·COMMERCIAL PRODUCTS ·TOXICOLOGY ·SYMPTOMS AND SIGNS OF POISONING
·CONFIRMATION OF ORGANOPHOSPHATE ABSORPTION
·TREATMENT OF ORGANOPHOSPHATE POISONING
Highly toxic*: tetraethyl pyrophosphate (TEPP), dimefox (Hanane,
Pestox XIV), phorate (Thimet, Rampart, AASTAR), disulfoton+ (Disyston),
fensulfothion (Dansanit), demeton+ (Systox), terbufos (Counter,
Contraven), mevinphos (Phosdrin,Duraphos), ethyl parathion (E605,
Parathion, Thiophos), azinphos-methyl (Gution, Gusathion), fosthietan
(Nem-A-Tak), chlormephos (Dotan), sulfotep (Thiotepp, Bladafum,
Dithione), carbophenothion (Trithion), chlorthiophos (Celathion),
fonofos (Dyfonate, N-2790), prothoate+ (Fac), fenamiphos (Nemacur),
phosfolan+ (Cyolane, Cylan), methyl parathion (E 601, Penncap-M),
schradan (OMPA), mephosfolan+ (Cytrolane), chlorfenvinphos (Apachlor,
Birlane), coumaphos (Co-Ral, Asuntol), phosphamidon (Dimecron),
methamidophos (Monitor), dicrotophos (Bidrin), monocrotophos (Azodrin),
methidathion (Supracide, Ultracide), EPN, isofenphos (Amaze, Oftanol),
endothion, bomyl (Swat), famphur (Famfos, Bo-Ana, Bash), fenophosphon
(trichloronate, Agritox), dialifor (Torak), cyanofenphos (Surecide),
dioxathion (Delnav), mipafox (Isopestox, Pestox XV).
Moderately toxic*: bromophos-ethyl (Nexagan), leptophos (Phosvel), dichlorvos (DDVP, Vapona), ethoprop (Mocap), demeton-S-methyl+ (Duratox, Metasystox (i)), triazophos (Hostathion), oxydemeton-methyl+ (Metasystox-R), quinalphos (Bayrusil), ethion (Ethanox), chlorpyrifos (Dursban, Lorsban, Brodan), edifenphos, oxydeprofos+ (Metasystox-S), sulprofos (Bolstar, Helothion), isoxathion (E-48, Karphos), propetamphos (Safrotin), phosalone (Zolone) , thiometon (Ekatin), heptenophos (Hostaquick), crotoxyphos (Ciodrin, Cypona), phosmet (Imidan, Prolate), trichlorfon (Dylox, Dipterex, Proxol, Neguvon), cythioate (Pro-ban, Cyflee), phencapton (G 28029), pirimiphos-ethyl (Primicid), DEF (De-Green, E-Z-Off D), methyl trithion,dimethoate (Cygon, DeFend), fenthion (mercaptophos, Entex, Baytex, Tiguvon), dichlofenthion (VC-13 Nemacide), bensulide (Betasan, Prefar), EPBP (S-Seven), diazinon (Spectracide), profenofos (Curacron), formothion (Anthio), pyrazophos (Afugan,Curamil), naled (Dibrom), phenthoate (dimephenthoate, Phenthoate), IBP (Kitazin), cyanophos (Cyanox), crufomate (Ruelene), fenitrothion (Accothion, Agrothion, Sumithion), pyridaphenthion (Ofunack), acephate (Orthene), malathion (Cythion),ronnel (fenchlorphos, Korlan), etrimfos (Ekamet), phoxim (Baythion), merphos (Folex, Easy off-D), pirimiphos-methyl (Actellic), iodofenphos (Nuvanol-N), chlorphoxim (Baythion-C), propyl thiopyrophosphate (Aspon), bromophos (Nexion),tetrachlorvinphos (Gardona, Appex, Stirofos), temephos (Abate, Abathion).
*Compounds are listed approximately in order of descending toxicity. "Highly toxic" organophosphates have listed oral LD 50 values (rat) less than 50 mg/kg; "moderately toxic" agents have LD 50 values in excess of 50mg/kg.
+These organophosphates are systemic; they are taken up by the plant and translocated into foliage and sometimes into the fruit.
Organophosphates poison insects and mammals primarily by
phosphorylation of the acetylcholinesterase enzyme (AChE) at nerve
endings. The enzyme is critical to normal control of nerve impulse
transmission from nerve fibers to muscle and gland cells, and also to
other nerve cells in autonomic ganglia and in the brain. Some critical
proportion of the tissue enzyme mass must be inactivated by
phosphorylation before symptoms and signs of poisoning become manifest.
