Organophosphate poisoning
Encyclopedia
Organophosphate poisoning results from exposure to organophosphates (OPs), which cause the inhibition of acetylcholinesterase
(AChE) leading to the accumulation of acetylcholine
(ACh) in the body. Organophosphate poisoning most commonly results from exposure to insecticides or nerve agents. OPs are one of the most common causes of poisoning worldwide, and are frequently intentionally used in suicides in agrarian areas. There are around 1 million OP poisonings per year with several hundred thousand resulting in fatalities annually.
Organophosphates inhibit AChE, causing OP poisoning by phosphorylating the serine hydroxyl residue on AChE, which inactivates AChE. This causes disturbances across the cholinergic synapses and can only be reactivated very slowly, if at all. Paraoxonase
(PON1) is a key enzyme involved in OP pesticides and has been found to be critical in determining an organism’s sensitivity to OP exposure.
(NTE) in lymphocytes, and of acetylcholinesterase
(AChE) activity in red blood cells. Due to both AChE and BuChE being the main targets of organophosphates, their measurement is widely used as an indication of an exposure to an OP. The main restriction on this type of diagnosis is that depending on the OP the degree to which either AChE or BuChE are inhibited differs; therefore, measure of metabolites in blood and urine do not specify for a certain OP. However, for fast initial screening, determining AChE and BuChE activity in the blood are the most widely used procedures for confirming a diagnosis of OP poisoning.
Other procedures used in the diagnosis of OP exposure are the identification and qualitative analysis of nerve agents in the plasma after exposure. This method is highly sophisticated, but this analysis of unbound nerve agents is the most specific method for diagnosis. However, the drawback to this method of diagnosis is the short life-time of nerve agents in the body, which will limit the time frame in which exposure can be detected. Other methods of diagnosis include, analysis of protein adducts and the quantitative analysis of decomposition products in by the plasma and urine, but again due to the rapid elimination of the nerve agents in the body. One method that works to expand the time interval for diagnosis involves incubating blood or plasma levels with high fluoride concentration. The drawback to this method is that it can be used for retrospective detection of OP exposure, but cannot be used as a method for verification.
The effects of organophosphate poisoning are recalled using the mnemonic
SLUDGEM (Salivation, Lacrimation, Urination
, Defecation
, Gastrointestinal motility, Emesis, miosis
) An additional mnemonic is MUDDLES: miosis, urination, diarrhea, diaphoresis, lacrimation, excitation, and salivation.
Neurotoxic effects have also been linked to poisoning with OP pesticides and cause four neurotoxic effects in humans: cholinergic syndrome, intermediate syndrome, organophosphate-induced delayed polyneuropathy (OPIDP), and chronic organophosphate-induced neuropsychiatric disorder (COPIND). These syndromes result after acute and chronic exposure to OP pesticides.
Cholinergic syndrome occurs in acute poisonings with OP pesticides and is directly related to levels of AChE activity. Symptoms include miosis, sweating, lacrimation, gastrointestinal symtoms, respiratory difficultires, dyspnea, bradycardia, cyanosis, vomiting, diarrhea, as well as other symptoms. Along with these central effects can be seen and finally seizures, convulsions, coma, respiratory failure. If the person survives the first day of poisoning personality changes can occur, aggressive events, psychotic episodes, disturbances and deficits in memory and attention, as well as other delayed effects. When death occurs, it is most commonly due to respiratory failure from the combination of central and peripheral effects, paralysis of respiratory muscles and depression of the brain respiratory center. For people afflicted with cholinergic syndrome, atropine sulfate combined with an oxime is used to combat the effects of the acute OP poisoning. Diazepam is sometimes also administered in combination with the atropine and oximes.
