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Cholinesterase |
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The transmission of nerve impulses across synapses and the junctions between nerve and an effector organ (gland, muscle, nerve) is accomplished by the release of a chemical agent, acetylcholine. If actions within the central nervous system and at peripheral nerve terminations are to be kept localized and capable of repetition, acetylcholine must be destroyed or inactivated at or near the site of its release, and with great speed. The destruction of acetylcholine at such sites is accomplished by an enzyme, acetylcholinesterase. Present at the neurosynaptic junctions, acetylcholinesterase breaks acetylcholine into acetyl and choline fragments. Acetylcholinesterase functions to increase the precision of nerve firing, enabling some nerve cells to fire as rapidly as 1,000 times per second without overlap of the of the neural impulses
The poisonous effects of organophosphorous and carbamate pesticides come about through the inhibition of cholinesterase, an enzyme produced in the liver. One form, acetylcholinesterase, can be found at the neurosynaptic junctions while another, butyryl cholinesterase, is primarily located in the plasma and pancreas, although small quantities of it exist in all tissues including our blood.
Organophosphorus compounds differ from one another in many important respects, although chemically, all can be considered to be derivatives of phosphoric or thiophosphoric acids. They differ widely in inherent toxicity and in their ability to penetrate the skin. However, mevinphos (Phosdrin) is extremely dangerous by both oral and dermal routes.
Some organophosphates act directly while others require activation by enzymes within the body. Some are destroyed and eliminated more rapidly than others. Also, they differ with respect to the manner of their reaction with the cholinesterase enzyme.
Organophosphate pesticides inhibit cholinesterase by forming covalent chemical bonds through a process called phosphorylation. Spontaneous enzymatic regeneration half-lifes may take days to months long. As with carbamates, the nature of the organophosphate involved, the dose received and the duration of exposure all affect the period for regeneration to occur. Because of the prolonged regeneration half-lives, (the time required for half of the cholinesterase to reactivate), organophosphate intoxication is usually considered more serious although some exposures to carbamates lead more rapidly to symptomatology and can be just as lethal. Organophosphates affect both red blood cells (RBC) and plasma cholinesterase activity whereas carbamates normally affect only the plasma fraction (Davies and Freed, 1981).
Carbamate insecticides inhibit cholinesterase activity in reversible fashion and normally affect only the plasma fraction. Because they interact with cholinesterase by weak, ionic chemical bonding, the cholinesterase usually regenerates itself spontaneously. The half-life of this spontaneous regeneration is on the order of minutes to hours and is dependent on the nature of the specific carbamate involved, the dosage received and the length of exposure (Davies and Freed, 1981).
Like the organophosphorous pesticides, members of the carbamate group vary widely in inherent toxicity and other toxicological properties. Carbaryl (Sevin), for instance, is not highly toxic by the oral route and is not readily absorbed through the skin. Aldicarb (Temik), on the other hand, is extremely toxic by both oral and dermal routes.
The signs and symptoms are similar for carbamates and organophosphate poisonings. These pesticides combine with cholinesterase at nerve endings in the brain and in the tissues of the body, thereby permitting the accumulation of acetylcholine. The occurrence of symptoms is primarily dependent upon the rate of cholinesterase decline. Most differences are due to the fact that cholinesterase reactivation is much more rapid after carbamate exposure than it is after organophosphate exposure. After carbamate exposure, choli- nesterase recovery may take from several hours to several weeks, depending on the degree of exposure. Also, the dose necessary to produce incapacita- ting symptoms is generally far from the lethal dose for carbamates, while the two doses are often quite close for organophosphates. Symptoms include the following:
Muscarine Effects
nausea blurring of vision
vomiting pain in chest
involuntary defecation and urination salivation
diarrhea lacrimation
sweating excessive bronical secretions
Nicotinic Effects
weakness
fasciculations
flaccid paralysis
muscle twitching
Respiratory failure can also occur as a blockage of small bronchi may result.
No one can tell when symptoms first appear whether the poisoning will be mild or severe. In many instances involving skin contamination, symptoms progress from mild to severe due to continued absorption, even though an attempt has been made to wash the material away. Such progression can be rapid. At the first signs of poisoning, the victim should be transported to the nearest medical facility. For organophosphate poisoning, atropine and pralidoxime (2-PAM, Protopam) chloride may be administered by the physician. Atropine should be given intravenously, but if this is not possible, the intramuscular route will suffice. Pralidoxime provides an important adjunct to atropine when it is administered within 36 hours of the organophosphate poisoning contact. Atropine is the only antidote necessary for the management of cholinesterase depression resulting from carbamate exposure (Davies and Freed, 1981).
