Organophosphate
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An organophosphate (sometimes abbreviated OP) is the general name for esters of phosphoric acid and is one of the organophosphorus compounds. They can be found as part of insecticides, herbicides, and nerve gases, amongst others. Some less-toxic organophosphates can be used as solvents, plasticizers, and EP additives.
Early pioneers in the field include Lassaigne (early 1800s) and Philip de Clermount (1854). In 1932, German chemist Willy Lange and his graduate student, Gerde von Krueger, first described the cholinergic nervous system effects of organophosphates, noting a choking sensation and a dimming of vision after exposure. This discovery later inspired German chemist Gerhard Schrader at company I.G. Farben in the 1930s to experiment with these compounds as insecticides. Their potential use as chemical warfare agents soon became apparent, and the Nazi government put Schrader in charge of developing organophosphate (in the broader sense of the word) nerve gases. Schrader's laboratory discovered the G series of weapons, which included Sarin, Tabun, and Soman. The Nazis produced large quantities of these compounds, though did not use them during World War II (likely because they feared the Allies possessed similar weapons). British scientists experimented with an anticholinergic organophosphate of their own, called Diisopropylfluorophosphate DFP, during the war. The British later produced VX nerve gas, which was many times more potent than the G series, in the early 1950s.
After World War II, American companies gained access to some information from Schrader's laboratory, and began synthesizing organophosphate pesticides in large quantities. Parathion was among the first marketed, followed later by malathion and azinphosmethyl. The popularity of these insecticides increased after many of the organochlorine insecticides like DDT, dieldrin, and heptachlor were banned in the 1970s.
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[edit] A Note on Nomenclature
The term organophosphate should strictly be reserved for an ester of phosphoric acid or one of its higher compounds (such as pyrophosphoric acid), but the term is used often to describe any organic phosphorus-containing compound, especially when dealing with neurotoxins. Many of the so called organophosphates contain C-P bonds which make them something else, for instance sarin is O-isopropyl methylphosphonofluoridate whose parent phosphorus acid is HP(O)(OH)2 which is phosphorous acid, not phosphoric acid. Also many compounds which are derivatives of phosphinic acid are used as organic phosphorus containing neurotoxin.
[edit] Organophosphate pesticides
In health, agriculture, and government, the word "organophosphates" refers to a group of insecticides or nerve agents acting on the enzyme acetylcholinesterase (the pesticide group Carbamates also act on this enzyme, but through a different mechanism). Organophosphate pesticides (as well as Sarin and VX nerve gas) irreversibly inactivate acetylcholinesterase, which is essential to nerve function in insects, humans, and many other animals. Organophosphate pesticides have tremendous variation in their ability to affect this enzyme, and thus in their potential for poisoning. For instance, parathion, one of the first OPs discovered, is many times more potent than malathion, an insecticide used in combatting the Mediterranean fruit fly (Med-fly) and West Nile Virus-transmitting mosquitoes.
Organophosphate pesticides tend to degrade rapidly on exposure to sunlight, air, and soil, though small amounts can persist and end up in food and drinking water. Their ability to degrade made them an attractive alternative to the persistent organochlorine pesticides, such as DDT, aldrin, and dieldrin, which were widely publicized in Rachel Carson's Silent Spring. While organophosphates degrade faster than the organochlorines, they have much greater acute toxicity, posing risks to farmworkers, pesticide applicators, and anyone else who may be exposed to large amounts. OP poisoning can be very serious and even cause death. See the Toxicity section below for the effects. Their toxicity is not limited to the acute phase, however, and chronic effects have long been noted. Neurotransmitters such as acetylcholine (which is affected by organophosphate pesticides) are profoundly important in the brain's development, and many OPs have neurotoxic effects on developing organisms even from low levels of exposure.
Commonly used organophosphates have included Parathion, Malathion, Methyl parathion, Chlorpyrifos, Diazinon, Dichlorvos, Phosmet, Azinphos methyl.
[edit] Chemical Overview of 'Organophosphate' neurotoxins
[edit] Basics
To act as an 'Organophosphate' neurotoxins the following structural requirements exist.
- A terminal oxygen bonded by a double bond to the phosphorus
- Two lipophilic groups bonded to the phosphorus
- A leaving group bonded to the phosphorus
[edit] Terminal oxygen vs. terminal sulfur
Note that these compounds bearing terminal sulfur atoms on the phosphorus atom are much less toxic than the compounds (such as sarin, VX and tetraethyl pyrophosphate) which have an oxygen in place of this terminal sulfur. This is because the P=S compound is not active as an acetylcholinesterase inhibitor in either mammals or insects, in mammals the animals metabolism tends to remove lipophilic side groups from the phosphorus atom while an insect tends to oxidise the compound so removing the terminal sulfur and replacing it with a terminal oxygen which causes the compound to be more able to act as an acetylcholinesterase inhibitor.
[edit] Fine tuning
Within these requirements a large number of different lipophilic and leaving groups have been used. The variation of these groups is one means of fine tuning the toxicity of the compound.
[edit] Example
A good example of this chemistry are the P-thiocyanate compounds which use an aryl (or alkyl) group and an alkylamino group as the lipophilic groups. The thiocyanate is the leaving group.
It was claimed in a German patent that the reaction of 1,3,2,4-dithiadiphosphetane 2,4-disulfides with dialkyl cyanamides formed plant protection agents which contained six membered (P-N=C-N=C-S-) rings. It has been proven in recent times by the reaction of diferrocenyl 1,3,2,4-dithiadiphosphetane 2,4-disulfide (and Lawesson's reagent) with dimethyl cyanamide that in fact a mixture of several different phosphorus-containing compounds is formed. Depending on the concentration of the dimethyl cyanamide in the reaction mixture either a different six membered ring compound (P-N=C-S-C=N-) or a nonheterocylic compound (FcP(S)(NR2)(NCS)) is formed as the major product, the other compound is formed as a minor product.
