PRINCIPLES OF TOXICOLOGY

350 PROPERTIES AND EFFECTS OF PESTICIDES
only cause OPIDN if a threshold of inhibition is reached. A high level of inhibition—70 percent to 80
percent inhibition of NTE in the brain, spinal cord, or peripheral nerve of the experimental animal—
soon after dosing with an organophosphate capable of causing OPIDN is necessary before this
condition can develop. Thus, the determining factor in the development of OPIDN is the formation of
a critical mass of aged-inhibited NTE.
A term used to express the concentration of a substrate (such as an organophosphate compound)
that is needed to inhibit 50 percent of an enzyme is IC 50 . One way of predicting whether a compound
will produce OPIDN compared to the levels that cause acute cholinergic signs, is to compare the AChE
and NTE IC 50 s for a specific compound. The in vitro and in vivo IC 50 s for NTE and AChE in humans
and hens (the test species used to evaluate the delayed neuropathic potential of organophosphate
insecticides) for several organophosphate compounds have been compared, and it was found that for
organophosphate compounds with a IC 50 AChE/IC 50 NTE ratio of less than one, OPIDN can occur
only after recovery and treatment from acute, otherwise fatal, cholinergic crisis.
The scientific literature indicates that for at least the few compounds known to cause OPIDN, that
have been analyzed, the AChE IC 50 /NTE IC 50 typically is less than unity. This means that the
concentration of a chemical that will inhibit 50 percent of the AChE molecules is less than the
concentration of the same chemical that is required to inhibit 50 percent of the NTE molecules.
Therefore, at a given concentration, AChE will be inhibited to a greater degree than NTE. As previously
stated, it is currently theorized that more than 50 percent of NTE (i.e., 70 percent to 80 percent) must
be inhibited in order to develop OPIDN. Likewise, a 50–80 percent inhibition of AChE results in
clinical manifestations. In fact, human case reports indicate that virtually all patients who develop
OPIDN were managed for a cholinergic crisis first.
It is important to note that carbamates do not cause delayed neuropathy. While some carbamates
are capable of inhibiting NTE, aging does not occur. In fact, experimental evidence has showed that
some carbamates that inhibit NTE actually protect hens against developing OPIDN.
Neurobehavioral Sequelae
Several studies have been conducted in persons exposed to organophosphates, either occupationally
or by accidental or intentional poisoning, to examined the delayed sequelae of organophosphate
poisoning. A majority of these studies did not detect any change in permanent memory impairment or
other psychological problems in individuals exposed or poisoned by organophosphate insecticides. A
majority of the papers in which neuropsychological changes in persons exposed to organophosphates
have been reported to contain serious methodological flaws, including failure to control for exposure
level, age, education, and alcohol consumption. One study examined 117 individuals who had experienced
acute organophosphate poisoning and found no neuropsychiatric symptoms attributable to the organophosphate
intoxication. While certain neurobehavioral symptoms (e.g., headache, tension, giddiness, confusion,
insomnia) may occur during the acute phase of organophosphate poisoning, there is no objective evidence
of permanent neurobehavioral sequelae associated with organophosphate intoxication.
Biological Monitoring for Organophosphates and Carbamates
The organophosphates and carbamates have the ability to inhibit pseudocholinesterase, red blood cell
cholinesterase, and nervous system cholinesterase, with biological effects due to the actual inhibition
of nervous system cholinesterase only. The levels of cholinesterase present in the blood, especially in
the red blood cells, can be used to estimate the degree the nervous system is being affected by
anticholinesterases. As mentioned earlier, a 50 percent depression of plasma and red blood cell
cholinesterase levels is typically necessary before clinical manifestations are seen. Acute overexposure
to organophosphates can be classified as mild (20–50 percent of baseline cholinesterase levels),
moderate (10–20 percent of baseline cholinesterase levels), or severe (10 percent or less of baseline
cholinesterase level).