Manganese - Toxicology of Metals - page 642

and Greger (1992), urinary excretion of manganese
by men was 7.0

disease, and epilepsy may be associated with an imbal-
ance in tissue levels of manganese (Aihara et al ., 1985;
Carl et al ., 1993; Tulikoura and Vuori, 1986). However,
no large-scale defi ciency has been reported, although
manganese intakes of many people are believed to be
less than the estimated safe and adequate daily dietary
intake. This may refl ect, in part, the lack of adequate
methods to monitor nutritional status in regard to
manganese (ATSDR, 2000).
In animals, it has been shown experimentally that
manganese defi ciency will cause skeletal abnormali-
ties and impaired growth (Underwood, 1971). Also
the inner ear can be affected, because maternal manga-
nese defi ciency will cause ataxia and defective otoliths
(Hurley and Theriault-Bell, 1974).
Doisy (1973) described the case of a male participant
in a vitamin K study, who was on a diet low in manga-
nese (0.35 mg manganese/day) and vitamin K during
16 weeks that resulted in a decreased level of clotting
proteins, decreased serum cholesterol, reddening of
black hair and beard, slow growth of hair and nails,
and scaly dermatitis. After vitamin K was returned to
the diet, the subject continued to exhibit these symp-
toms, but when manganese was returned to the diet
the symptoms were eliminated.
In a study by Friedman et al . (1987), fi ve of seven
men fed a manganese-defi cient diet for 39 days exhib-
ited dermatitis ( Miliaria cristallina ). The dermatitis
cleared rapidly when manganese was returned to the
normal diet. Considering the fact supported by studies
in humans that manganese is an essential element, the
US Food and Nutrition Board of the National Research
Council established ESADDI (estimated safe and ade-
quate daily dietary intake) levels as follows: 0.3-0.6 mg/
day for infants from birth to 6 months; 0.6-1.0 mg/day
for infants from 6 months to 1 year; 1.0-1.5 mg/day for
children from 1-3 years; 1.0-2.0 mg/day for children
from 4-6 years and 7-10 years; and 2.0-5.0 mg/day
for adolescents (>11 years) and adults (NRC, 1989).
However, the Food and Nutrition Board has cautioned
that upper levels of these provisional dietary intake of
ESADDIs should not be exceeded on a routine basis,
because toxic levels may be only several times the
usual intake levels (NRC, 1989).

µ mole/g creatinine and by women

9.3 mole/day. Urinary excretion was not responsive

to oral intake of manganese.
Animals on low-manganese diets still show a sub-
stantial excretion of manganese. This indicates that the
ability to conserve manganese by decreasing excretion
is limited (Britton and Cotzias, 1966) and that increase
of dietary manganese is important for the homeostasis
(Abrams et al ., 1976).
After exposure to the organic compound MMT,
manganese excretion takes place to a large extent
through urine and is of the same magnitude as the
gastrointestinal excretion. This has been explained as
a result of biotransformation of the organic compound
in the kidney (Moore et al ., 1975). Manganese originating
from clinical application of mangafodipir is primarily
excreted in the feces through the bile and is incom-
pletely cleared from the body 24 hours after administra-
tion, and approximately 7-8% of a dose is still retained
in the body after 1 week (Hustvedt et al ., 1997).
A qualitative physiologically based pharmacokinetic
model (PBPK) for manganese disposition in humans
and animals was developed some years ago (1999) by
Andersen et al . Because several data gaps exist con-
cerning manganese pharmacokinetics, this model is
anticipated to change with time and might also include
a separate compartment for the brain regions versus a
general CNS compartment (Andersen et al ., 1999).

µ

6 HEALTH EFFECTS

6.1 Manganese Defi ciency
Manganese, like zinc and copper, is essential for
normal prenatal and neonatal development. It is essen-
tial for humans and animals and plays a role in bone
mineralization, protein and energy metabolism, meta-
bolic regulation, cellular protection from damaging free
radical species, and the formation of glycosaminogly-
cans (Welder, 1994). Mitochondrial superoxide-dis-
mutase, pyruvate carboxylase, and liver arginase are
known manganese metalloenzymes (NAS/NRC,
1989; Welder, 1994). Several enzyme systems, trans-
ferases, decarboxylases, hydrolases, dehydrogenases,
synthetases, and lyases, have been reported to inter-
act with or depend on manganese for their catalytic
or regulatory function (Welder, 1994). Manganese has
been shown to stimulate the synthesis of chondroitin
sulfate, an important constituent of the cartilage and
connective tissue (Utter, 1976). There is limited evi-
dence that some disorders or diseases in humans such
as amyotrophic lateral sclerosis, acromegaly, catabolic

6.2 Acute Effects
Manganese is less toxic than most of the metals
(Bienvenu et al ., 1963). The average LD 50 values range
from 400-830 mg/Mn/kg (guinea pig, mouse, rat) for
oral administration of soluble manganese compounds
(Sigan and Vitvickaja, 1971) and from 38-64 mg Mn/kg
(rat, mouse) for parenteral injections (Bienvenu et al .,
1963; Holbrook et al ., 1975). It has been suggested that