milk and milk products 0.02 1
Egg and egg dishes 0 0
Fat spreads 0 0
Meat and meat products 0.16 7
Fish and fish dishes 0.02 1
Vegetables, potatoes and savoury snacks 0.44 19
Fruits and nuts 0.09 4
Sugar, confectionery and preserves 0.09 4
Beverages 0.18 8
- of which tea 0.14 6
Miscellaneous 0.05 2
Mean intake from food 2.31 100

Intake from dietary supplements Negligible
Mean intake from food and supplements 2.31
11
NDNS: young people aged 4-18 years. 1997/8. 15-18 year group
______________________________________________________________________________
38
Table 4: Manganese intake from supplements
Consumers of Manganese intake from

manganese supplements (consumers
supplements only) (mg/day)
Age/sex Number % Median Range
Infants (1986)
6-12 mths/M&F 0 0 0 0
Pre-school children (1992/3)
1½-4½ yrs/M&F 14 <1 0.1 <0.1 - 0.4
Young people (1997/8)
4-10 yrs/M&F 4 <1 <0.1 <0.1 - 0.1
11-18 yrs/M 0 0 0 0
11-18 yrs/F 1 <1 0.5 0.5
Older people free-living in the community (1994/5)
65 and over/M 10 2 1.0 0.1 - 1.3
65 and over/F 12 2 0.1 <0.1 - 2.8
Older people living in institutions (1994/5)
65 and over/M 3 1 0.5 0.2 - 2.1
65 and over/F 5 2 0.1 0.1 - 0.6
______________________________________________________________________________
39
Annex 2. Tables referred to in this review
Table 1 Summary of human toxicity studies.
Exposure Endpoint Dose NOAEL/LOAEL Duration Comment Reference

Families: Mn in Mild to fatal 1 mg/kg bw/day Both. Some A few weeks Possible exposure Kawamura et al,
drinking water neurotoxicity (estimated) unaffected but from other toxins. Not 1941
exposed considered to be (ILSI)
classic manganese
toxicity.
Adults: Mn in Neurotoxicity 0.016-0.12 NOAEL > 10 years Kondakis et al,
drinking water mg/day 1989
Children (11-13) Neurotoxicity 0.48-0.69 mg/day LOAEL Lifetime Abstract only He et al, 1994
Mn in food and
drinking water.
Adults: Mn in Neurotoxicity 0.6-4.3 mg/day NOAEL 10-40 years Vieregge et al,
drinking water 1995
Adults: Mn in Parkinsons Not given Little data and Goldsmith 1990
food and drinking possible confounding
water by other exposures.
Child given total Neurotoxicity > 2 years Ono et al. 1995
parenteral
nutrition
Learning disabled Manganese higher Other exposure Collipp et al, 1983
children than controls possible. Correlative
study only
Exposure Endpoint Dose NOAEL/LOAEL Duration Comment Reference
______________________________________________________________________________ 41 41
This paper has been prepared for discussion by the Expert group on Vitamins and Minerals and does not necessarily represent the final views of the Group.
Adult prisoners Manganese higher Gottschalk et al,

than controls in 1991
violent felons
______________________________________________________________________________ 42 42
Table 2 Summary of animal toxicity studies.
Species Endpoint/findings Dose NOAEL/LOAEL Duration Comment Reference

F344 rats Reduced body 185 mg/kg bw/day NOAEL 14 days NTP (1993)
weights, diarrhoea, = 59 mg Mn/kg
increased bw/day
neutrophil and
leukocyte counts
B6C3F1 Increased liver 25,000 mg/kg in NOAEL 14 days Problems with NTP (1993)
mice weights diet manganese randomisation and
sulphate. =1200 body weights.
mg/ Mn/kg
F344 rats Decreased liver and 110 mg/kg bw/day LOAEL ? 13 weeks Significant NTP (1993)
lung weights, manganese changes?
alterations to sulphate
haematological =35 mg Mn/kg
parameters bw/day
Albino Increased blood 60 mg/kg bw/day LOAEL 6 months Khandelwal and
rabbits (but not plasma Mn 2+ Tandon, 1981
Mn, plasma Cu and
serum total
cholesterol,
decreased alkaline
phosphatase levels,
decreased
haemoglobin in
first few months.
______________________________________________________________________________ 43 43

