Organophosphate poisoning is

poisoning Poisoning is the harmful effect which occurs when Toxicity, toxic substances are introduced into the body. The term "poisoning" is a derivative of poison, a term describing any chemical substance that may harm or kill a living organism upon ...

due to

organophosphates In organic chemistry, organophosphates (also known as phosphate esters, or OPEs) are a class of organophosphorus compounds with the general structure , a central phosphate molecule with alkyl or aromatic substituents. They can be considered ...

(OPs). Organophosphates are used as

insecticides Insecticides are pesticides used to kill insects. They include ovicides and larvicides used against insect eggs and larvae, respectively. The major use of insecticides is in agriculture, but they are also used in home and garden settings, in ...

, medications, and

nerve agent Nerve agents, sometimes also called nerve gases, are a class of organic chemistry, organic chemicals that disrupt the mechanisms by which nerves transfer messages to organs. The disruption is caused by the blocking of acetylcholinesterase (ACh ...

s. Symptoms include increased saliva and tear production,

diarrhea Diarrhea (American English), also spelled diarrhoea or diarrhœa (British English), is the condition of having at least three loose, liquid, or watery bowel movements in a day. It often lasts for a few days and can result in dehydration d ...

, vomiting, small pupils, sweating, muscle tremors, and confusion. While onset of symptoms is often within minutes to hours, some symptoms can take weeks to appear. Symptoms can last for days to weeks. Organophosphate poisoning occurs most commonly as a

suicide attempt A suicide attempt is an act in which an individual tries to kill themselves but survives. Mental health professionals discourage describing suicide attempts as "failed" or "unsuccessful", as doing so may imply that a suicide resulting in death is ...

in farming areas of the

developing world A developing country is a sovereign state with a less-developed industrial base and a lower Human Development Index (HDI) relative to developed countries. However, this definition is not universally agreed upon. There is also no clear agreeme ...

and less commonly by accident. Exposure can be from drinking, breathing in the vapors, or skin exposure. The underlying mechanism involves the inhibition of acetylcholinesterase (AChE), leading to the buildup of

acetylcholine Acetylcholine (ACh) is an organic compound that functions in the brain and body of many types of animals (including humans) as a neurotransmitter. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Par ...

(ACh) in the body. Diagnosis is typically based on the symptoms and can be confirmed by measuring butyrylcholinesterase activity in the blood. Carbamate poisoning can present similarly. Prevention efforts include banning very toxic types of organophosphates. Among those who work with pesticides the use of protective clothing and showering before going home is also useful. In those who have organophosphate poisoning the primary treatments are

atropine Atropine is a tropane alkaloid and anticholinergic medication used to treat certain types of nerve agent and pesticide poisonings as well as some types of slow heart rate, and to decrease saliva production during surgery. It is typically give ...

oximes In organic chemistry, an oxime is an organic compound belonging to the imines, with the general formula , where R is an organic side-chain and R' may be hydrogen, forming an aldoxime, or another organic group, forming a ketoxime. O-substituted ...

such as pralidoxime, and

diazepam Diazepam, sold under the brand name Valium among others, is a medicine of the benzodiazepine family that acts as an anxiolytic. It is used to treat a range of conditions, including anxiety disorder, anxiety, seizures, alcohol withdrawal syndr ...

. General measures such as

oxygen Oxygen is a chemical element; it has chemical symbol, symbol O and atomic number 8. It is a member of the chalcogen group (periodic table), group in the periodic table, a highly reactivity (chemistry), reactive nonmetal (chemistry), non ...

and

intravenous fluids Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutr ...

are also recommended. Attempts to decontaminate the stomach, with

activated charcoal "Activated" is a song by English singer Cher Lloyd. It was released on 22 July 2016 through Vixen Records. The song was made available to stream exclusively on ''Rolling Stone'' a day before to release (on 21 July 2016). Background In an inter ...

or other means, have not been shown to be useful. While there is a theoretical risk of health care workers taking care of a poisoned person becoming poisoned themselves, the degree of risk appears to be very small. OPs are one of the most common causes of poisoning worldwide. There are nearly 3 million poisonings per year resulting in two hundred thousand deaths. Around 15% of people who are poisoned die as a result. Organophosphate poisoning has been reported at least since 1962. It is considered the primary cause of Gulf War syndrome.