At sufficient dosage,loss of enzyme function allows accumulation of acetylcholine (ACh, the impulse-transmitting substance) at cholinergic neuroeffector junctions (muscarinic effects), at skeletal nerve-muscle junctions and autonomic ganglia (nicotinic effects),and in the brain. At cholinergic nerve junctions with smooth muscle and gland cells, high ACh concentration causes muscle contraction and secretion, respectively. At skeletal muscle junctions, excess ACh may be excitatory (cause muscle twitching), but may also weaken or paralyze the cell by depolarizing the end-plate. In the brain, high ACh concentrations cause sensory and behavioral disturbances, incoordination and depressed motor function. Depression of respiration and pulmonary edema are the usual causes of death from organophosphate poisoning. Recovery depends ultimately on generation of new enzyme in all critical issues.
Organophosphates are efficiently absorbed by inhalation, ingestion,
and skin penetration. To a degree, the occurrence of poisoning depends
on the rate at which the pesticide is absorbed. Breakdown occurs
chiefly by hydrolysis in the liver;
rates of hydrolysis vary widely from one compound to another. In the case of certain organophosphates whose breakdown is relatively slow, significant temporary storage in body fat may occur.
Many organophosphates readily undergo conversion from -thions (P=S) to -oxons (P=O). Conversion occurs in the environment under the influence of oxygen and light, and, in the body, chiefly by the action of liver microsomes. -Oxons are much more toxic than -thions, but -oxons break down more readily than -thions. Ultimately, both -oxons and -thions are hydrolyzed at the ester linkage, yielding alkyl phosphates and leaving groups. These are of relatively low toxicity. They are either excreted or further transformed in the body before excretion. Within one to two days of initial organophosphate binding to acetylcholinesterase, some phosphorylated acetylcholinesterase enzyme can be de-phosphorylated (reactivated) by the oxime antidote pralidoxime. As time progresses, the enzyme-phosphoryl bond is strengthened by loss of one alkyl group from the phosphoryl adduct. Pralidoxime reactivation is thereafter no longer possible ("aging").
Rarely, certain organophosphates have caused a different kind of neurotoxicity consisting of damage to the axons of peripheral and central nerves and associated with inhibition of "neurotoxic esterase" (NTE). Manifestations have been chiefly weakness or paralysis and paresthesia of the extremities, predominantly the legs, persistent for weeks to years. Most of these rare occurrences have followed (8-21 days) an acute poisoning episode of the anticholinesterase type, but some have not been preceded by acute poisoning. Only a few of the many organophosphates used as pesticides have been implicated as causes of delayed neuropathy in humans. EPA guidelines require that organophosphate and carbamate compounds which are candidate pesticides be tested in susceptible animal species for this neurotoxic property.
Other specific properties of individual organophosphates may render them more hazardous than basic toxicity data suggest. By-products can develop in long-stored malathion which strongly inhibit the hepatic enzymes operative in malathion degradation, thus enhancing its toxicity. Certain organophosphates are exceptionally prone to storage in fat tissue, prolonging the need for antidote as stored pesticide is released back into the circulation. Animal studies have demonstrated potentiation of effect when two or more organophosphates are absorbed simultaneously: enzymes critical to the degradation of one are inhibited by the other. Whether this interaction is a significant factor in human poisonings is not known.
SYMPTOMS AND SIGNS OF POISONING
Symptoms of acute organophosphate poisoning develop during exposure,
or within 12 hours (nearly always within four hours) of contact. The
most commonly reported early symptoms are headache, nausea, and
dizziness . Anxiety and restlessness are prominent. Worsening of the
poisoned state is manifest as muscle twitching , weakness ,
incoordination, tremor, vomiting, abdominal cramps, and diarrhea.
hypersecretion is often prominent: sweating, salivation, tearing,
rhinorrhea, and bronchorrhea. Blurred and/or dark vision may be
reported, and miosis is often a helpful diagnostic sign. Tightness in
the chest, wheezing, and productive cough may progress to frank
pulmonary edema . Bradycardia may progress to sinus arrest, or may be
superseded by tachycardia and hypertension from nicotinic (sympathetic
ganglia) stimulation. Toxic psychosis, manifest as confusion or bizarre
behavior, has been misdiagnosed as acute alcoholism. Toxic
myocardiopathy has been a prominent feature of some severe
organophosphate poisonings. Unconsciousness, incontinence, convulsions,
and depression of respiratory drive signify life-threatening severity
Repeated absorption of organophosphate at significant dosage, but in amounts not sufficient to cause acute poisoning, may cause persistent weakness, anorexia, and malaise.
Some recently reported cases of organophosphate poisoning, mostly from suicidal ingestion of large quantities, have been characterized by prolonged (1-3 weeks) paralysis of muscles of the head, neck, limbs, and thorax, commencing one to four days following apparent resolution of acute cholinergic manifestations. Continuous medical support of pulmonary ventilation was necessary to sustain life in these cases.
