Toxicology of Industrial Compounds

eactive chemical intermediates. Once a free radical is formed it can initiate
a chain of reactions as the free electron is passed from one molecule to the
other. In vivo, free radicals involving oxygen species are continuously
produced and evolution has also provided the body with defence
mechanisms such as superoxide dismutase (SOD), catalase, and scavengers
such as glutathione, ascorbate, etc.
Oxidative stress by free radicals may be an important neuropathological
mediator following exposure to a number of neurotoxic agents (LeBel and
Bondy, 1991). Examples of neurotoxic chemicals suspected of causing free
radicals include chlordecone, ethanol, methamphetamine, methyl mercury,
toluene, triethyl lead and trimethyltin. Of special interest is a ‘designer’
drug called MPTP 1 causing destruction of dopaminergic neurons of the
basal ganglia with symptoms similar to Parkinson’s disease. It is the
neurotoxic metabolite MPP +2 that has been found to induce cerebral
oxygen radical formation in vitro. There is also suggestive evidence to
indicate that free radical scavengers may provide protection of the basal
ganglia against neuro-toxic effects of MPP + (LeBel and Bondy, 1991). The
occurrence of these kinds of compounds has led, among other things, one
to suspect possible involvement of environmental chemicals and factors
associated with diet and/or lifestyle in Parkinson’s disease (Russell, 1992;
Semchuk et al., 1993).
Model neurotoxins
In order to validate an approach based on changes in these proposed
biomarkers experimental studies were performed using various model
neuro-toxicants, including trimethyltin, kainic acid, heavy metals such as
lead, methylmercury and manganese, and developmental neurotoxicants,
e.g. polychlorinated biphenyls.
Trimethyltin
K.J.VAN DEN BERG ET AL. 241
Trimethyltin (TMT) is known to cause in adult rats a rather selective
neuronal degeneration in specific regions of the brain, notably in limbic
structures such as the hippocampus where extensive loss of pyramidal cells
in CA fields are observed by standard histopathological procedures
(O’Callaghan, 1988). A single systemic dose of TMT (7.5 mg kg −1 ) given to
adult rats caused, after a period of 3 weeks, an approximately three-fold
enhanced level of GFAP in hippocampus (Figure 18.1, upper left panel). In
a number of other brain regions, e.g. different parts of the cortex,
thalamus, striatum, cerebellum and brain stem, no significant changes in
GFAP were observed. Assessment of synaptophysin, a structural protein of
synaptic vesicles of neurons (Jahn et al. 1985) in the same brain regions is
given in Figure 18.1 (lower left panel). TMT induced a significant