Signs and symptoms

The symptoms of organophosphate poisoning include muscle weakness, fatigue, muscle cramps, fasciculation, and paralysis. Other symptoms include hypertension, and hypoglycemia. Overstimulation of

nicotinic acetylcholine receptors Nicotinic acetylcholine receptors, or nAChRs, are receptor polypeptides that respond to the neurotransmitter acetylcholine. Nicotinic receptors also respond to drugs such as the agonist nicotine. They are found in the central and peripheral ner ...

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 overstimulation due to excess acetylcholine at muscarinic acetylcholine receptors symptoms of visual disturbances, tightness in chest, wheezing due to bronchoconstriction, increased bronchial secretions, increased salivation, lacrimation, sweating, peristalsis, and urination can occur. The effects of organophosphate poisoning on muscarinic receptors are recalled using the

mnemonic A mnemonic device ( ), memory trick or memory device is any learning technique that aids information retention or retrieval in the human memory, often by associating the information with something that is easier to remember. It makes use of e ...

SLUDGEM ( salivation,

lacrimation Tears are a clear liquid secreted by the lacrimal glands (tear gland) found in the eyes of all land mammals. Tears are made up of water, electrolytes, proteins, lipids, and mucins that form layers on the surface of eyes. The different types of ...

urination Urination is the release of urine from the bladder through the urethra in Placentalia, placental mammals, or through the cloaca in other vertebrates. It is the urinary system's form of excretion. It is also known medically as micturition, v ...

defecation Defecation (or defaecation) follows digestion and is the necessary biological process by which organisms eliminate a solid, semisolid, or liquid metabolic waste, waste material known as feces (or faeces) from the digestive tract via the anus o ...

gastrointestinal motility Gastrointestinal physiology is the branch of Human body, human physiology that addresses the physical function of the Human gastrointestinal tract, gastrointestinal (GI) tract. The function of the GI tract is to process ingested food by mechanical ...

emesis Vomiting (also known as emesis, puking and throwing up) is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose. Vomiting can be the result of ailments like food poisoning, gastroenteritis, pregna ...

miosis Miosis, or myosis (), is excessive constriction of the pupil.Farlex medical dictionary
citing: ...

) An additional mnemonic is MUDDLES: miosis, urination, diarrhea, diaphoresis, lacrimation, excitation, and salivation. These mnemonics do not take into account the critical CNS and nicotinic effects of organophosphates. The onset and severity of symptoms, whether acute or chronic, depends upon the specific chemical, the route of exposure (skin, lungs, or GI tract), the dose, and the individuals ability to degrade the compound, which the PON1 enzyme level will affect.

Reproductive 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 insecticides 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 ejaculate. 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 to a conclusive finding. Evidence of OP exposure in pregnant mothers are linked to several health effects in the fetus. Some of these effects include delayed mental development,

Pervasive developmental disorder The diagnostic category pervasive developmental disorders (PDD), as opposed to specific developmental disorders (SDD), was a group of disorders characterized by delays in the development of multiple basic functions including socialization and ...

(PDD), morphological abnormalities in the cerebral surface.

Neurotoxic effects

Neurotoxic effects have also been linked to poisoning with OP pesticides causing 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 symptoms, respiratory difficulties,

shortness of breath Shortness of breath (SOB), known as dyspnea (in AmE) or dyspnoea (in BrE), is an uncomfortable feeling of not being able to breathe well enough. The American Thoracic Society defines it as "a subjective experience of breathing discomfort that con ...

, slowed heart rate,

cyanosis Cyanosis is the change of Tissue (biology), tissue color to a bluish-purple hue, as a result of decrease in the amount of oxygen bound to the hemoglobin in the red blood cells of the capillary bed. Cyanosis is apparent usually in the Tissue (bi ...

