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defecation, and dyspnea. After lethal doses, death results from failure of the
respiratory system. Variations in the specific nerves affected, in how the body
metabolizes the individual chemical, in where the chemical enters the body,
and in the route of administration employed will change the specific clinical
presentation seen for an individual exposure scenario.
Inhibition of acetylcholinesterase, the enzyme responsible for ending the
transmission of a nerve impulse in our body, is due to a reversible change in
its structure. A major variable in this process is that with continued exposure,
or, for some specific chemicals, after any exposure, the organophosphate
interaction with this enzyme may  age and become permanent. In scientific
lingo, this is a covalent nonreversible inhibition of the cholinesterase due to
phosphorylation of its active site. This results in a prolongation and potenti-
ation of toxic effect. This phenomenon is seen with the most toxic members
of this class of organophosphates (for example, the chemical warfare agents)
but not with the safer compounds. This is the primary difference between the
carbamate and organophosphate classes since the carbamates do not undergo
this aging process and thus their actions are readily reversible. This also signif-
icantly decreases their inherent toxicity relative to the organophosphates. For
some compounds,  aging can be reversed through the use of so-called regen-
erators such as pralidoxime chloride (2-PAM), one of the antidotes issued to
our soldiers in the Gulf War in the event of chemical warfare attacks.
There are some other toxicologic manifestations of organophosphates that
deserve mention. For example, accumulation of low levels of chemicals that
irreversibly bind to cholinesterase may result in no signs of overt toxicity until
the critical threshold is passed, whereby there is insufficient cholinesterase
present to control synaptic function. This effect will not occur after ingestion
of trace amounts in food. As discussed in this book, the scenario applies to the
simultaneous home use of flea bombs, animal dips, carpet sprays, and no-pest
strips in the same room. The signs are acute intoxication. This is a common
presentation to veterinarians for dogs living in households of overzealous pet
owners.
TOXICOLOGY PRIMER 173
Other cholinesterases are also inhibited by these pesticides. For example,
plasma aliesterases, which normally destroy circulating pesticides through
ester hydrolysis, also are inhibited. Thus slow accumulation of one com-
pound may bind to both target cholinesterases and detoxifying esterases. This
is more pronounced with those agents that tightly bind to the enzyme. In such
cases, exposure to normally nontoxic levels of a second organophosphate
or carbamate could trigger acute toxicity. This exposure can be detected if
plasma cholinesterase is assayed and depression is observed in the absence of
clinical signs of neurotoxicity. Other manifestations of organophosphate-
induced toxicity include blockage of acetylcholinestersase in the central nerv-
ous system where acetylcholine accumulation results in tension, anxiety,
headache, psychological changes, and ultimately tremors, ataxia, convul-
sions, coma, and death due to respiratory failure. Again, these are high-dose
effects.
There is a final toxicologic manifestation of organophosphates that is
mediated by a different mechanism of action. This was originally described in
1930 as  ginger paralysis or  jake leg, secondary to a Jamaican rum additive
contaminated with the organophosphate triorthocresyl phosphate (TOCP).
The syndrome, now termed organophosphate-induced delayed neuropathy
(OPIDN), is a neurotoxicity seen 10 to 14 days post chemical exposure associ-
ated with motor weakness and sensory loss. Severely affected patients are
ataxic (lose control of muscles) and spastic. The pathology is characterized by
a  dying back and demyelination of neurons. The precise mechanism is
under intense investigation. Permanent injury usually results. OPIDN has
only been associated in humans with high-dose occupational exposure to DFP,
leptofos, mipofox, merpos, and trichlorfon. This effect is not seen with other
organophosphates and is irrelevant to the issue of low-level residues in food.
The treatment of organophosphate and carbamate intoxication is dictated
by their common mechanism of action directed at cholinesterase inhibition.
First, respiration must be maintained by artificial means since this is usually
the cause of death. Second, atropine sulfate is given to competitively inhibit
acetylcholine binding to the postsynaptic receptors. This effectively reverses
symptomology. Finally, enzyme regenerators such as pralidoxime hydrochlo-
ride (2-PAM), pralidoxime methanesulphonate, obidoxime, or pyrimidoxime,
should be immediately administered to help generate free enzyme by revers-
ing the  aging process discussed above. Diazepam is used to counter convul-
sions if present.
Most organophosphates are readily absorbed by oral, inhalational, and
dermal routes of exposure. Acute toxicity is generally related to either acci- [ Pobierz całość w formacie PDF ]