Chemistry Reference
In-Depth Information
Neither of these mechanisms of toxic action is susceptible to the kind of QSAR
analysis referred to earlier, the employment of which depends on knowledge of the
structure of particular binding sites.
13.4 toxIc reSPonSeS tHat SHare common
PatHwayS of exPreSSIon
When chemicals have toxic effects, the initial molecular interaction between the
chemical and its site of action (receptor, membrane, redox system, etc.), is followed
by a sequence of changes at the cellular and whole-organism levels that eventually
lead to the appearance of overt symptoms of intoxication. Until now, discussion has
been focused upon mechanisms of toxicity, that is, on the primary interaction of
toxic chemicals with their sites of action. As we have seen, biomarker assays such as
the measurement of acetylcholinesterase inhibition can monitor this initial interac-
tion in a causal chain that leads to the overt expression of toxicity. Such mechanistic
biomarkers are specific for particular types of chemicals acting at particular sites. By
contrast, other biomarkers that measure consequent changes at higher levels of orga-
nization, for example, the release of stress proteins, damage to cellular organelles,
and disturbances to the nervous system or endocrine system are less specific, and
can, in principle, provide integrated measures of the effects of diverse chemicals in
a mixture operating through contrasting mechanisms of action. It is possible, there-
fore, to measure the combined effects of chemicals working through different modes
of action if these effects are expressed through a common pathway (e.g., the nervous
system or the endocrine system) that can be monitored by a higher-level biomarker
assay. For example, two chemicals may act on different receptors in the nervous
system, but they may both produce similar disturbances such as tremors, hyperexcit-
ability, and even certain changes in the EEG pattern, all of which can be measured
by higher-level biomarker assays.
When moving from the primary toxic lesion to the knock-on effects at higher
levels of organization, the higher one goes, the harder it becomes to relate mea-
sured effects to particular mechanisms of toxic action. Thus, it is advantageous to use
combinations of biomarkers operating at different organizational levels rather than
single biomarker assays when investigating toxic effects of mixtures of dissimilar
compounds; it becomes possible to relate initial responses to higher-level responses
in the causal chain of toxicity. Although they often do not give clear evidence of the
mechanism of action, higher-level biomarker assays (e.g., scope for growth in mol-
lusks, or behavioral effects in vertebrates) have the advantage that they can give an
integrated measure of the toxic effects caused by a mixture of chemicals.
Taken together, combinations of biomarker assays working at different organiza-
tional levels can give an “in-depth” picture of the sequence of adverse changes that
follows exposure to toxic mixtures, when compounds in the mixture with different
modes of action cause higher-level changes through a common pathway of expres-
sion. Two prime examples are (1) chemicals that cause endocrine disruption, and (2)
neurotoxic compounds. To illustrate these issues further in more depth and detail,
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