The intermediate syndrome (IMS) appears in the interveal between the end of the cholinergic crisis and the onset of OPIDP. Symptoms associated with IMS manifest within 24-96 hours after exposure. The exact etiology, incidence, and risk factors associated with IMS are not clearly understood, but IMS is recognized as a disorder of neuromuscular junctions. IMS occurs when a person has a prolonged and severe inhibition of AChE and has been linked to specific OP pesticides such as methylparathion, dichlorvos, and parathion. Patients present with weakness of neck flexion and proximal limb muscle weakness, as well as respiratory deficiency. Recovery from IMS can occur within 5-18 days after the onset of the symptoms, as long as respiratory failure is promptly recognized and treated. Respiratory support, as well as atropine and oximes should be administered as soon as identified, since IMS is considered a life threatening syndrome.
In a small percentage of cases, roughly two weeks after exposure temporary paralysis occurs. This loss of function and ataxia of peripheral nerves and spinal cord is the phenomenon of OPIDP. Once the symptoms begin with shooting pains in both legs, the symptoms continue to worse for 3-6 months. In the most severe cases quadriplegia has been observed. Treatment only affects sensory nerves, not motor neurons which may permanently lose function. The aging and phosphorylation of more than 70% of functional NTE in peripheral nerves is one of the processes involved in OPIDP. Standard treatments for OP poisoning are ineffective for OPIDP.
COPIND occurs without cholinergic symptoms and is not dependent on AChE inhibition. COPIND appears with a delay and is long lasting. Symptoms associated with COPIND include cognitive deficit, mood change, autonomic dysfunction, peripheral neuropathy, and extrapyramidal symptoms. The underlying mechanisms of COPIND have not been determined, but it is hypothesized that withdrawal of OP pesticides after chronic exposure or acute exposure could be a factor.
Evidence of exposure to OP pesticides during gestation and early postnatal period have been linked to neurodevelopmental effects in animals, specifically rats. Animals exposed in utero to chlorpyrifos exhibited decreased balance, poorer cliff avoidance, decreased locomotion, delays in maize performance, and increased gait abnormalities. Early gestation is believed to be a critical time period for the neurodevelopmental affects of pesticides. OP’s affect the cholinergic system of fetuses, so exposure to chlorpyrifos during critical periods of brain development potentially could cause cellular, synaptic, and neurobehavioral abnormalities in animals. More research is being done on animals and human fetuses to determine the effects of OP’s during critical periods of development.
The use of the organophosphates in aviation lubricating oils and hydraulic fluid
s and its impact on health and flight safety is currently being researched. Aerotoxic Syndrome
is a medical condition allegedly caused by exposure to contaminated bleed air
.
Purdey (1998) suggested that organophosphates, in particular Phosmet
, induced the transmissible spongiform encephalopathy
epidemic of BSE
. A European Union
food safety Scientific Steering Committee examined the evidence and did not find a link.
in conjunction with pralidoxime
or other pyridinium
oxime
s (such as trimedoxime or obidoxime
), though the use of "-oximes" has been found to be of no benefit, or possibly harmful, in at least two meta-analyses. Atropine is a muscarinic antagonist, and thus blocks the action of acetylcholine peripherally. These antidotes are effective at preventing lethality from OP poisoning, but current treatment lack the ability to prevent post-exposure incapacitation, performance deficits, or permanent brain damage.
Enzyme bioscavengers are being developed as a pretreatment to sequester highly toxic OPs before they can reach their physiological targets and prevent the toxic effects from occurring. Significant advances with cholinesterases (ChEs), specifically human serum BChE (HuBChE) have been made. HuBChe can offer a broad range of protection for nerve agents including soman, sarin, tabun, and VX. HuBChE also posses a very long retention time in the human circulation system and because it is from a human source it will not produce any antagonistic immunological responses. HuBChE is currently being assessed for inclusion into the protective regimen against OP nerve agent poisoning. Currently there is potential for PON1 to be used to treat sarin exposure, but recombinant PON1 variants would need to first be generated to increase its catalytic efficiency.
