Manganese - Toxicology of Metals - page 639

barrier, on transport mechanisms associated with reg-
ulation of manganese uptake and release by astrocytes
and its requirement for glutamine synthetase function
and regulation. The transport across blood-brain bar-
rier was recently attributed to an active carrier-medi-
ated mechanism for the infl ux into the brain and to a
passive diffusive mechanism for the effl ux from the
brain (Crossgrove and Yokel, 2005; Yokel and Cross-
grove, 2004). This would be an important mechanism to
explain the occurrence of a brain overload after exces-
sive absorption of manganese but also after prolonged
exposure to low doses. In a review on the transport
of manganese across the blood-brain barrier, puta-
tive carriers for manganese into and out of the brain
were examined, with an alternative explanation for the
effl ux of manganese from the brain (Aschner, 2006).
Vitarella et al . (2000) exposed adult rats to airborne
doses of particulate manganese, as Mn phosphate, at
0, 0.03, 0.3, 3 mg/manganese/m 3 . The particles had
a mean diameter of 1.5

The distribution of manganese in the brain was
investigated in Cebus (Newland and Weiss, 1992;
Newland et al ., 1989) and Macaque (Newland et al .,
1989) monkeys given intravenous injections of MnCl 2
that reached a cumulative dose of 10-40 mg manga-
nese/kg. Magnetic resonance images indicated a sym-
metrical hyperintensity in the globus pallidus and
substantia nigra consistent with an accumulation of
manganese in these areas. Substantial accumulation
of manganese was also noted in the pituitary at low
cumulative doses. London et al . (1989) reported a
rapid localization of manganese in the choroid plexus
observed on MRI.
Some of the experimental animal studies showed
that large increases in tissue levels of manganese com-
pared with the controls occurred in rats over the fi rst
24 days of exposure to 214 mg manganese/kg (body
weight)/day (as Mn 3 O 4 ), for up to 224 days. But levels
tended to decrease toward the control levels as exposure
was continued (Kristensson et al ., 1986; Rehnberg et al .,
1980). This pattern is thought to be due to a homeo-
static mechanism that leads to decreased absorption
and/or increased excretion of manganese when man-
ganese intake levels are high (Abrams et al ., 1976;
Ballatory et al ., 1987; Mena et al ., 1967). Davis et al .
(1992b) and Malecki et al . (1996) demonstrated that rats
fed elevated levels of manganese for several weeks had
increased tissue manganese concentrations, despite
increased gut endogenous losses of manganese, as
biliary manganese.
Manganese penetrates the placental barrier in all
species. Children are exposed in utero because manga-
nese in maternal blood crosses the placenta to satisfy
the fetus's need for manganese. Manganese has been
measured in cord blood plasma of premature and full-
term infants and their mothers (Wilson et al ., 1991).
In a human study on manganese levels during
pregnancy and at birth performed in a southwest Que-
bec population (Takser et al ., 2004), it was shown that
mothers' manganese blood levels increased signifi -
cantly during pregnancy, and cord blood manganese
levels were signifi cantly higher than those for mothers'
blood. This study also indicated that lifestyle (mothers'
smoking habit) and environmental factors might inter-
fere with the balance and homeostatic mechanisms
required to maintain manganese at optimal levels for
physiological changes during pregnancy. In a previous
study, levels of Mn in the umbilical cord and in mater-
nal blood were compared between 160 pairs of moth-
ers-neonates in Montreal and 206 pairs in Paris. The
prevalence of high Mn levels in umbilical cord blood
was found signifi cantly higher in Montreal, where
MMT was in use in gasoline in 1977 (Smargiassi et al .,
2002).

m. Exposure lasted for 6
hours/day for either 5 days/week (10 exposures) or 7
days/week (14 exposures). The following tissues were
analyzed for manganese content by use of neutron
activation analysis: plasma, erythrocytes, olfactory
bulb, striatum, cerebellum, lung, liver, femur, and skel-
etal muscle after exposure to 3 mg/m 3 (after either dos-
ing regiment). A lower dose of 0.3 mg/m 3 resulted in
increased manganese concentrations in olfactory bulb
and lung (14-dose regimen only). Striatal manganese
levels were increased at the two highest doses only after
14 days of exposure. Concentrations in the cerebellum
were similarly elevated, which was interpreted by the
authors to indicate that accumulation of manganese
was not selective for the striatum. Red blood cell and
plasma manganese levels were increased only in rats
exposed to the highest dose for the 10-day exposure
period. These data indicate that even at lower doses,
manganese can accumulate in the olfactory bulb. How-
ever, it must be noted that tissues were collected and
analyzed at the cessation of exposure. It is not clear
whether the distribution of manganese would be simi-
lar if tissues had been analyzed at a later time (ATSDR,
2000).
Studies in humans with chronic liver disease or
some other liver dysfunction (e.g., cirrhosis, porta-
caval shunt) after oral exposure, presumably through
the diet, with impaired manganese excretion showed
that manganese preferentially accumulates in the
basal ganglia, especially the globus pallidus and the
substantia nigra. For determining the accumulation
of manganese Tl-weighted MRI or neutron activa-
tion analysis was used (Devenyi et al ., 1994; Fell et al .,
1996; Hauzer et al ., 1996; Lucchini et al ., 2000; Pomier-
Layrargues et al ., 1998; Rose et al ., 1999).

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