Manganese - Toxicology of Metals - page 640

Manganese is secreted into milk. Its concentrations
in breast milk vary between 3.4-10

22 mg manganese/kg were also compared with those
after injection of the same manganese dose of MnCl 2 .
The manganese level in brain after MnCl 2 exposure fol-
lowed the same increasing trend over 24-hour analysis
as in the case of MMT application but was somewhat
higher at each time point with a maximum value of
>2.0

µ g/L (Arnaud and

Favier, 1995; Collip et al ., 1983).
Manganese is more uniformly distributed in fetal
than in adult tissue. A study on age-related retention
and distribution of ingested Mn 3 O 4 in rats (Cahill et al .,
1980) demonstrated that 24 hours after ingestion, infant
rats retained up to 20 times more Mn than the adoles-
cent or the adult. The retention of manganese was also
a function of age at exposure within infancy. The liver
was the principal site of deposition at all ages. Brain
concentrations of manganese from a single dose were
easily detectable in infants but not adults. A study
measuring the retention of a single oral dose of radi-
olabeled manganese in adult and neonatal rats indi-
cated that retention of the label 6 days after exposure
was much greater in pups. The addition of manganese
to the animals' drinking water decreased radiolabel
retention in pups and adults (Kostial et al ., 1989).
A high rate of manganese absorption and distri-
bution in selected tissues, especially the cerebrum,
hypothalamus, and pituitary, was found in prewean-
ling rats dosed daily with particulate Mn 3 O 4 for 12 or
27 days postpartum (Rehnberg et al ., 1982).
In the blood, manganese is bound to proteins. In
the trivalent state, it can be bound to transferrin, and
in the bivalent state to an

µ g/g wet weight compared with ~1.4 µ g/g wet

weight after MMT exposure.
Another study included young adult rats, which
were administered MMT dissolved in propylene
glycol by subcutaneous injection at a dose of 1 mg
manganese/kg (McGinley et al ., 1987). The rats were
sacrifi ced 1.5, 3, 6, 12, 24, 48, or 96 hours after injection.
Maximum accumulation of MMT-derived manganese
measured 3 hours after dosing was found primarily in
lung (~ 9 mg/kg), kidney (3.9 mg/kg), liver (2.75 mg/
kg), and blood (~0.75 mg/kg). Concentrations of man-
ganese in these four tissues were still elevated (~1 mg/
kg) 96 hours after dosing. Brain manganese concentra-
tions were not signifi cantly elevated over control levels
in MMT-treated animals.
In connection with the clinical use of mangafodipir
as a contrast agent, several studies have shown the
qualitative presence of manganese in liver because
of increased signal in that organ after mangafodipir
administration of 0.17-0.83 mg manganese/kg on Tl-
weighted MRI (Bernardino et al ., 1992; Lim et al ., 1991;
Padovani et al ., 1996; Wang et al ., 1997). Several studies
(Gallez et al ., 1997; Grant et al ., 1997; Hustvedt et al .,
1997) have determined the distribution of manganese
in tissues of animals after intravenous administration
of mangafodipir. The results of these studies indicate
that single, clinical doses of mangafodipir are not likely
to cause persistent accumulation in the brain.

-macroglobulin (Gibbons
et al ., 1976). The plasmatic content of manganese is
lower than the manganese content in red blood cells
(ratio 1:5) (Weissman, 1981). After absorption, man-
ganese is transported in blood bound to proteins. The
quote of erythrocytary manganese is approximately
85% (Weissman, 1981) or 66% according to Milne et al .
(1990).
The organic manganese compound MMT is rapidly
metabolized in rats. After oral exposure and injection,
Moore et al . (1975) found that the liver, kidney, and
lungs contained the highest concentrations. The distri-
bution in general was similar to that seen after exposure
to inorganic manganese. Similar results were obtained
in some of the studies performed later. In 1985, Gianut-
sos et al . administered 0, 11, or 22 mg manganese/kg
as MMT (dissolved in propylene glycol) to male adult
mice by subcutaneous injection. The experiment was
divided into an acute study (one dose) or a “chronic”
study (10 doses), and the accumulation of manganese
in brain was followed. The brain manganese level 24
hours after the single dose of MMT was signifi cantly
higher than the control values: after 10 doses of 11 mg/
kg and 22 mg/kg, the brain manganese levels in both
cases were signifi cantly higher than the control val-
ues and were signifi cantly different than the levels
reported after the acute exposure. Manganese levels
in the brains of mice given a single dose of MMT at

α

5.3 Metabolism
Manganese is capable of existing in a number
of oxidation states, and limited data suggest that it
may undergo changes in oxidation state in the body.
The oxidation state of the manganese ion in several
enzymes seems to be Mn(III) (Leach and Lilburn, 1978;
Utter, 1976), whereas most manganese intake from
the environments is either Mn(II) or Mn(IV). How-
ever, Gibbons et al . (1976) suggested that the oxida-
tion of manganese occurs in the body. It was observed
that human ceruloplasmin led to the oxidation of
Mn(II) to Mn(III) in vitro , and although the process
was not studied in vivo , it is a likely mechanism for
manganese oxidation in the blood. The same authors
also noted that manganese oxidation led to a shift in
manganese binding in vitro from α 2 -macroglobulin

to transferrin and that in vivo clearance on Mn(II)-
α 2 −macroglobulin from cows was much more rapid