One other agent that is being researched is the Class III anti-arrhythmic agents. Hyperkalemia of the tissue is one of the symptoms associated with OP poisoning. While the cellular processes leading to cardiac toxicity are not well understood, the potassium current channels are believed to be involved. Class II anti-arrhythmic agents block the potassium membrane currents in cardiac cells, which makes them a candidate for become a therapeutic of OP poisoning.
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 abortifacient
s and cooking oil
, respectively.
(FQPA), passed in 1996, designated the United States 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.
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.
Acetylcholinesterase
"Acetylcholinesterase, also known as AChE or acetylcholine acetylhydrolase, is an enzyme that degrades the neurotransmitter acetylcholine, producing choline and an acetate group. It is mainly found at neuromuscular junctions and cholinergic nervous system, where its activity serves to terminate...
(AChE) leading to the accumulation of acetylcholine
Acetylcholine
The chemical compound acetylcholine is a neurotransmitter in both the peripheral nervous system and central nervous system in many organisms including humans...
(ACh) in the body. Organophosphate poisoning most commonly results from exposure to insecticides or nerve agents. OPs are one of the most common causes of poisoning worldwide, and are frequently intentionally used in suicides in agrarian areas. There are around 1 million OP poisonings per year with several hundred thousand resulting in fatalities annually.
Organophosphates inhibit AChE, causing OP poisoning by phosphorylating the serine hydroxyl residue on AChE, which inactivates AChE. This causes disturbances across the cholinergic synapses and can only be reactivated very slowly, if at all. Paraoxonase
Paraoxonase
Paraoxonases are a group of enzymes involved in the hydrolysis of organophosphates.-History:PON was identified as an enzyme having organophosphates as its substrates. Reports of the geographic differences in population frequencies of paraoxonase activity and genetic analysis led to uncovering the...
(PON1) is a key enzyme involved in OP pesticides and has been found to be critical in determining an organism’s sensitivity to OP exposure.
Examples
- Insecticides including malathionMalathionMalathion is an organophosphate parasympathomimetic which binds irreversibly to cholinesterase. Malathion is an insecticide of relatively low human toxicity, however one recent study has shown that children with higher levels of organophosphate pesticide metabolites in their urine are more likely...
, parathionParathionParathion, also called parathion-ethyl or diethyl parathion, is an organophosphate compound. It is a potent insecticide and acaricide. It was originally developed by IG Farben in the 1940s. It is highly toxic to non-target organisms, including humans. Its use is banned or restricted in many...
, diazinonDiazinonDiazinon , a colorless to dark brown liquid, is a thiophosphoric acid ester developed in 1952 by Ciba-Geigy, a Swiss chemical company...
, fenthionFenthionFenthion is an organothiophosphate insecticide, avicide, and acaricide. Like most other organophosphates, its mode of action is via cholinesterase inhibition. Due to its relatively low toxicity towards humans and mammals, fenthion is listed as moderately toxic compound in U.S. Environmental...
, dichlorvosDichlorvosDichlorvos or 2,2-dichlorovinyl dimethyl phosphate is a highly volatile organophosphate, widely used as a insecticide to control household pests, in public health, and protecting stored product from insects. It is effective against mushroom flies, aphids, spider mites, caterpillars, thrips, and...
, chlorpyrifosChlorpyrifosChlorpyrifos is a crystalline organophosphate insecticide that inhibits acetylcholinesterase and is used to control insect pests. It is known by many trade names...
, ethionEthionEthion is an organophosphate insecticide.... - Nerve GasesNerve agentNerve agents are a class of phosphorus-containing organic chemicals that disrupt the mechanism by which nerves transfer messages to organs...
including somanSomanSoman, or GD , is an extremely toxic chemical substance. It is a nerve agent, interfering with normal functioning of the mammalian nervous system by inhibiting the cholinesterase enzyme. As a chemical weapon, it is classified as a weapon of mass destruction by the United Nations according to UN...