, vomiting, diarrhea, trouble sleeping, 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, in addition to aggressive behavior, psychotic episodes, memory and attention disturbances, and other delayed effects. When death occurs, it is most commonly due to respiratory failure due to paralysis of respiratory muscles and depression of central nervous system, which is responsible for respiration. For people affected by cholinergic syndrome,

sulfate combined with an

oxime In organic chemistry, an oxime is an organic compound belonging to the imines, with the general Chemical formula, formula , where R is an organic Side chain, side-chain and R' may be hydrogen, forming an aldoxime, or another organic functional g ...

is used to combat the effects of the acute OP poisoning.

Diazepam Diazepam, sold under the brand name Valium among others, is a medicine of the benzodiazepine family that acts as an anxiolytic. It is used to treat a range of conditions, including anxiety disorder, anxiety, seizures, alcohol withdrawal syndr ...

is sometimes also administered if convulsions or muscle

fasciculation A fasciculation, or muscle twitch, is a spontaneous, involuntary muscle contraction and relaxation, involving fine muscle fibers. They are common, with as many as 70% of people experiencing them. They can be benign, or associated with more seriou ...

s begin. The intermediate syndrome (IMS) appears in the interval between the end of the cholinergic crisis and the onset of OPIDP. Symptoms associated with IMS manifest between 24 and 96 hours after exposure. The exact etiology, incidence, and risk factors associated with IMS are not well understood, but IMS is recognized as a disorder of

neuromuscular junctions A neuromuscular junction (or myoneural junction) is a chemical synapse between a motor neuron and a muscle fiber. It allows the motor neuron to transmit a signal to the muscle fiber, causing muscle contraction. Muscles require innervation to ...

. IMS occurs when a person has a prolonged and severe inhibition of AChE. It has been linked to specific OP pesticides such as parathion, methylparathion, and dichlorvos. Patients generally present with increasing weakness in the facial, neck flexor, and respiratory muscles. OPIDP occurs in a small percentage of cases, roughly two weeks after exposure, where 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 worsen 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 independent of AChE inhibition. COPIND appears with a delay and is long lasting. Symptoms associated with COPIND include cognitive deficit, mood changes, 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.

Pregnancy

Evidence of exposure to OP pesticides during

gestation Gestation is the period of development during the carrying of an embryo, and later fetus, inside viviparous animals (the embryo develops within the parent). It is typical for mammals, but also occurs for some non-mammals. Mammals during pregn ...

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 maze performance, and increased gait abnormalities. Early gestation is believed to be a critical time period for the neurodevelopmental effects of pesticides. OPs 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. In rats exposed to methylparathion, studies found reduced AChE activity in all brain regions and subtle alterations in behaviors such as locomotor activity and impaired cage emergence. Organophosphates as whole have been linked to decreases in the length of limbs, head circumference, and slower rates of postnatal weight gain in mice.

Cancer

The International Agency for Research on Cancer (IARC) found that organophosphate exposure may increase cancer risk. Tetrachlorvinphos and

parathion Parathion, also called parathion-ethyl or diethyl parathion, is an organophosphate insecticide and acaricide. It was originally developed by IG Farben in the 1940s. It is highly toxic to non-target organisms, including humans, so its use has been ...

were classified as "possibly carcinogenic",

malathion Malathion is an organophosphate insecticide which acts as an acetylcholinesterase inhibitor. In the USSR, it was known as carbophos, in New Zealand and Australia as maldison and in South Africa as mercaptothion. The compound's name is presumably ...

, and

diazinon Diazinon (IUPAC name: ''O'',''O''-Diethyl ''O''- -methyl-6-(propan-2-yl)pyrimidin-2-ylphosphorothioate, INN - Dimpylate), a colorless to dark brown liquid, is a thiophosphoric acid ester developed in 1952 by Ciba-Geigy, a Swiss chemical company ...

