Organophosphate

General chemical structure of an organophosphate

An organophosphate (sometimes abbreviated OP) is the general name for esters of phosphoric acid. Phosphates are probably the most pervasive organophosphorus compounds. Many of the most important biochemicals are organophosphates, including DNA and RNA as well as many cofactors that are essential for life. Organophosphates are also the basis of many insecticides, herbicides, and nerve gases. Organophosphates are widely used as solvents, plasticizers, and EP additives.

Organophosphates are widely employed both in natural and synthetic applications because of the ease with which organic groups can be linked together. Being a triprotic acid, phosphoric acid can form triesters whereas carboxylic acids only form monoesters. Esterification entails the attachment of organic groups to phosphorus through oxygen linkers. The precursors to such esters are alcohols. Encompassing many thousands of natural and synthetic compounds, alcohols are diverse and widespread.

OP(OH)₃ + ROH → OP(OH)₂(OR) + H₂O

OP(OH)₂(OR) + R'OH → OP(OH)(OR)(OR') + H₂O

OP(OH)(OR)(OR') + R"OH → OP(OR)(OR')(OR") + H₂O

The phosphate esters bearing OH groups are acidic and partially deprotonated in aqueous solution. For example, DNA and RNA are polymers of the type [PO₂(OR)(OR')^-]_n. Polyphosphates also form esters; an important example of an ester of a polyphosphate is ATP, which is the monoester of triphosphoric acid (H₅P₃O₁₀).

Alcohols can be detached from phosphate esters by hydrolysis, which is the reverse of the above reactions. For this reason, phosphate esters are common carriers of organic groups in biosynthesis.

[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). The term is used often to describe virtually any organic phosphorus(V)-containing compound, especially when dealing with neurotoxic compounds. Many of the so-called organophosphates contain C-P bonds. For instance, sarin is O-isopropyl methylphosphonofluoridate, which is formally derived from phosphorous acid (HP(O)(OH)₂), not phosphoric acid (P(O)(OH)₃). Also, many compounds which are derivatives of phosphinic acid are used as neurotoxic organophosphates.

Organophosphate pesticides (as well as sarin and VX nerve agent) irreversibly inactivate acetylcholinesterase, which is essential to nerve function in insects, humans, and many other animals. Organophosphate pesticides affect this enzyme in varied ways, and thus in their potential for poisoning. For instance, parathion, one of the first OPs commercialized, 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 degrade rapidly by hydrolysis on exposure to sunlight, air, and soil, although small amounts can be detected in food and drinking water. Their ability to degrade made them an attractive alternative to the persistent organochloride pesticides, such as DDT, aldrin and dieldrin. Although organophosphates degrade faster than the organochlorides, they have greater acute toxicity, posing risks to people who may be exposed to large amounts (see the Toxicity section below).

Commonly used organophosphates have included parathion, malathion, methyl parathion, chlorpyrifos, diazinon, dichlorvos, phosmet, tetrachlorvinphos, and azinphos methyl.

[edit] Organophosphates as nerve agents

[edit] History of nerve agents

Early pioneers in the field include Jean Louis Lassaigne (early 19th century) 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 IG 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. British scientists experimented with a cholinergic organophosphate of their own, called diisopropylfluorophosphate (DFP), during the war. The British later produced VX nerve agent, which was many times more potent than the G series, in the early 1950s, almost 20 years after the Germans had discovered the G series.

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 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.

[edit] Structural features of organophosphates

Effective organophosphates have the following structural features:

• A terminal oxygen connected to phosphorus by a double bond, i.e. a phosphoryl group
• Two lipophilic groups bonded to the phosphorus
• A leaving group bonded to the phosphorus, often a halide

[edit] Terminal oxygen vs. terminal sulfur

Thiophosphoryl compounds, those bearing the P=S functionality, are much less toxic than related phosphoryl derivatives, which include sarin, VX and tetraethyl pyrophosphate. Thiophosphoryl compounds are not active inhibitors of acetylcholinesterase in either mammals or insects; in mammals, metabolism tends to remove lipophilic side groups from the phosphorus atom while in insects it tends to oxidize the compound, thus removing the terminal sulfur and replacing it with a terminal oxygen, which allows the compound to more efficiently 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 toxicithe compound. 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.