, sarinSarinSarin, or GB, is an organophosphorus compound with the formula [2CHO]CH3PF. It is a colorless, odorless liquid, which is used as a chemical weapon. It has been classified as a weapon of mass destruction in UN Resolution 687...
, tabunTabunTabun may refer to:* Tabun Cave, a cave near Tabun, Israel where remains of Neanderthal Man were found.* A tabun oven, a clay oven used to make tabun bread...
, VXVX (nerve agent)VX, IUPAC name O-ethyl S-[2-ethyl] methylphosphonothioate, is an extremely toxic substance whose only application is in chemical warfare as a nerve agent. As a chemical weapon, it is classified as a weapon of mass destruction by the United Nations in UN Resolution 687... - Ophthalmic agents: echothiophateEchothiophateEchothiophate is a parasympathomimetic and a phosphorothioate. It is an acetylcholinesterase inhibitor.- Uses :It is used as an ocular antihypertensive in the treatment of chronic glaucoma and, in some cases, accommodative esotropia...
, isoflurophate - AntihelminticsAnthelminticAnthelmintics or antihelminthics are drugs that expel parasitic worms from the body, by either stunning or killing them. They may also be called vermifuges or vermicides .-Pharmaceutical classes:...
such as trichlorfon - Herbicides including tribufos [DEF], merphos are tricresyl phosphate–containing industrial chemicals.
Diagnosis
A number of measurements exist to assess exposure and early biological effects for organophosphate poisoning. Measurements of OP metabolites in both the blood and urine can be used to determine if a person has been exposed to organophosphates. Specifically in the blood, metabolites of cholinesterases , such as butylrylcholinesterase (BuChE) activity in plasma, neuropathy target esteraseNeuropathy target esterase
Neuropathy target esterase also known as patatin-like phospholipase domain-containing protein 6 is a neuropathy target esterase enzyme that in humans is encoded by the PNPLA6 gene....
(NTE) in lymphocytes, and of acetylcholinesterase
Acetylcholinesterase
"Acetylcholinesterase, also known as AChE or acetylcholine acetylhydrolase, is an enzyme that degrades the neurotransmitter acetylcholine, producing choline and an acetate group. It is mainly found at neuromuscular junctions and cholinergic nervous system, where its activity serves to terminate...
(AChE) activity in red blood cells. Due to both AChE and BuChE being the main targets of organophosphates, their measurement is widely used as an indication of an exposure to an OP. The main restriction on this type of diagnosis is that depending on the OP the degree to which either AChE or BuChE are inhibited differs; therefore, measure of metabolites in blood and urine do not specify for a certain OP. However, for fast initial screening, determining AChE and BuChE activity in the blood are the most widely used procedures for confirming a diagnosis of OP poisoning.
Other procedures used in the diagnosis of OP exposure are the identification and qualitative analysis of nerve agents in the plasma after exposure. This method is highly sophisticated, but this analysis of unbound nerve agents is the most specific method for diagnosis. However, the drawback to this method of diagnosis is the short life-time of nerve agents in the body, which will limit the time frame in which exposure can be detected. Other methods of diagnosis include, analysis of protein adducts and the quantitative analysis of decomposition products in by the plasma and urine, but again due to the rapid elimination of the nerve agents in the body. One method that works to expand the time interval for diagnosis involves incubating blood or plasma levels with high fluoride concentration. The drawback to this method is that it can be used for retrospective detection of OP exposure, but cannot be used as a method for verification.