B6C3F1 Decreased 3300 – 3700 mg/kg NOAEL 13 weeks NTP (1993)
mice haematocrit and bw/day
RBC count. = 1056-1184 mg
Anaemia? Mn/kg bw/day
ddY mice Alterations to 2000 mg/kg in diet LOAEL 1 year Effect most marked Komura and
biogenic amines in (estimated to be with manganese Sakamoto, 1991
brain, suppression 300 mg/kg bw) dioxide.
of motor activity manganese Manganese acetate
chloride, dioxide, most toxic divalent
acetate, carbonate compound
= 130, 189, ? 198,
143 mg Mn/kg
F344 rats Increased severity 200-230 mg/kg NOAEL 2 years Increased incidence NTP (1993)
of nephropathy and bw/day manganese of pancreatic
related lesions. sulphate = 64-74 hyperplasia, but not
mg Mn/kg bw/day significant.
B6C3F1 Increased thyroid 540- 700 mg/kg bw NOAEL 2 years Equivocal evidence NTP (1993)
mice follicle dilation, manganese
increased thyroid sulphate = 173-224
adenomas. mg/Mn kg/bw
Long Anaemia (in 50.6 mg/kg bw/day NOAEL In utero and Adverse effects in Carter et al, 1980
Evans combination with Manganese oxide lifetime combination with
Rats low iron diet) with normal iron low iron diet
diet
______________________________________________________________________________ 44 44

Long Reduced fertility, 44-48 mg/kg NOAEL In utero and in No effect on litter Laskey et al,
Evans delayed bw/day subsequent size, resorptions 1982
Rats reproductive diet. Bred at etc.
development in 90-100 days of Effect on males or
males age behavioural
______________________________________________________________________________ 45 45
Table 3 Genotoxicity of manganese compounds in vitro (adapted from US DHHS, 1997)
Species (test system) Compound Endpoint Strain Results (+ Results (- activation) Reference
activation)
Salmonella MnCl2 Gene Mutation TA98 - - Wong, 1988
typhimurium (plate TA102 - -
incorporation assay) TA1535 - -
TA 1537 - +
MnSO4 Gene Mutation TA97 - - Motelmans et al.,

TA98 - - 1986
TA100 - -
TA1535 - -
TA 1537 - -
Salmonella MnSO4 Gene Mutation TA 97 ND + Pagano and Zelger,
typhimurium 1992
(preincubation assay) MnCl2 Gene Mutation TA102 ND - DeMéo et al., 1991
TA100 ND - DeMéo et al., 1991
Photobacterium MnCl2 Gene Mutation (restored Pf-13 ND + Ulitzar and Barak,
fischers luminescence) 1988
(bioluminescence test)
Escherichia coli MnCl2 Gene Mutation KMBL 3835 ND + Zakour and
Glickman, 1984
Bacteriophage MnSO4 Gene Mutation T4 ND + Orgel and Orgel, 1965
Bacillus subtilis MnCl2 Inhibition of growth in M45 (Rec) ND + Nishioka, 1975
(recombination assay) Mn(NO3)2 recombination deficient - +
MnSO4 mutant (Rec) compared to + -
Mn (CH2COO)2 wild type (Rec’) - +
KMnO4 - -
Bacillus subtilis MnCl2 Inhibition of growth in M45 (Rec) ND - Kanematsu et al.,
(recombination assay) Mn(NO3)2 recombination deficient - 1980
Mn (CH2COO)2 mutant (Rec) compared to
wild type (Rec’)
______________________________________________________________________________ 46 46
Species (test system) Compound Endpoint Strain Results (+ Results (- activation) Reference
activation)
Saccharomyces MnSO4 Gene conversion, D7 ND + Singh, 1984
cerevisiae reverse mutation -
Mouse lymphoma MnCl2 Gene mutation L5178Y TK+/- ND + Oberley et al., 1982
cells
Syrian hamster ovary MnCl2 Enhancement of SA7 ND + Casto et al., 1979
cells transformation
Human lymphocytes MnCl2 DNA damage lymphocyte - + DeMéo et al., 1991
(Single-cell gel assay)
Chinese hamster MnSO4 Chromosomal aberrations/ +- + NTP, 1993
ovary cells sister chromatid exchange
ND = No data
- = negative result
+ = positive result
MnCl2 = manganous chloride

