Combined Actions and Interactions of Chemicals in Mixtures

Apoptosis, programmed cell death, plays a significant role during brain development.
Interference by neurotoxicants on apoptotic processes during development may be
important.
An example of toxic interaction in relation to developmental neurotoxicity is the
interaction between dimethoate and lead. Predosing of rats with low doses of
dimethoate (a pesticide) accentuates the developmental neurotoxicity of lead as
measured by electrophysiological parameters. Predosing with lead has the same effect
on dimethoate neurotoxicity, but not as pronounced (Nagymajtényi et al., 1998).
7.6.4 Consequences of adverse effects on the nervous system
The nervous system is central in the physical and psychological performance of man.
It is one of the most complex organ systems in terms of both structure and function.
The risk of permanent damage to the nervous system after toxic injury is greater than
for many other target organs, as mature neurons are not capable of regeneration. The
nervous system possesses great plasticity, which means that injuries do not necessarily
become apparent immediately after the insult.
Proper function of the nervous system depends on a delicate electrochemical balance
for uncompromized communication of information throughout the body. Large energy
supply and unaffected neuron function maintain this. Chemicals affecting these
elements may cause neurotoxicity. Theoretically, there are many possibilities for
interaction between chemicals on the above-mentioned targets (membranes,
intracellular transport, energy supply).
7.6.4.1 Mechanism of interaction
The mechanism of action is unknown for the majority of neurotoxicants, especially in
the CNS. In the PNS, a well-known mode of action for peripheral neuropathy is the
inhibition of the anterograde transport of cellular components. Interaction is possible
between chemicals which both affect this transport system, even if the target is not
identical.
7.6.4.2 Most important test systems
Animal studies performed according to present guideline methods give information
about nervous system effects. Investigation of potential interaction with other
chemicals is normally not a part of such studies. The complexity of research on
mixtures and dose-response relations is obvious, considering the possible number of
binary combinations for a single mixture.
It is difficult to study interactions in epidemiological investigations because of
uncertainties regarding exposure levels and duration and because the effects of
individual factors normally cannot be isolated.
7.6.5 Examples of interactions: Mechanisms
7.6.5.1 Reactive oxygen species
Generation of reactive oxygen species (ROS) is a mechanism whereby similar action
by chemicals can occur. ROS generation may initiate cellular injury leading to
neurotoxicity and/or neurodegeneration. Several chemicals may lead to increased
ROS generation. Various ROS types may be generated, depending on the chemical.
Although the neurotoxic effect of the various ROS types may vary, at least an additive
effect is expected.
119