Symptoms
The health effects associated with organophosphate poisoning are a result of excess acetylcholine (ACh) present at different nerves and receptors in the body because acetyocholinesterase is blocked. Accumulation of ACh at motor nerves causes overstimulation of nicotinic expression at the neuromuscular junction. When this occurs symptoms such as muscle weakness, fatigue, muscle cramps, fasciculation, and paralysis can be seen. When there is an accumulation of ACh at autonomic ganglia this causes overstimulation of nicotinic expression in the sympathetic system. Symptoms associated with this are hypertension, increased heartbeat and blood pressure, hypertension, and hypoglycemia. Overstimulation of nicotinic receptors in the central nervous system, due to accumulation of ACh, results in anxiety, headache, convulsions, ataxia, depression of respiration and circulation, tremor, general weakness, and potentially coma. When there is expression of muscarinic overstiumation due to excess acetylcholine at muscarinic receptors symptoms of visual disturbances, tightness in chest, wheezing due to bronchoconstriction, increased bronchial secretions, increased salivation, acrimation, sweating, peristalsis, and urination can occur.The effects of organophosphate poisoning are recalled using the mnemonic
Mnemonic
A mnemonic , or mnemonic device, is any learning technique that aids memory. To improve long term memory, mnemonic systems are used to make memorization easier. Commonly encountered mnemonics are often verbal, such as a very short poem or a special word used to help a person remember something,...
SLUDGEM (Salivation, Lacrimation, Urination
Urination
Urination, also known as micturition, voiding, peeing, weeing, pissing, and more rarely, emiction, is the ejection of urine from the urinary bladder through the urethra to the outside of the body. In healthy humans the process of urination is under voluntary control...
, Defecation
Defecation
Defecation is the final act of digestion by which organisms eliminate solid, semisolid or liquid waste material from the digestive tract via the anus. Waves of muscular contraction known as peristalsis in the walls of the colon move fecal matter through the digestive tract towards the rectum...
, Gastrointestinal motility, Emesis, miosis
Miosis
Miosis is the constriction of the pupil of the eye to two millimeters or less...
) An additional mnemonic is MUDDLES: miosis, urination, diarrhea, diaphoresis, lacrimation, excitation, and salivation.
Health Effects
Certain reproductive effects in fertility, growth, and development for males and females have been linked specifically to OP pesticide exposure. Most of the research on reproductive effects has been conducted on farmers working with pesticides and insecticdes in rural areas. For those males exposed to OP pesticides, poor semen and sperm quality have been seen, including reduced seminal volume and percentage motility, as well as a decrease in sperm count per ejacuate. In females menstrual cycle disturbances, longer pregnancies, spontaneous abortions, stillbirths, and some developmental effects in offspring have been linked to OP pesticide exposure. Prenatal exposure has been linked to impaired fetal growth and development. The effects of OP exposure on infants and children are at this time currently being researched to come a conclusive finding.Neurotoxic effects have also been linked to poisoning with OP pesticides and cause four neurotoxic effects in humans: cholinergic syndrome, intermediate syndrome, organophosphate-induced delayed polyneuropathy (OPIDP), and chronic organophosphate-induced neuropsychiatric disorder (COPIND). These syndromes result after acute and chronic exposure to OP pesticides.
Cholinergic syndrome occurs in acute poisonings with OP pesticides and is directly related to levels of AChE activity. Symptoms include miosis, sweating, lacrimation, gastrointestinal symtoms, respiratory difficultires, dyspnea, bradycardia, cyanosis, vomiting, diarrhea, as well as other symptoms. Along with these central effects can be seen and finally seizures, convulsions, coma, respiratory failure. If the person survives the first day of poisoning personality changes can occur, aggressive events, psychotic episodes, disturbances and deficits in memory and attention, as well as other delayed effects. When death occurs, it is most commonly due to respiratory failure from the combination of central and peripheral effects, paralysis of respiratory muscles and depression of the brain respiratory center. For people afflicted with cholinergic syndrome, atropine sulfate combined with an oxime is used to combat the effects of the acute OP poisoning. Diazepam is sometimes also administered in combination with the atropine and oximes.