In addition small traces of other compounds are also formed in the reaction. It is unlikely that the ring compound (P-N=C-S-C=N-) {or its isomer} would act as a plant protection agent, but (FcP(S)(NR2)(NCS)) compounds can act as nerve poisons in insects.
[edit] Organophosphate poisoning
| ICD-10 | T60.0 |
|---|---|
| ICD-9 | 989.3 |
Many organophosphates are potent neurotoxins, functioning by inhibiting the action of acetylcholinesterase (AChE) in nerve cells. They are one of the most common causes of poisoning worldwide, and are frequently intentionally used in suicides in agricultural areas.
The effects of organophosphate poisoning are recalled using the mnemonic "SLUD" or "SLUDGE", for salivation, lacrimation, urination, defecation, gastrointestinal upset, and emesis.
Atropine can be used as an antidote in conjunction with pralidoxime, though the use of "-oximes" has been found to be of no benefit, or possibly harmful, in at least two meta-analyses (Rahimi 2006 and Peter 2006).
The use of the organophosphates in aviation lubricating oils and hydraulic fluids and its impact on health and flight safety is a matter of some debate. Airline employees set up a non profit group in 2001 to highlight their concerns called the Aviation Organophosphate Information Site (AOPIS)[1].
Purdey (1998) suggested that organophosphates, in particular Phosmet, induced the transmissible spongiform encephalopathy epidemic of BSE. An European Union food safety Scientific Steering Committee examined the evidence and did not find a link[2].
As opposed to the two examples given above, the toxicological literature on persistent chronic toxicity from acute poisonings or long-term low level exposure is quite extensive. The phenomenon of OPIDP (organophosphate induced delayed polyneuropathy, also OPIDN), which causes degeneration of the peripheral nerves, has been noted to occur several weeks after exposure to some organophosphates. Current issues in organophosphate toxicology
A striking example of OPIDN occurred during the 1930s Prohibition Era when thousands of men in the American South and Midwest developed arm and leg weakness and pain after drinking a "medicinal" alcohol substitute. The drink, called "Ginger Jake," contained an adulterated Jamaican ginger extract containing tri-ortho-cresyl phosphate (TOCP) which resulted in partially reversible neurologic damage. The damage resulted in the limping "Jake Leg" or "Jake Walk" which were terms frequently used in the blues music of the period. Europe and Morocco both experienced outbreaks of TOCP poisoning from contaminated abortifacients and cooking oil, respectively (Morgan 1978).
Other studies suggest a link between chronic low level organophosphate exposure and neuropsychiatric and behavioral effects. Jamal has suggested the term COPIND, or "Chronic Organophosphate-Induced Neurologic Dysfunction," and Abou Donia the term, OPICN, or Organophosphate-Induced Chronic Neuropathy for describing these effects.
Low-level effects on the developing brains of fetuses, infants, and children have been documented as well.
The U.S. Food Quality Protection Act (FQPA), passed in 1996, designated the Environmental Protection Agency (EPA) to conduct a 10 year review process of the health and environmental effects of all pesticides, beginning with the Organophosphates. The process has taken longer than expected, but was recently concluded and eliminated or modified thousands of uses. NYTimes Aug 4, 2006
Many non-governmental and research groups, as well as the EPA's Office of Inspector General, have published concerns that the review did not take into account possible neurotoxic effects on developing fetuses and children, an area of developing research. OIG report. A group of leading EPA scientists sent a letter to the chief administrator, Stephen Johnson, decrying the lack of developmental neurotoxicity data in the review process. EPA Letter EHP article New studies have shown toxicity to developing organisms during certain "critical periods" at doses much lower than those previously suspected to cause harm (see Slotkin et. al.).
[edit] See also
- Pesticide toxicity to bees
- Activity based protein profiling using organophosphate-containing activity based probes
[edit] References
- Abou-Donia MB. "Organophosphorus ester-induced chronic neurotoxicity." Arch Environ Health. 2003 Aug;58(8):484-97. PMID: 15259428
- Costa LG. Current issues in organophosphate toxicology. Clin Chim Acta. 2006 Apr;366(1-2):1-13. Epub 2005 December 6. Review. PMID: 16337171.
- Jamal GA. "Neurological syndromes of organophosphorus compounds." Adverse Drug React Toxicol Rev. 1997 Aug;16(3):133-70. PMID: 9512762
- Morgan JP, Tulloss TC. The Jake Walk Blues. A toxicologic tragedy mirrored in American popular music. Annals of Internal Medicine. 1976 Dec;85(6):804-8. PMID: 793467.
- Peter JV, Moran JL, Graham P. Oxime therapy and outcomes in human organophosphate poisoning: an evaluation using meta-analytic techniques. Crit Care Med. 2006 Feb;34(2):502-10. Review. PMID 16424734
- Purdey M. High-dose exposure to systemic phosmet insecticide modifies the phosphatidylinositol anchor on the prion protein: the origins of new variant transmissible spongiform encephalopathies? Med Hypotheses 1998;50:91-111. PMID 9572563.
- Rahimi R, Nikfar S, Abdollahi M. Increased morbidity and mortality in acute human organophosphate-poisoned patients treated by oximes: a meta-analysis of clinical trials. Hum Exp Toxicol. 2006 Mar;25(3):157-62. PMID 16634335
- Slotkin TA, Levin ED, Seidler FJ. Comparative developmental neurotoxicity of organophosphate insecticides: effects on brain development are separable from systemic toxicity. Environ Health Perspect. 2006 May;114(5):746-51. PMID: 16675431
