Forthcoming will be two messages, parts 1& 2 on organophosphates, more scary
pesticides which cause twitching:
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From:   [log in to unmask] (Tebay, Wendy)
To:     [log in to unmask] (athome)
Date: 95-06-29 12:21:47 EDT
 
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Commercial Products
 
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 (Thio-tepp, 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 (Proban, Cyflee),
phencapton (G 28029), pirimiphos-ethyl (Primicid), DEF (De-Green, E-Z-Off
D), methyl trithion, dimethoate (Cygon, DeFend), fen-thion (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 LD50 values (rat) less
than 50 mg/kg; "moderately toxic" agents have LD50 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.
 
 
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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
organophos-phate 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 pseudo-cholinesterase.
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 that
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.
 
 
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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, incoordina-tion, tremor, vomiting,
abdominal cramps, and diarrhea. HYPERSECRE-TION 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 of poisoning.
 
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.
 
 
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Toxicology
 
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 choliner-gic 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 depo-larizing 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
acetyl-cholinesterase, some phosphorylated acetylcholinesterase enzyme can
be dephosphorylated (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.
 
 
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Treatment of EXTERNAL 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 follow-ing
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 ventila-tion 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
thorough-ly 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.
 
 
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Treatment of Organophosphate Poisoning by Ingestion
 
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
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