The intermediate syndrome (IMS) appears in the interveal between the end of the cholinergic crisis and the onset of OPIDP. Symptoms associated with IMS manifest within 24-96 hours after exposure. The exact etiology, incidence, and risk factors associated with IMS are not clearly understood, but IMS is recognized as a disorder of neuromuscular junctions. IMS occurs when a person has a prolonged and severe inhibition of AChE and has been linked to specific OP pesticides such as methylparathion, dichlorvos, and parathion. Patients present with weakness of neck flexion and proximal limb muscle weakness, as well as respiratory deficiency. Recovery from IMS can occur within 5-18 days after the onset of the symptoms, as long as respiratory failure is promptly recognized and treated. Respiratory support, as well as atropine and oximes should be administered as soon as identified, since IMS is considered a life threatening syndrome.
In a small percentage of cases, roughly two weeks after exposure temporary paralysis occurs. This loss of function and ataxia of peripheral nerves and spinal cord is the phenomenon of OPIDP. Once the symptoms begin with shooting pains in both legs, the symptoms continue to worse for 3-6 months. In the most severe cases quadriplegia has been observed. Treatment only affects sensory nerves, not motor neurons which may permanently lose function. The aging and phosphorylation of more than 70% of functional NTE in peripheral nerves is one of the processes involved in OPIDP. Standard treatments for OP poisoning are ineffective for OPIDP.
COPIND occurs without cholinergic symptoms and is not dependent on AChE inhibition. COPIND appears with a delay and is long lasting. Symptoms associated with COPIND include cognitive deficit, mood change, autonomic dysfunction, peripheral neuropathy, and extrapyramidal symptoms. The underlying mechanisms of COPIND have not been determined, but it is hypothesized that withdrawal of OP pesticides after chronic exposure or acute exposure could be a factor.
Evidence of exposure to OP pesticides during gestation and early postnatal period have been linked to neurodevelopmental effects in animals, specifically rats. Animals exposed in utero to chlorpyrifos exhibited decreased balance, poorer cliff avoidance, decreased locomotion, delays in maize performance, and increased gait abnormalities. Early gestation is believed to be a critical time period for the neurodevelopmental affects of pesticides. OP’s affect the cholinergic system of fetuses, so exposure to chlorpyrifos during critical periods of brain development potentially could cause cellular, synaptic, and neurobehavioral abnormalities in animals. More research is being done on animals and human fetuses to determine the effects of OP’s during critical periods of development.
The use of the organophosphates in aviation lubricating oils and hydraulic fluid
Hydraulic fluid
Hydraulic fluids, also called hydraulic liquids, are the medium by which power is transferred in hydraulic machinery. Common hydraulic fluids are based on mineral oil or water...
s and its impact on health and flight safety is currently being researched. Aerotoxic Syndrome
Aerotoxic syndrome
Aerotoxic syndrome is a term describing the alleged short-term and long-term ill-health effects that are attributed to exposure to cabin air that has been contaminated with atomized engine oils and other chemicals. The documentary film Welcome Aboard Toxic Airlines suggests the term was first...
is a medical condition allegedly caused by exposure to contaminated bleed air
Bleed air
Bleed air in gas turbine engines is compressed air taken from within the engine, after the compressor stage and before the fuel is injected in the burners. While in theory bleed air could be drawn in any gas turbine engine, its usage is generally restricted to jet engines used in aircraft...
.
Purdey (1998) suggested that organophosphates, in particular Phosmet
Phosmet
Phosmet is a phthalimide-derived, non-systemic, organophosphate insecticide used on plants and animals. It is mainly used on apple trees for control of coddling moth, though it is also used on a wide range of fruit crops, ornamentals, and vines for the control of aphids, suckers, mites, and fruit...
