Organophosphate Insecticides
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CHAPTER 4 HIGHLIGHTS Organophosphate Insecticides Acts through phosphorylation of the acetylcholinesterase enzyme Since the removal of organochlorine insecticides from use, organophosphate at nerve endings insecticides have become the most widely used insecticides available today. More Absorbed by inhalation, than forty of them are currently registered for use and all run the risk of acute ingestion, and skin and subacute toxicity. Organophosphates are used in agriculture, in the home, penetration in gardens, and in veterinary practice. All apparently share a common mecha- Muscarinic, nicotinic & CNS nism of cholinesterase inhibition and can cause similar symptoms. Because they effects share this mechanism, exposure to the same organophosphate by multiple routes or to multiple organophosphates by multiple routes can lead to serious additive Signs and Symptoms: toxicity. It is important to understand, however, that there is a wide range of Headache, hypersecretion, toxicity in these agents and wide variation in cutaneous absorption, making muscle twitching, nausea, specific identification and management quite important. diarrhea Respiratory depression, seizures, loss of consciousness Toxicology Miosis is often a helpful Organophosphates poison insects and mammals primarily by phosphory- diagnostic sign lation of the acetylcholinesterase enzyme (AChE) at nerve endings. The result is a loss of available AChE so that the effector organ becomes overstimulated by Treatment: the excess acetylcholine (ACh, the impulse-transmitting substance) in the nerve Clear airway, improve tissue ending. The enzyme is critical to normal control of nerve impulse transmission oxygenation from nerve fibers to smooth and skeletal muscle cells, glandular cells, and Administer atropine sulfate autonomic ganglia, as well as within the central nervous system (CNS). Some intravenously critical proportion of the tissue enzyme mass must be inactivated by phospho- Pralidoxime may be rylation before symptoms and signs of poisoning become manifest. indicated At sufficient dosage, loss of enzyme function allows accumulation of ACh Proceed concurrently with peripherally at cholinergic neuroeffector junctions (muscarinic effects), skeletal decontamination nerve-muscle junctions, and autonomic ganglia (nicotinic effects), as well as centrally. At cholinergic nerve junctions with smooth muscle and gland cells, high ACh concentration causes muscle contraction and secretion, respectively. Contraindicated: At skeletal muscle junctions, excess ACh may be excitatory (cause muscle twitch- Morphine, succinylcholine, theophylline, ing), but may also weaken or paralyze the cell by depolarizing the end-plate. In phenothiazines, reserpine the CNS, high ACh concentrations cause sensory and behavioral disturbances, incoordination, depressed motor function, and respiratory depression. Increased pulmonary secretions coupled with respiratory failure are the usual causes of death from organophosphate poisoning. Recovery depends ultimately on gen- eration of new enzyme in all critical tissues. 34 ORGANOPHOSPHATES COMMERCIAL PRODUCTS acephate VC-13 Nemacide hosalone phosmet Orthene dichlorvos Zolone Imidan azinphos-methyl+ DDVP IBP Prolate Gusathion Vapona Kitazin phosphamidon+ Guthion dicrotophos+ iodofenphos Dimecron bensulide Bidrin Nuvanol-N phostebupirim Betasan dimefos+ isazofos Aztec Lescosan Hanane Brace phoxim bomyl+ Pestox XIV Miral Baythion Swat dimethoate Triumph pirimiphos-ethyl bromophos Cygon isofenphos+ Primicid Nexion DeFend Amaze pirimiphos-methyl bromophos-ethyl dioxathion+ Oftanol Actellic Nexagan Delnav isoxathion profenofos cadusafos disulfoton+ E-48 Curacron Apache Disyston Karphos propetamphos Ebufos ditalimfos leptophos Safrotin Rugby edifenphos Phosvel propyl thiopyro- carbophenothion+ endothion+ malathion phosphate+ Trithion EPBP Cythion Aspon chlorethoxyfos S-Seven mephosfolan+ prothoate Fortress EPN+ Cytrolane Fac chlorfenvinphos ethion merphos pyrazophos Apachlor Ethanox Easy off-D Afugan Birlane ethoprop Folex Curamil chlormephos+ Mocap methamidophos+ pyridaphenthion Dotan ethyl parathion+ Monitor Ofunack chlorphoxim E605 methidathion+ quinalphos Baythion-C Parathion Supracide Bayrusil chlorpyrifos thiophos Ultracide ronnel Brodan etrimfos methyl parathion+ Fenchlorphos Dursban Ekamet E 601 Korlan Lorsban famphur+ Penncap-M schradan+ chlorthiophos+ Bash methyl trithion OMPA Celathion Bo-Ana mevinphos+ sulfotep+ coumaphos+ Famfos Duraphos Bladafum Asuntol fenamiphos+ Phosdrin Dithione Co-Ral Nemacur mipafox+ Thiotepp crotoxyphos fenitrothion Isopestox sulprofos Ciodrin Accothion Pestox XV Bolstar Cypona Agrothion monocrotophos+ Helothion crufomate Sumithion Azodrin temephos Ruelene fenophosphon+ naled Abate cyanofenphos+ Agritox Dibrom Abathion Surecide trichloronate oxydemeton-methyl terbufos cyanophos fensulfothion+ Metasystox-R Contraven Cyanox Dasanit oxydeprofos Counter cythioate fenthion Metasystox-S tetrachlorvinphos Cyflee Baytex phencapton Gardona + Indicates high toxicity. Highly Proban Entex G 28029 Rabon toxic organophosphates have DEF Tiguvon phenthoate tetraethyl pyrophos- listed oral LD50 values (rat) less + + De-Green fonofos dimephenthoate phate than or equal to 50 mg/kg body E-Z-Off D Dyfonate Phenthoate TEPP weight. Most other organo- + + demeton N-2790 phorate triazophos phosphates included in this table systox formothion Rampart Hostathion are considered moderately toxic, demeton-S-methyl Anthio Thimet trichlorfon with LD50 values in excess of 50 + Duratox fosthietan phosalone Dipterex mg/kg and less than 500 mg/kg. MetasystoxI Nem-A-Tak Azofene Dylox dialifor+ heptenophos Zolone Neguvon Torak Hostaquick phosfolan+ Proxol diazinon hiometon Cylan dichlorofenthion Ekatin Cyolane ORGANOPHOSPHATES 35 Organophosphates are efficiently absorbed by inhalation, ingestion, and skin penetration. There is considerable variation in the relative absorption by these various routes. For instance, the oral LD50 of parathion in rats is between 3-8 mg/ kg, which is quite toxic,1,2 and essentially equivalent to dermal absorption with 2 an LD50 of 8 mg/kg. On the other hand, the toxicity of phosalone is much lower from the dermal route than the oral route, with rat LD50s of 1500 mg/kg and 120 mg/kg, respectively.2 In general, the highly toxic agents are more likely to have high-order dermal toxicity than the moderately toxic agents. Chemical Classes: To some 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. Some organophos- phates such as diazinon and methyl parathion have significant lipid solubility, allowing fat storage with delayed toxicity due to late release.3 Delayed toxicity may also occur atypically with other organophosphates, specifically dichlorofenthion and demeton-methyl.4 Many organothiophosphates 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. Ultimately, both thions and oxons are hydrolyzed at the ester linkage, yielding alkyl phosphates and leaving groups, both of which are of relatively low toxicity. They are either excreted or further transformed in the body before excretion. The distinction between the different chemical classes becomes important when the physician interprets tests from reference laboratories. This can be espe- cially important when the lab analyzes for the parent compound (i.e., chlorpyrifos in its thiophosphate form) instead of the metabolite form (chlorpyrifos will be completely metabolized to the oxon after the first pass through the liver). Within one or two days of initial organophosphate binding to AChE, some phosphorylated acetylcholinesterase enzyme can be de-phosphorylated (reac- tivated) by the oxime antidote pralidoxime. As time progresses, the enzyme- phosphoryl bond is strengthened by loss of one alkyl group from the phosphoryl adduct, a process called aging. Pralidoxime reactivation is therefore no longer possible after a couple of days,5 although in some cases, improvement has still been seen with pralidoxime administration days after exposure.6 OPIDN: Rarely, certain organophosphates have caused a different kind of neurotoxicity consisting of damage to the afferent fibers of peripheral and cen- tral nerves and associated with inhibition of neuropathy target esterase (NTE). This delayed syndrome has been termed organophosphate-induced delayed neuropathy (OPIDN), and is manifested chiefly by weakness or paralysis and paresthesia of the extremities.7 OPIDN predominantly affects the legs and may 36 ORGANOPHOSPHATES persist for weeks to years. These rare occurrences have been found shortly after an acute and often massive exposure, but in some cases, symptoms have per- sisted for months to years. 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 neuro- toxic property. Three epidemiologic studies with an exposed group and a control group also suggest that a proportion