Toxicology of Industrial Compounds

246 NEUROTOXICITY TESTING OF INDUSTRIAL COMPOUNDS
Experimental studies were done to investigate the vulnerability of the
basal ganglia in manganism. Manganese (as Mn 2+ ) was applied
intrastriatally to rats and region-specific brain damage was assessed by
determining regional 45 Ca accumulation using quantitative
autoradiographic procedures developed in this laboratory (Gramsbergen
and Van der Sluijs-Gelling, 1993). It appeared that Mn 2+ induced a timedependent
45 Ca accumulation in most of the regions constituting the basal
ganglia, e.g. striatum and several other structures such as globus pallidus,
entopeduncular nucleus, several thalamic nuclei and substantia nigra (Sloot
et al., 1994).
As monoaminergic neurotransmission plays a predominant role in the
basal ganglia, recent studies have indicated that concentrations of biogenic
amines such as dopamine and its major metabolites, serotonin and
noradrenaline were also reduced in striatum by Mn 2+ . The kinetics of this
process indicated that concentrations of most monoamines and metabolites
were temporarily reduced except for dopamine and metabolites in striatum
that remained at a permanently reduced level (>90 days) (Sloot et al.,
1994). In order to demonstrate the specificity of the manganese effects,
several other compounds were studied, including ferrous ions (Fe 2+ ). An
equimolar dose of Fe 2+ , applied intrastriatally, produced, however, a much
more extensive and widespread 45 Ca accumulation throughout the basal
ganglia and, in addition, in nucleus accumbens and cerebral cortex.
Ferrous ions were also three times more potent than manganese ions in
causing depletion of dopamine in striatum (Sloot et al., 1994).
The results based on both 45 Ca accumulation and biogenic amine levels
are in concordance with the hypothesis that the basal ganglia, which are
enriched in iron and iron-binding proteins, represent a selective target for
manganese. The role and fate of endogenous iron in the brain, and the
basal ganglia in particular, under toxic conditions including chronic
manganese exposure, merits further investigations.
Oxidative stress by free radical formation may play a role in these toxic
events. Transition metals are known as strong promoters of reactive
oxygen species. Especially iron, as the ferrous ion (Fe 2+ ), has been found to
react with hydrogen peroxide to form the hydroxyl radical in the so-called
Fenton reaction (Halliwell et al., 1992; Aust et al., 1993). It is thought that
this mechanism plays an important direct role in iron poisoning (Aust et
al., 1993). In an indirect way oxidative stress by iron may be initiated by
chemicals that are able to ‘liberate’ iron from stores such as ferritin,
transferrin, haemoglobin, etc. Recently, evidence has been obtained that a
number of chemicals, including the pesticides paraquat and diquat, may
release iron from ferritin in vivo as well as in vitro (Aust et al., 1993),
involving organic radical and superoxide formation.
These observations are particularly relevant for the interpretation of the
observed neurotoxic effects of iron described above. Dopamine is relatively