, induced the transmissible spongiform encephalopathy
Transmissible spongiform encephalopathy
Transmissible spongiform encephalopathies , also known as prion diseases, are a group of progressive conditions that affect the brain and nervous system of many animals, including humans. According to the most widespread hypothesis they are transmitted by prions, though some other data suggest an...
epidemic of BSE
Bovine spongiform encephalopathy
Bovine spongiform encephalopathy , commonly known as mad-cow disease, is a fatal neurodegenerative disease in cattle that causes a spongy degeneration in the brain and spinal cord. BSE has a long incubation period, about 30 months to 8 years, usually affecting adult cattle at a peak age onset of...
. A European Union
European Union
The European Union is an economic and political union of 27 independent member states which are located primarily in Europe. The EU traces its origins from the European Coal and Steel Community and the European Economic Community , formed by six countries in 1958...
food safety Scientific Steering Committee examined the evidence and did not find a link.
PON1 Influence
Paraoxonase (PON1) is a key enzyme in the metabolism of organophosphates. PON1 can inactivate some OPs through hydrolysis. PON1 hydrolyzes the active metabolites in several OP insecticides such as chlorpyrifos, oxon, and diazoxon, as well as, nerve agents such as soman, sarin, and VX. PON1 hydrolyzes the metabolites, not the parent compounds of insectides. The presence of PON1 polymorphisms causes there to be different enzyme levels and catalytic efficiency of this esterase, which in turn suggests that different individuals may be more susceptible to the toxic effect of OP exposure. The level of PON1 plasma hydrolytic activity provides more protection against OP pesticides. Rats injected with purified PON1 from rabbit serum were more resistant to acute cholinergic activity than the control rats. PON1 knockouts in mice are found to be more sensitive to the toxicity of pesticides, like chlorpyrifos. Animal experiments indicate that while PON1 plays a significant role in regulating the toxicity of OPs its degree of protection given depends on the compound (ie. Chlorpyrifos oxon or diazoxon). The catalytic efficiency with which PON1 can degrade toxic OPs determines the degree of protection that PON1 can provide for organism. The higher the concentration of PON1 the better the protection provided. PON1 activity is much lower in neonates, so neonates are more sensitive to OP exposure.Treatment
Current antidotes for OP poisoning consist of a pretreatment with carbamates to protect AChE from inhibition by OP compounds and post-exposure treatments with anti-cholinergic drugs. Anti-cholinergic drugs work to counteract the effects of access acetylcholine and reactivate AChE. Atropine can be used as an antidoteAntidote
An antidote is a substance which can counteract a form of poisoning. The term ultimately derives from the Greek αντιδιδοναι antididonai, "given against"....
in conjunction with pralidoxime
Pralidoxime
Pralidoxime or 2-PAM, usually as the chloride or methiodide salts, belongs to a family of compounds called oximes that bind to organophosphate-inactivated acetylcholinesterase. It is used to combat poisoning by organophosphates or acetylcholinesterase inhibitors , in conjunction with atropine and ...
or other pyridinium
Pyridinium
Pyridinium refers to the cationic form of pyridine. This can either be due to protonation of the ring nitrogen or because of addition of a substituent to the ring nitrogen, typically via alkylation. The lone pair of electrons on the nitrogen atom of pyridine is not delocalized, and thus pyridine...
oxime
Oxime
An oxime is a chemical compound belonging to the imines, with the general formula R1R2C=NOH, where R1 is an organic side chain and R2 may be hydrogen, forming an aldoxime, or another organic group, forming a ketoxime. O-substituted oximes form a closely related family of compounds...
s (such as trimedoxime or obidoxime
Obidoxime
Obidoxime is a member of the oxime family used to treat nerve gas poisoning. Oximes are drugs known for their ability to reverse the binding of organophosphorus compounds to the enzyme acetylcholinesterase ....
), though the use of "-oximes" has been found to be of no benefit, or possibly harmful, in at least two meta-analyses. Atropine is a muscarinic antagonist, and thus blocks the action of acetylcholine peripherally. These antidotes are effective at preventing lethality from OP poisoning, but current treatment lack the ability to prevent post-exposure incapacitation, performance deficits, or permanent brain damage.