One of the products of the reaction of Fc₂P₂S₄ with dimethyl cyanamide

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

Many organophosphates are potent nerve agents, 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. Organophosphorus pesticides can be absorbed by all routes, including inhalation, ingestion, and dermal absorption. 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. Other organophosphates are not toxic, yet their main metabolites, such as their oxons are.

Signs of organophosphate poisoning include:

• salivation
• lacrimation
• urinary incontinence
• defecation
• GI upset/diarrhea
• emesis
• miosis

Chronic exposure is most often a problem in the occupational setting killing around 300,000 people each year, particularly among poor rural populations where populations work and live in close proximity to fields and orchards where chemicals are applied and stored. The mnemonic acronym "SLUDGE" is frequently cited as an aid for healthcare professionals in recognizing the first six signs listed above.

agLearn.net^[1] describes the signs and symptoms of onset of organophosphorous poisoning: At first:

• Person feels sick
• Complains of headache
• General weakness or tiredness

Then

• Person begins to sweat and salivate, may vomit and have diarrhea
• Complains of stomach cramps
• Pupils (of the eyes) become very small
• Person may mention blurred vision
• Muscles twitch and hands shake
• Breathing becomes bubbly
• Person has a fit and becomes unconscious

[edit] Health effects

The signs and symptoms of acute organophosphate poisoning are an expression of the effects caused by excess acetylcholine (cholinergic syndrome); they may occur in various combinations and can be manifest at different times. Signs and symptoms can be divided into three groups: • muscarinic effect • nicotinic effect • central nervous system effect Those individuals who are exposed to organophosphorus pesticides with pre-existing/ organic diseases of the central nervous system, mental disorders & epilepsy, pronounced endocrine & vegetative disorders, pulmonary tuberculosis, bronchial asthma, chronic respiratory diseases, cardiovascular diseases & circulatory disorders, gastrointestinal diseases (peptic ulcer), gastroenterocolitis, diseases of liver & kidneys, eye diseases (chronic conjunctivitis & keratitis) /are at elevated risk from exposure/.

Chronic fatigue is common amongst those who consider their health is affected by pesticides and research from 2003 suggested there was an association between exposure to organophosphates and chronic fatigue symptoms^[2].

A 2007 study linked the organophosphate insecticide chlorpyrifos, which is used on some fruits and vegetables, with delays in learning rates, reduced physical coordination, and behavioral problems in children, especially ADHD.^[3]

A 2010 study has found that organophosphate exposure is associated with an increased risk of Alzheimer's disease.^[4]

Another 2010 study found that organophosphate exposure is associated with an increased risk of ADHD in children. Researchers analyzed the levels of organophosphate residues in the urine of more than 1,100 children aged 8 to 15 years old, and found that those with the highest levels of dialkyl phosphates, which are the breakdown products of organophosphate pesticides, also had the highest incidence of ADHD. Overall, they found a 35% increase in the odds of developing ADHD with every 10-fold increase in urinary concentration of the pesticide residues. The effect was seen even at the low end of exposure: children who had any detectable, above-average level of pesticide metabolite in their urine were twice as likely as those with undetectable levels to record symptoms ADHD.^[5]

[edit] See also

• Organophosphate poisoning
• Activity based protein profiling using organophosphate-containing activity based probes
• Mark Purdey
• Pesticide toxicity to bees
• Toxic Syndrome (Spain)

[edit] References

• Costa LG. Current issues in organophosphate toxicology. Clin Chim Acta. 2006 Apr;366(1-2):1-13. Epub 2005 December 6. Review. PMID: 16337171.

[edit] External links

• ATSDR Case Studies in Environmental Medicine: Cholinesterase Inhibitors, Including Pesticides and Chemical Warfare Nerve Agents U.S. Department of Health and Human Services
• Organophosphates - an article by Frances M Dyro, MD
• Pesticides Action Network, North America
• NYTimes: E.P.A. Recommends Limits On Thousands of Pesticides
• EPA OP pesticide site