Neurotoxicity and Behavioral Effects of Environmental Chemicals - Organic Pollutants: An Ecotoxicological Perspective - page 300

BOX 16.1 teCHnIqueS fOR meaSuRInG tHe
InteRaCtIOn Of neuROtOXIC CHemICalS
WItH tHeIR SIteS Of aCtIOn
A central theme of this text is the development of biomarker assays to measure
the extent of toxic effects caused by chemicals both in the field studies and for
the purposes of environmental risk assessment.
Considering the examples given in Table 16.1, a number of possibilities
present themselves. In the first place, competitive binding studies may reveal
the extent to which a toxic compound is attached to a critical binding site. For
example, the convulsant TBPS binds to the same site on GABA-A receptors of
rat brain as do cyclodiene insecticides such as dieldrin. In samples preexposed
to dieldrin, the binding of radiolabeled TBPS will be less than in controls not
exposed to the cyclodiene (Abalis et al. 1985). The difference in binding of
the radioactive ligand to the treated sample in comparison to binding to the
control sample provides a measure of the extent of binding of dieldrin to this
target. Similarly, the competitive binding of tetrodotoxin and saxitoxin to the
Na + channel may be exploited to develop an assay procedure.
In cases where the mode of action is the strong or irreversible inhibition
of an enzyme system, the assay may measure the extent of inhibition of this
enzyme. This may be accomplished by first measuring the activity of the
inhibited enzyme and then making comparison with the uninhibited enzyme.
This practice is followed when studying acetylcholinesterase inhibition by
organophosphates (OP). Acetylcholinesterase activity is measured in a sample
of tissue of brain from an animal that has been exposed to an OP. Activity is
measured in the same way in tissue samples from untreated controls of the
same species, sex, age, etc. Comparison is then made between the two activity
measurements, and the percentage inhibition is estimated.
“aging”; the inhibited enzyme undergoes chemical modification, and inhibition then
becomes effectively irreversible.
A few OP compounds cause delayed neuropathy in vertebrates because they
inhibit another esterase located in the nervous system, which has been termed neu-
ropathy target esterase (nte). This enzyme is described in Chapter 10, Section
10.2.4. OPs that cause delayed neuropathy include diisopropyl phosphofluoridate
(DFP), mipafox, leptophos, methamidophos, and triorthocresol phosphate. The delay
in the appearance of neurotoxic symptoms following exposure is associated with the
aging process. In most cases, nerve degeneration is not seen with initial inhibition of
the esterase but appears some 2-3 weeks after commencement of exposure, as the
inhibited enzyme undergoes aging (see Section 16.4.1). The condition is described as
OP-induced delayed neuropathy (OPIDN).
Organometallic compounds such as alkylmercury fungicides, and tetraethyl lead,
used as an antiknock in petrol, are neurotoxic, especially to the central nervous system
of vertebrates (Wolfe et al. 1998, Environmental Health Criteria 101, and Chapter 8,