Enzyme bioscavengers are being developed as a pretreatment to sequester highly toxic OPs before they can reach their physiological targets and prevent the toxic effects from occurring. Significant advances with cholinesterases (ChEs), specifically human serum BChE (HuBChE) have been made. HuBChe can offer a broad range of protection for nerve agents including soman, sarin, tabun, and VX. HuBChE also posses a very long retention time in the human circulation system and because it is from a human source it will not produce any antagonistic immunological responses. HuBChE is currently being assessed for inclusion into the protective regimen against OP nerve agent poisoning. Currently there is potential for PON1 to be used to treat sarin exposure, but recombinant PON1 variants would need to first be generated to increase its catalytic efficiency.
One other agent that is being researched is the Class III anti-arrhythmic agents. Hyperkalemia of the tissue is one of the symptoms associated with OP poisoning. While the cellular processes leading to cardiac toxicity are not well understood, the potassium current channels are believed to be involved. Class II anti-arrhythmic agents block the potassium membrane currents in cardiac cells, which makes them a candidate for become a therapeutic of OP poisoning.
Ginger Jake
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 gingerJamaican ginger
Jamaica Ginger extract was a late 19th century patent medicine that provided a convenient way to bypass Prohibition laws, since it contained between 70-80% ethanol by weight.-History:...
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 abortifacient
Abortifacient
An abortifacient is a substance that induces abortion. Abortifacients for animals that have mated undesirably are known as mismating shots....
s and cooking oil
Cooking oil
Cooking oil is purified fat of plant origin, which is usually liquid at room temperature ....
, respectively.
Governmental review
The U.S. Food Quality Protection ActFood Quality Protection Act
The Food Quality Protection Act , or H.R.1627, was passed unanimously by Congress in 1996 and was signed into law by former U.S. President Bill Clinton on August 3, 1996...
(FQPA), passed in 1996, designated the United States Environmental Protection Agency
United States Environmental Protection Agency
The U.S. Environmental Protection Agency is an agency of the federal government of the United States charged with protecting human health and the environment, by writing and enforcing regulations based on laws passed by Congress...
(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.
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.
Organophosphate Pesticides Reports
- Epidemiological study of the relationships between exposure to organophosphate pesticides and indices of chronic peripheral neuropathy, and neuropsychological abnormalities in sheep farmers and dippers.Phase 1. Development and validation of an organophosphate uptake model for sheep dippers by C Sewell and others. Institute of Occupational MedicineInstitute of Occupational MedicineThe Institute of Occupational Medicine was founded in 1969 by the National Coal Board as an independent charity. The IOM is a major independent centre of scientific excellence in the fields of occupational health and environmental health, occupational hygiene and occupational safety...
Research Report TM/99/02a
- Epidemiological study of the relationships between exposure to organophosphate pesticides and indices of chronic peripheral neuropathy, and neuropsychological abnormalities in sheep farmers and dippers. Phase 2. Cross-sectional exposure response study of sheep-dippers by A Pilkington and others. Institute of Occupational MedicineInstitute of Occupational MedicineThe Institute of Occupational Medicine was founded in 1969 by the National Coal Board as an independent charity. The IOM is a major independent centre of scientific excellence in the fields of occupational health and environmental health, occupational hygiene and occupational safety...
Research Report TM/99/02b
- Epidemiological study of the relationships between exposure to organophosphate pesticides and indices of chronic peripheral neuropathy, and neuropsychological abnormalities in sheep farmers and dippers. Phase 3. Clinical neurological, neurophysiological and neurophysiological study by A Pilkington and others. Institute of Occupational MedicineInstitute of Occupational MedicineThe Institute of Occupational Medicine was founded in 1969 by the National Coal Board as an independent charity. The IOM is a major independent centre of scientific excellence in the fields of occupational health and environmental health, occupational hygiene and occupational safety...
Research Report TM/99/02c