PRINCIPLES OF TOXICOLOGY

348 PROPERTIES AND EFFECTS OF PESTICIDES
they are bound to the cholinesterase enzyme is called “aging.” Aging involves the dealkylation of the
compound once it is bound to the cholinesterase enzyme. In this “aged” form, the organophosphate
compound is tightly bound to the enzyme and will not release itself from the enzyme. Once the aging
reaction has occurred, treatment with medications (such as pralidoxime, that is discussed later) is not
effective on these aged complexes. Once a cholinesterase molecule has been irreversibly inhibited (via
the aging process), the only manner in which the enzyme activity may be restored is through synthesis
of new enzyme.
In addition to the aging reaction, organophosphates can also undergo various phase I and II
biotransformation pathways, including oxidative, hydrolytic, GSH-mediated transfer, and conjugation
reactions.
Carbamate compounds do not require metabolic activation in order to inhibit cholinesterase.
Further, carbamate insecticides are not considered irreversible inhibitors like some organophosphate
insecticides. Cholinesterase inhibition by carbamate compounds is readily reversible, with reversal of
inhibition occurring typically within a few hours after exposure. This rapid reversal of the cholinesterase
enzyme activity leads to a much shorter duration of action and thus shorter period of
intoxication than is seen in cases of organophosphate overexposure. Also, carbamates do not undergo
“aging” as do the organophosphates. As with the organophosphates, carbamates also can undergo
various phase I and phase II metabolism reactions.
Acute Effects of Organophosphate and Carbamate Insecticides
The effects of organophosphate and carbamate insecticides can be either local (e.g., sweating from
localized dermal exposure) or systemic. Signs and symptoms of overexposure to organophosphate and
carbamate compounds occur fairly rapidly after exposure, with effects typically seen beginning from
5 min to 12 h after exposure. A diagnosis of organophosphate intoxication typically is based on an
exposure history of 6 h or less before the onset of signs and symptoms. It has been suggested that if
symptoms appear more than 12 h after the exposure, then another etiology should be considered, and
if the symptoms begin 24 h after the exposure, then organophosphate intoxication should be considered
to be equivocal.
Symptoms of carbamate overexposure generally develop within 15 min to 2 h of exposure and
typically last only several hours, a duration much shorter than that of the typical overexposure to
organophosphate pesticide. Symptoms that are present 24 h following exposure are likely not a result
of overexposure to carbamate insecticides.
The acute signs and symptoms seen in cases of over-exposure to both organophosphate and
carbamate pesticides are related to the degree of inhibition of acetylcholinesterase in the individual.
The clinical manifestation of overexposure to organophosphate and carbamate compounds is a result
of muscarinic, nicotinic, and CNS symptoms. In systemic intoxications with organophosphate and
carbamate compounds, the muscarinic effects are generally the first effects to develop.
Muscarinic symptoms (parasympathetic nervous system) include sweating, increased salivation,
increased lacrimation, bronchospasm, dyspnea, gastrointestinal effects (nausea, vomiting, abdominal
cramps, and diarrhea), miosis (pinpoint pupils), blurred vision, urinary frequency and incontinence,
wheezing, and bradycardia (decreased heart rate). Nicotinic effects (sympathetic and motor nervous
system) include pallor, hypertension, muscle fasciculations, muscle cramps, motor weakness, tachycardia
(increased heart rate), and paralysis. Central nervous system signs include giddiness, tension,
anxiety, restlessness, insomnia, nightmares, headache, tremors, drowsiness, confusion, slurred speech,
ataxia, coma, Cheyne–Stokes respiration, and convulsions.
Organophosphate intoxication is diagnosed on the basis of an opportunity for exposure to the
compound, signs and symptoms consistent with organophosphate overexposure, and significant
inhibition (i.e., 50 percent inhibition) of cholinesterase enzyme as measured in the plasma and in red
blood cells (this will be discussed later). Signs and symptoms resulting from overexposure to these
organophosphate and carbamate compounds can be best described by the mnemonic DUMBELS:
Diarrhea, Urination, Miosis (pinpoint pupils), Bronchospasm, Emesis (vomiting), Lacrimation (tear-