Workers occupationally exposed to organophosphate pesticides should be offered an initial pre-employment cholinesterase determination (base-line value) followed by subsequent cholinesterase testing on a regular basis (usually monthly). The laboratory method should be one that provides both red blood cell and plasma values. Red blood cell values are more infor- mative of exposure than are plasma and workers should be withdrawn from exposure when exhibiting greater than 50% inhibition (Davies and Freed, 1981).
There is considerable variation in the normal activity of the cholinesterase enzymes from individual to individual. Therefore, for cholinesterase measurement to be maximally useful, the applicator must have a pre-season or pre-exposure measurement (base-line value) to which his later values can be compared. Many methods of measuring cholinesterase activity are available. Most depend upon the release of acid when acetylcholine or other choline ester is hydrolyzed. The following table shows the approximate cholinesterase activity in normal human blood for two methods of testing. Because measurement techniques vary among laboratories, more accurate estimates of normal values are usually provided by the individual.
Cholinesterase Activity in Normal Human Blood
1. Michel (change in pH) Method
Men Women
Range Mean Range Mean
Red Cells 0.39-1.02 0.766 0.34-1.10 0.750
Plasma 0.44-1.63 0.953 0.24-1.54 0.817
(Values = change in pH in 1 hour)
2. pH-stat (continuous acid titration) Method
Red Cells 6.85-11.27 9.06
Plasma 4.91-9.83 7.38
Whole Blood 3.55-5.99 4.73
(Values = micromoles of acid per ml/min)
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From Smith, P.W. 1974. Medical Problems in Aerial Application.
ORGANOPHOSPHATES
Oral LD50 Dermal LD50
acephate (Orthene) 945 >2000
Aspon 891 1700
azinphos-methyl (Guthion) 13-16 220
carbophenothion (Trithion) 32 54
chlorfenvinphos (Birlane) 10-39 >3000
chlorpyrifos (Dursban, Lorsban) 163 >2000
coumaphos (Co-Ral) 56-320 860
crotoxyphos (Ciodrin, Ciovap) 125 385
crufomate (Ruelene) 770 >2000
demeton (Systox) 2-12 24
diazinon (Diazinon, Spectracide) 300 4000
dichlorvos (DDVP, Vapona) 56 107
dicrotophos (Bidrin) 22 225
dimethoate (Cygon, De-Fend) 320 >700
dioxathion (Delnav) 43 107
disulfoton (Di-Syston) 2-12 20
EPN 33 30-50
ethion 70 915
ethoprop (Mocap) 62 26
famphur 36-62 1460-5090
fenitrothion (Sumithion) 500 1300
fensulfothion (Dasanit) 2-10 3-30
fenthion (Baytex, Tiguvon) 250 330
fonofos (Dyfonate) 8 147
malathion (Cythion) 1375 4100
methamidophos (Monitor) 21 118
methidathion (Supracide) 65 640
methyl parathion 9-25 300-400
mevinphos (Phosdrin) 3-7 13-55
monocrotophos 8-23 354
naled (Dibrom) 430 1100
oxydemeton-methyl (Metasystox-R) 65 100-125
parathion (Niran, Phoskil) 13 40
phorate (Thimet) 2 70-300
phosalone (Zolone) 120 >2000
phosmet (Imidan, Prolate) 300 3160
phosphamidon (Dimecron) 20 267
temephos (Abate) 8600 >4000
TEPP 2 5
terbufos (Counter) 4 29
tetrachlorvinphos (Rabon, Ravap) 4000 >5000
trichlorfon (Dylox, Neguvon) 450 5000
CARBAMATES
aldicarb (Temik) 1 5
bendiocarb (Ficam) 143 >1000
carbaryl (Sevin) 500 >2000
carbofuran (Furadan) 11 3400->10,000
methiocarb (Mesurol) 87-130 350-500
methomyl (Lannate, Nudrin) 17 >1000
oxamyl (Vydate) 5 2960
pirimicarb (Pirimor) 147 >500
propoxur (Baygon) 100 >1000
Davies, J.E. and V. H. Freed, editors. 1981. An agromedical approach
to pesticide management:
some health and environmental considerations. Consortium for International
Crop Protection, Berkeley, CA. 370 pp.
Golz, H.H. and C. B. Shaffer. 1960. Toxicological information on cyanamid insecticides. American Cyanamid Co., Princeton, NJ. 80 pp.
Smith, P.W. 1974. Medical problems in aerial application. Dept. of Transportation, FAA Bull. 16 pp.
Prepared by William G. Smith, Chemicals-Pesticides Program, Department of Entomology, Comstock Hall, Cornell University.
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