Manganese - Toxicology of Metals - page 643

manganese cations are more toxic than the anionic
forms and that bivalent cation is approximately three
times more toxic than a trivalent cation (EPA, 1975).
The inhalation LD 50 for MMT was determined to be
62 mg Mn/m 3 (247 mg MMT/m 3 ) for a 1-hour expo-
sure and 19 mg Mn/m 3 for a 4-hour exposure.
Because manganese is regarded as a metal with rela-
tively low toxicity, acute poisoning by manganese in
humans is rare. There is a case report on methemoglo-
binemia induced by ingestion of potassium permanga-
nate (Mahomedy et al ., 1975). Hobbesland et al . (1997)
reported a signifi cantly increased incidence in sudden
death mortality for workers in ferromanganese/sili-
comanganese plants during their employment period
(standardized mortality ratio, SMR = 2.47). However,
the authors caution that the association of increased
death and manganese exposure is speculative, and
the incidence in sudden death could also be caused by
common furnace work conditions (heat, stress, noise,
carbon monoxide, etc.).
There is only one study (Kawamura et al ., 1941) in
which death in humans may have been associated with
ingestion of manganese. In this report, death from
“emaciation” occurred in two adults who ingested
drinking water contaminated with high levels of man-
ganese (14 ml/L). Although many of the symptoms
in the group of six Japanese families (approximately
25 persons) could be connected with the exposure
to manganese, there is considerable doubt that all
of the features of this outbreak (particularly the
deaths) were due to manganese alone (ATSDR, 2000).
Namely, symptoms seemed to have developed very
quickly; the course of the disease was very rapid, in
one case progressing from initial symptoms to death
in 3 days; all survivors recovered from the symptoms
even before the manganese content of the well had
decreased signifi cantly after removal of the batteries
buried near the well from where manganese leached
to the drinking water.
Freshly formed manganese oxide fumes of respir-
able particles size, along with a number of other met-
als, may cause metal fume fever.

6.3.1.1 Mode of Action
Studies of the neuropathological bases for manga-
nese neurotoxicity have pointed to the involvement of
the corpus striatum and the extrapyramidal motor sys-
tem (Archibald and Tyree, 1987, Eriksson et al ., 1987;
1992). The specifi c area of injury in humans seems to be
primarily in the globus pallidus. The substantia nigra
is sometimes affected but generally to a lesser extent
(Katsuragi et al ., 1996; Yamada et al ., 1986). Studies
in nonhuman primates have produced similar fi nd-
ings (Newland et al ., 1989; 1992.). The likelihood that
the CNS effects of manganese are mediated down-
stream of the substantia nigra, predominantly in the
globus pallidus, was also supported in the discussions
at the International Conference on Manganese, 1997
(Aschner, 2002).
Limited evidence suggests that dopamine levels in
caudate nucleus and putamen are decreased in affected
patients (Bernheimer et al ., 1973). In terms of the neu-
rochemistry of manganese toxicity, some other studies
have shown that dopamine levels are affected by man-
ganese exposure in humans, monkeys, and rodents, with
various indications of an initial increase in dopamine
followed by a longer-term decrease (Barbeau, 1984; Don-
aldson, 1984). The loss of dopamine in the brain and the
concomitant neuronal cell damage could be expressed
as an increase in motor activity (Bonilla, 1984; Nachtman
et al ., 1986). Calabresi et al . (2001) also reported that Mn-
treated rats exhibited a complex behavior syndrome
with increased activity in the absence of signifi cant stri-
atal neuronal loss and gliosis.
The precise biochemical mechanism by which man-
ganese leads to selective destruction of dopaminergic
neurons is not known, but many researchers believe
that manganese ion enhances the autooxidation or
turnover of various intracellular catecholamines, lead-
ing to increased production of free radicals (Donaldson
et al ., 1982), reactive oxygen species, and other cyto-
toxic metabolites, along with a depletion of cellular
antioxidant defense mechanism (Barbeau, 1984; Don-
aldson, 1987; Graham et al ., 1984; Liccione and Maines,
1988; Nachtman, 1986; Verity, 1999). Desole et al . (1994)
in an experimental study performed on 6-month-old
rats provided supporting evidence for the hypoth-
esis that high levels of manganese exert neurotoxicity
through oxidation. However, a study by Sziraki et al .
(1999) demonstrated atypical antioxidative properties
of manganese in iron-induced brain lipid peroxidation
and copper-dependent low-density lipoprotein conju-
gation, but the underlying mechanisms of the antioxi-
dant effects are not clear. In a study by Brenneman et al .
(1999), in which reaction oxygen species in the brains of
neonatal rats administered up to 22 mg/manganese/
kg/day for up to 49 days were followed, also did not

6.3 Adverse Effects of Prolonged Exposure
6.3.1 Neurotoxic Effect

Central nervous system (CNS) is the primary target
of manganese toxicity. Although it is known that man-
ganese is a cellular toxicant that can impair transport
systems, enzyme activities, and receptor functions, the
principal manner in which manganese neurotoxicity
occurs has not been yet clearly established (Aschner
and Aschner, 1991).