Cause

OP poisoning typically occurs after exposure to OP pesticides by inhalation, ingestion and dermal contact. OP pesticides have been considered relatively safe, given their tendency to degrade quickly when exposed to air and light; however, residues may remain on fruits and vegetables. Certain OP pesticides have been banned for use on some crops, For example, methyl parathion is banned from use on some crops and permitted on others. It can also occur through deliberate poisoning using nerve agents such as

sarin Sarin (NATO designation GB nerve_agent#G-series.html" ;"title="hort for nerve agent#G-series">G-series, "B" is an extremely toxic organophosphorus compound.tabun.

Examples

Insecticides Insecticides are pesticides used to kill insects. They include ovicides and larvicides used against insect eggs and larvae, respectively. The major use of insecticides is in agriculture, but they are also used in home and garden settings, in ...

including

fenthion Fenthion 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 mo ...

dichlorvos Dichlorvos (2,2-dichlorovinyl dimethyl phosphate, commonly abbreviated as an DDVP) is an organophosphate widely used as an insecticide to control household pests, in public health, and protecting stored products from insects. The compound has be ...

chlorpyrifos Chlorpyrifos (CPS), also known as chlorpyrifos ethyl, is an organophosphate pesticide that has been used on crops, animals, in buildings, and in other settings, to kill several pests, including insects and worms. It acts on the nervous systems ...

, ethion,

trichlorfon Metrifonate ( INN) or trichlorfon ( USAN) is an irreversible organophosphate acetylcholinesterase inhibitor. It is a prodrug which is activated non-enzymatically into the active agent dichlorvos. It is used as an insecticide. According to the US ...

Nerve agent Nerve agents, sometimes also called nerve gases, are a class of organic chemistry, organic chemicals that disrupt the mechanisms by which nerves transfer messages to organs. The disruption is caused by the blocking of acetylcholinesterase (ACh ...

s including soman,

sarin Sarin (NATO designation GB nerve_agent#G-series.html" ;"title="hort for nerve agent#G-series">G-series, "B" is an extremely toxic organophosphorus compound.tabun, VX *

Herbicides Herbicides (, ), also commonly known as weed killers, are substances used to control undesired plants, also known as weeds.EPA. February 201Pesticides Industry. Sales and Usage 2006 and 2007: Market Estimates. Summary in press releasMain page f ...

including tribufos EF merphos are tricresyl phosphate–containing industrial chemicals. The U.S.

Environmental Protection Agency Environmental Protection Agency may refer to the following government organizations: * Environmental Protection Agency (Queensland), Australia * Environmental Protection Agency (Ghana) * Environmental Protection Agency (Ireland) * Environmenta ...

maintains an extensive list of commercially-sold organophosphate products for anyone worried about possible exposure. It can be foun
here
(in the blue sidebars of the document). Exposure to any of the above-listed organophosphates may occur through inhalation, skin absorption, and ingestion, most commonly of food that has been treated with an OP herbicide or insecticide. Exposure to these chemicals can occur at public buildings, schools, residential areas, and in agricultural areas. Chlorpyrifos and Malathion have been linked to reproductive effects,

neurotoxicity Neurotoxicity is a form of toxicity in which a biological, chemical, or physical agent produces an adverse effect on the structure or function of the central and/or peripheral nervous system. It occurs when exposure to a substance – specifical ...

, kidney/liver damage, and birth defects. Dichlorvos has also been linked to reproductive effects, neurotoxicity, and kidney/liver damage. It is also recognized to be a possible carcinogen.

Pathophysiology

The health effects associated with organophosphate poisoning are a result of excess

(ACh) present at different nerve

synapse In the nervous system, a synapse is a structure that allows a neuron (or nerve cell) to pass an electrical or chemical signal to another neuron or a target effector cell. Synapses can be classified as either chemical or electrical, depending o ...

s and

neuromuscular junction A neuromuscular junction (or myoneural junction) is a chemical synapse between a motor neuron and a muscle fiber. It allows the motor neuron to transmit a signal to the muscle fiber, causing muscle contraction. Muscles require innervation to ...

s across the body. Specifically,

acetylcholinesterase Acetylcholinesterase (HUGO Gene Nomenclature Committee, HGNC symbol ACHE; EC 3.1.1.7; systematic name acetylcholine acetylhydrolase), also known as AChE, AChase or acetylhydrolase, is the primary cholinesterase in the body. It is an enzyme th ...

