PRINCIPLES OF TOXICOLOGY

Mechanism of Action
O C
Carbaryl
Both organophosphate and carbamate classes of compounds have the same mechanism of action in
insects as well as in mammals (including humans): the inhibition of the enzyme acetylcholinesterase.
The inhibition of acetylcholinesterase by organophosphates and carbamates is the mechanism of action
that is responsible for the acute symptomatology associated with these compounds.
Acetylcholinesterase is an enzyme located in the synaptic cleft and its function is the breakdown
of acetylcholine, the neurotransmitter present at the following cites: postganglionic parasympathetic
nerves, somatic motor nerves endings in skeletal muscle, preganglionic fibers in the parasympathetic
and sympathetic nerves, and in some synapses in the central nervous system. Organophosphate and
carbamate insecticides act by inhibiting the enzyme acetylcholinesterase at its esteratic site, resulting
in an accumulation of the neurotransmitter acetylcholine in nerve tissue and at the effector organ. This
accumulation then results in the continued stimulation of cholinergic synapses and at sufficient levels
leads to the signs and symptoms associated with overexposure to these compounds (discussed later in
this section).
Absorption and Metabolism
15.1 ORGANOPHOSPHATE AND CARBAMATE INSECTICIDES 347
O
NH CH 3
SMe
HC N O CNHCH 3
Aldicarb
Figure 15.2 Examples of carbamate insecticides.
Organophosphates and carbamates can be readily absorbed via ingestion, dermal, and inhalation routes
because of their lipophilic nature. For organophosphate insecticides not requiring metabolic activation
(discussed below), also called direct inhibitors, these can produce local toxic effects at the site of
exposure, including sweating (dermal exposure), miosis or pinpoint pupils (eye contact), and/or
bronchospasms (inhalation exposure). Both the organophosphate and carbamate insecticides have
relatively short biological half-lives and are fairly rapidly metabolized and excreted.
Within the class of organophosphate insecticides, there are direct organophosphate inhibitors
(those containing ?O) and organophosphate indirect inhibitors (those containing ?S), depending
on whether or not they require metabolic activation before they can inhibit acetylcholinesterase.
In other words, the indirect organophosphate compounds (containing ?S) must undergo bioactivation
to become biologically active (containing ?O). The indirect inhibiting compounds,
including organophosphates such as parathion, diazinon, malathion, and chlorpyrifos, become
more toxic than the parent compound on metabolism. In the case of these indirect inhibitors,
oxidative desulfuration (replacement of the sulfur atom with an oxygen atom as described above)
results in the formation of the oxon of the parent compound (e.g., parathion → paraoxon, diazinon
→ diazoxon, malathion → maloxon, and chlorpyrifos → chlorpyrifos–oxon). This metabolism
occurs via the mixed function oxidase system of the liver.
Once cholinesterase activity has been inhibited in the body by an organophosphate compound, the
recovery of that compound is dependent on the reversal of inhibition, aging, and the rate of regeneration
of a new enzyme. A chemical reaction that organophosphate insecticides can undergo in the body once
O