CONFIRMATION OF ORGANOPHOSPHATE ABSORPTION
CAUTION: If there are strong clinical indications of acute organophosphate poisoning, treat patient immediately. Do not wait for laboratory confirmation.
Depressions of plasma pseudocholinesterase and/or RBC
acetylcholinesterase enzyme activities are generally available
biochemical indicators of excessive organophosphate absorption. A
minimum amount of organophosphate must be absorbed to depress blood
cholinesterase activities, but enzyme activities are lowered by dosage
considerably less than are required to cause symptomatic poisoning.
The enzyme depression is usually apparent within a few minutes or
hours of significant absorption of organophosphate. Depression of the
plasma enzyme generally persists several days to a few weeks; the RBC
enzyme activity may not reach its minimum for several days, and usually
remains depressed longer, sometimes 1-3 months, until new enzyme
replaces that inactivated by organophosphate. Table 1 lists
approximate lower limits of normal for plasma and RBC cholinesterase
activities of human blood, measured by several methods. Lower levels
usually indicate excessive absorption of a cholinesterase-inhibiting
chemical. Whenever possible, comparison of the test sample with a
pre-exposure value offers the best confirmation of organophosphate
absorption. A cholinesterase depression of 25% or more is generally
regarded as evidence of excessive absorption.
In certain conditions, the activities of plasma and RBC cholinesterase are depressed in the absence of chemical inhibition. About 3% of individuals have a genetically determined low level of plasma pseudocholinesterase. These persons are particularly vulnerable to the action of the muscle-paralyzing drug succinylcholine, often administered to surgical patients. They are usually more sensitive to organophosphate toxicity, although this has not been proven. Patients with advanced liver disease, malnutrition, chronic alcoholism, and dermatomyositis exhibit low plasma cholinesterase activities. A number of toxicants, notably carbon disulfide, benzalkonium salts, organic mercury compounds, ciguatoxins, and solanines may reduce plasma pseudocholinesterase activity. Early pregnancy and birth control pills may also cause some depression. The RBC acetylcholinesterase is less likely than the plasma enzyme to be affected by factors other than organophosphates. It is reduced, however, in certain rare conditions t hat damage the red cell membrane, such as hemolytic anemias.
The alkyl phosphates and phenols to which organophosphates are hydrolyzed in the body can often be detected in the urine during pesticide absorption and up to 48 hours thereafter. These analyses are sometimes useful in identifying the actual pesticide to which workers have been exposed. Urinary alkyl phosphate and phenol analyses can demonstrate organophosphate absorption at lower dosages than those required to depress cholinesterase activities and at much lower dosages than those required to produce symptoms and signs.
Detection of intact organophosphates in the blood is usually not possible except during or soon after absorption of substantial amounts.
In general, organophosphates do not remain unhydrolyzed in the blood more than a few minutes or hours, unless the quantity absorbed is large or the hydrolyzing liver enzymes are inhibited.
TREATMENT OF ORGANOPHOSPHATE POISONING
CAUTION: Persons attending the victim should avoid direct contact
with heavily contaminated clothing and vomitus. Wear rubber gloves
while washing pesticide from skin and hair.
1.Insure that a clear airway exists by aspiration of secretions, if necessary. Administer oxygen by mechanically assisted pulmonary ventilation if respiration is depressed. Improve tissue oxygenation as much as possible before administering atropine, so as to minimize the risk of ventricular fibrillation.
·In severe poisonings, it may be necessary to support pulmonary ventilation mechanically for several days.
2.Administer atropine sulfate intravenously, or intramuscularly if intravenous injection is not possible.
·The objective of atropine antidotal therapy is to antagonize the effects of excessive concentrations of acetylcholine at end-organs having muscarinic receptors. Depending on the severity of poisoning, doses of atropine ranging from small to very large may be required. Atropine does not reactivate the cholinesterase enzyme or accelerate disposition of organophosphate. Recrudescence of poisoning may occur if tissue concentrations of organophosphate remain high when the effect of atropine wears off. Atropine is effective against muscarinic manifestations, but it is ineffective against nicotinic actions, specifically muscle weakness and twitching, and respiratory depression.
Despite these limitations, atropine is often a lifesaving agent in organophosphate poisonings. Favorable response to a test dose of atropine (1 mg in adults, 0.01 mg/kg in children under 12 years) can help differentiate poisoning by anticholinesterase agents from other conditions.