(AChE), the enzyme that normally and constantly breaks down acetylcholine, is inhibited by the organophosphate substance. ACh accumulates in the

parasympathetic nervous system The parasympathetic nervous system (PSNS) is one of the three divisions of the autonomic nervous system, the others being the sympathetic nervous system and the enteric nervous system. The autonomic nervous system is responsible for regulat ...

, the

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain, spinal cord and retina. The CNS is so named because the brain integrates the received information and coordinates and influences the activity o ...

, and in nicotinic neuromuscular junctions.Vohra, Rais (2022). "Organophosphorus and carbamate insecticides". ''Poisoning & Drug Overdose'' (8th ed.). McGraw Hill. Organophosphate inhibition of AChE may be reversible or irreversible, depending on whether

covalent bonding A covalent bond is a chemical bond that involves the sharing of electrons to form electron pairs between atoms. These electron pairs are known as shared pairs or bonding pairs. The stable balance of attractive and repulsive forces between atoms ...

(also called "aging" in this context) occurs. Chemically, organophosphates cause poisoning by phosphorylating the

serine Serine (symbol Ser or S) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α- amino group (which is in the protonated − form under biological conditions), a carboxyl group (which is in the deprotonated − ...

hydroxyl residue on AChE, which inactivates AChE. This causes disturbances across the

cholinergic Cholinergic agents are compounds which mimic the action of acetylcholine and/or butyrylcholine. In general, the word " choline" describes the various quaternary ammonium salts containing the ''N'',''N'',''N''-trimethylethanolammonium cation ...

synapses and can only be reactivated very slowly, if at all. Paraoxonase 1 ( PON1) is a key enzyme involved in organophosphate toxicity and has been found to be critical in determining an organism's sensitivity to organophosphate exposure.

Sensitivity

PON1 can inactivate some OPs through

hydrolysis Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution reaction, substitution, elimination reaction, elimination, and solvation reactions in which water ...

. PON1 hydrolyzes the active

metabolites In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...

in several OP insecticides such as

chlorpyrifos oxon Chlorpyrifos (CPS), also known as chlorpyrifos ethyl, is an organophosphate pesticide that has been used on crops, animals, in buildings, and in other settings, to kill several pest (organism), pests, including insects and worms. It acts on the n ...

, and diazoxon, as well as nerve agents such as soman,

sarin Sarin (NATO designation GB nerve_agent#G-series.html" ;"title="hort for nerve agent#G-series">G-series, "B" is an extremely toxic organophosphorus compound.VX. PON1 hydrolyzes the metabolites, not the parent compounds of insectides. PON1

gene polymorphism A gene is said to be polymorphic if more than one allele occupies that gene's Locus (genetics), locus within a population. In addition to having more than one allele at a specific locus, each allele must also occur in the population at a rate of ...

can lead to a variety of different enzyme levels and catalytic efficiency of this

esterase In biochemistry, an esterase is a class of enzyme that splits esters into an acid and an alcohol in a chemical reaction with water called hydrolysis (and as such, it is a type of hydrolase). A wide range of different esterases exist that differ ...

, which in turn suggests that different individuals may be more or less susceptible to the toxic effect of OP exposure. Higher levels of PON1 plasma hydrolytic activity provide a greater degree of protection against OP pesticides. Rats injected with purified PON1 from rabbit serum were more resistant to acute

activity than the control rats. PON1 knockouts in mice are found to be more sensitive to the toxicity of pesticides, like

. 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 (i.e. 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 In common terminology, a baby is the very young offspring of adult human beings, while infant (from the Latin word ''infans'', meaning 'baby' or 'child') is a formal or specialised synonym. The terms may also be used to refer to Juvenile (orga ...