MnSO4 = manganous sulphate
KMnO4 = potassium permanganate
Mn(NO3)2 = manganous nitrate
Mn (CH3COO)2 = manganous carbonate
______________________________________________________________________________ 47 47
Table 4 Genotoxicity of Manganese Compounds In Vivo (adapted from US DHHS, 1997)
Species (test system) Compound End Point Exposure Route Results Reference
Drosophila melangoster MnSO4 Sex-linked, recessive Feeding - Valencia et al., 1986
lethal Injection -
Drosophila melangoster MnCl2 Somatic mutation Soaking larvae - Rasmuson, 1985
Albino rat Chromosomal aberrations Oral - Dikshith and Chandra,
(bone marrow cells) MnCl2 1978
(Spermatogonial cells)
Albino mouse MnSO4 Chromosomal aberrations Oral + Joardar and Sharma, 1990
KMnO4 +
ND = No data
- = negative result
+ = positive result
MnCl2 = manganous chloride

MnSO4 = manganous sulphate
KMnO4 = potassium permanganate
______________________________________________________________________________ 48 48
Annex 3
EXTRACT FROM TOX/94/58 THE COT REVIEW OF MANGANESE.
Available in the hard copy of this review only.
______________________________________________________________________________ 49

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EVM/99/22.

EXPERT GROUP ON VITAMINS AND MINERALS

REVIEW OF MANGANESE - REVISED VERSION

The attached review of manganese is a revised version of the paper presented to

The following annexes are included with this paper:

Annex 1 Intakes of manganese from food and supplements in the UK diet

Expert Group on Vitamins and Minerals Secretariat

Chemistry and geochemistry

1. Manganese is a metallic Group VIIa element. It has an atomic weight of 64.9.

2. Manganese is usually associated with iron ores. Important ores of manganese

Occurrence in food, food supplements and medicines.

5. Manganese is present in a variety of foods including cereals and nuts. Data

6. A number of multi-vitamin and/or mineral food supplement preparations

8. EU Directive 80/778/EEC set a Maximum Admissible Concentration for

Licensed medicinal products for oral use

9. Manganese (as the glycerophosphate or sulphate) may be included in products

10. Manganese additives are used in fuel.

Intake and Exposure

volunteers, Friedman et al (1987) calculated that the minimum requirement for

0.003 mg/d (0-6 months) 0.6 mg/d (7-12 months)

Analysis of tissue manganese levels and manganese status

20. Manganese is a component of enzymes such as pyruvate carboxylase,

22. Manganese deficiency was inadvertently induced in a participant in a study on

24. In animal species, manganese deficiency is associated with growth retardation,

Overview of reported non-nutritional beneficial effects

27. Based on the study by Reginster et al (1988), the Committee on Medical

30. Co-administration of 7.5 or 15 mg manganese (as manganese chloride) with 3

Other dietary components

38. Manganese may decrease magnesium absorption and increase excretion,

increased by stressors such as alcohol, ozone, interleukin-1 and tumour necrosis

44. Absorption of manganese occurs in the small intestine. The efficiency of

45. Manganese absorption is thought to have the characteristics of a carrier-

47. It has been suggested that absorption of manganese is higher in infants.

49. In the rat, manganese absorption is thought to be a rapidly saturable process

Distribution and metabolism

proportion of manganese is oxidised to Mn3+, becomes bound to transferrin and enters

54. Within the cell, manganese is sequestered in the mitochondria. It thus,

55. The distribution of different forms of manganese compounds can vary

56. Manganese also accumulates in the brain. Magnetic resonance imaging of

57. Chronic ingestion of manganese in drinking water alters regional brain

59. Systemic manganese homeostasis is achieved through hepato-biliary and

62. Manganese-deficient rats conserved manganese through a 70-fold reduction in

63. Approximately 3.4% of a single gavage dose of 0.2, 1 or 10 mg Mn/kg bw (as

64. Excretion of manganese may be reduced in neonatal animals, possibly due to

66. Following acute ingestion of potassium permanganate, local corrosion but no

67. As noted in paragraphs 27-42 of Annex 2, excessive manganese exposure is

69. An episode of 15 cases of manganese poisoning was reported in a study of six

70. In a study conducted by Kondakis et al (1989), populations in the Northwest

72. The effects of exposure to manganese in well water were investigated in a

73. A cluster of Parkinson’s disease cases in Israel was investigated by Goldsmith

74. A case of possible manganese toxicity as a result of dietary supplement

76. A statistically significant increase in the level of hair manganese in learning

Liver disease and Cholestasis

80. However, in a study by Mena et al (1967) a group of miners suffering from

82. No carcinogenicity studies have been identified.

83. Chromosomal aberrations have been reported in workers occupationally

Human supplementation studies

84. Patients given a supplement of 30 mg manganese citrate in a mildly alcoholic

Adverse drug reactions

85. Suspected adverse reactions to medicinal products are reported to the

87. Subjects with impaired biliary excretion may be vulnerable to manganese

89. No data have been identified.