·In moderately severe poisoning (hypersecretion and other end-organ manifestations without central nervous system depression) the following dosage schedules have proven effective:
·Dosage of ATROPINE : ·Adults and children over 12 years: 0.4-2.0 mg repeated every 15 minutes until atropinization is achieved: flushing, dry mouth, dilated pupils, and tachycardia (pulse of 140 per minute). Maintain atropinization by repeated doses for 2-12 hours or longer depending on severity of poisoning. Rales in the lung bases indicate inadequate atropinization. Miosis, nausea, bradycardia, and other cholinergic manifestations also signal the need for more atropine.
·Children under 12 years: 0.05 mg/kg body weight, repeated every 15 minutes until atropinization is achieved. Maintain atropinization with repeated dosage of 0.02-0.05 mg/kg body weight.
·Severely poisoned individuals may exhibit remarkable tolerance to atropine; two or more times the dosages suggested for moderately severe poisoning may be needed. The dose of atropine may be increased and the dosing interval decreased as needed to control symptoms. Continuous intravenous infusion of atropine may be necessary when atropine requirements are massive. Reversal of muscarinic symptoms and signs , not an arbitrary dose limit, is the desired end-point.
Preservative-free atropine products should be used whenever possible.
·Note: Persons not poisoned or only slightly poisoned by organophosphates may develop signs of atropine toxicity from such large doses: fever , muscle fibrillations, and delirium are the main signs of atropine toxicity. If these signs appear while the patient is fully atropinized, atropine administration should be discontinued, at least temporarily, while the severity of the poisoning is reevaluated.
3.Draw a blood sample (heparinized) for cholinesterase analysis before administration of pralidoxime, which tends to reverse the cholinesterase depression.
4.Administer Pralidoxime (Protopam, 2-PAM), a cholinesterase reactivator, in cases of severe poisoning by organophosphate pesticides in which respiratory depression, muscle weakness, and twitching are severe. When administered early (usually less than 48 hours after poisoning) pralidoxime relieves the nicotinic as well as the muscarinic effects of poisoning.
·Note: Pralidoxime is of limited value, and may be hazardous, in poisonings by the cholinesterase-inhibiting carbamate compounds.
·Dosage of PRALIDOXIME :
·Adults and children over 12 years: 1.0-2.0 gm intravenously at no more than 0.2 gm per minute.
·Children under 12 years: 20-50 mg/kg body weight (depending on severity of poisoning) intravenously, injecting no more than half the total dose per minute.
·Dosage of pralidoxime may be repeated in one to two hours, then at 10-12 hour intervals if needed. In very severe poisonings, dosage rates may be doubled. Repeated doses of pralidoxime are usually required. In cases that involve continuing absorption of organophosphate (as after ingestion of a large amount), or continuing transfer of highly lipophilic organophosphate from fat into blood, it may be necessary to continue administration of pralidoxime for several days beyond the 48 hour post-exposure interval usually cited as the limit of its effectiveness.
·Slow administration of pralidoxime is strongly recommended and may be achieved by administering the total dose in 250 ml 5% glucose solution over 30 minutes, or longer. Blood pressure should be monitored during administration because of the occasional occurrence of hypertensive crisis. Administration should be slowed or stopped if blood pressure rises to hazardous levels. Be prepared to assist pulmonary ventilation mechanically if respiration is depressed during or after pralidoxime administration. If intravenous injection is not possible, pralidoxime may be given by deep intramuscular injection.
5.In patients who have been poisoned by organophosphate contamination of skin, clothing, hair, and/or eyes, decontamination must proceed concurrently with whatever resuscitative and antidotal measures are necessary to preserve life.
Contamination of the eyes should be removed by flushing with copious amounts of clean water. If no symptoms are evident in a patient who remains alert and physically able, a prompt shower and shampoo may be appropriate, provided the patient is carefully observed to insure against sudden appearance of poisoning. If there are any indications of weakness, ataxia, or other neurologic impairment, clothing should be removed and a complete bath and shampoo given while the victim is recumbent, using copious amounts of soap and water. Attendants should wear rubber gloves. Surgical green soap is excellent for this purpose, but ordinary soap is about as good. The possibility of pesticide sequestered under fingernails or in skin folds should not be overlooked. Contaminated clothing should be promptly bagged and not returned until it has been thoroughly laundered. Contaminated leather shoes should be discarded. The possibility that pesticide has contaminated the inside surfaces of glove, boots, and headgear should be kept in mind.
6.If organophosphate has been ingested in quantity probably sufficient to cause poisoning, the stomach and intestine must be emptied.
·Because central nervous system depression may develop rapidly, gastric lavage through a large bore orogastric tube, with rigorous protection of the airway, is probably preferable to emesis in nearly all cases of poisoning by ingested organophosphate. Effectiveness of lavage diminishes rapidly with the passage of time.
(N.B. Extract only for information - full copies are available elsewhere on the web e.g. http://www.igc.apc.org)
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