, so neonates are more sensitive to OP exposure. In 2006, up to a 13-fold degree of variation was seen in PON1 levels in adults; connected findings showed that biological sensitivity to diazoxon showed similar or even greater variance.

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 butyrylcholinesterase (BuChE) activity in plasma, neuropathy target esterase (NTE) in lymphocytes, and of

(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 which OP agent is responsible for the poisoning. 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. The most widely used portable testing device is the Test-mate ChE field test, which can be used to determine levels of Red Blood Cells (RBC), AChE and plasma (pseudo) cholinesterase (PChE) in the blood in about four minutes. This test has been shown to be just as effective as a regular laboratory test and because of this, the portable ChE field test is frequently used by people who work with pesticides on a daily basis.

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 excess acetylcholine and reactivate AChE.

Atropine Atropine is a tropane alkaloid and anticholinergic medication used to treat certain types of nerve agent and pesticide poisonings as well as some types of slow heart rate, and to decrease saliva production during surgery. It is typically give ...

can be used as an

antidote An antidote is a substance that can counteract a form of poisoning. The term ultimately derives from the Greek term φάρμακον ἀντίδοτον ''(pharmakon antidoton)'', "(medicine) given as a remedy". An older term in English which is ...

in conjunction with pralidoxime or other pyridinium

s (such as trimedoxime or obidoxime), though the use of "-

" has been found to be of no benefit, or to be possibly harmful, in at least two

meta-analyses Meta-analysis is a method of synthesis of quantitative data from multiple independent studies addressing a common research question. An important part of this method involves computing a combined effect size across all of the studies. As such, th ...

. 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 treatments lack the ability to prevent post-exposure incapacitation, performance deficits, or permanent brain damage. While the efficacy of atropine has been well-established, clinical experience with pralidoxime has led to widespread doubt about its efficacy in treatment of OP poisoning. 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 The enzyme cholinesterase (EC 3.1.1.8, choline esterase; systematic name acylcholine acylhydrolase) catalyses the hydrolysis of choline-based esters: : an acylcholine + H2O = choline + a carboxylate Several of these serve as neurotransmitter ...

(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 possess 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. Another potential treatment being researched is the Class III anti-arrhythmic agents.

Hyperkalemia Hyperkalemia is an elevated level of potassium (K+) in the blood. Normal potassium levels are between 3.5 and 5.0 mmol/L (3.5 and 5.0 mEq/L) with levels above 5.5mmol/L defined as hyperkalemia. Typically hyperkalemia does not cause symptoms. Oc ...

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 III anti-arrhythmic agents block the potassium membrane currents in cardiac cells, which makes them a candidate for become a therapeutic of OP poisoning. There is insufficient evidence to support using plasma alkalinisation to treat a person with organophosphate poisoning.

Epidemiology

Organophosphate pesticides are one of the top causes of poisoning worldwide, with an annual incidence of poisonings among agricultural workers varying from 3-10% per country.

History

Ginger Jake

A striking example of OPIDN occurred during the 1930s

Prohibition Era Prohibition is the act or practice of forbidding something by law; more particularly the term refers to the banning of the manufacturing, manufacture, storage (whether in barrels or in bottles), transportation, sale, possession, and consumption ...

when thousands of men in the

American South The Southern United States (sometimes Dixie, also referred to as the Southern States, the American South, the Southland, Dixieland, or simply the South) is census regions United States Census Bureau. It is between the Atlantic Ocean and the ...

and

Midwest The Midwestern United States (also referred to as the Midwest, the Heartland or the American Midwest) is one of the four census regions defined by the United States Census Bureau. It occupies the northern central part of the United States. It ...

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 neurological damage. The damage resulted in the limping "Jake Leg" or "Jake Walk" which were terms frequently used in the

blues Blues is a music genre and musical form that originated among African Americans in the Deep South of the United States around the 1860s. Blues has incorporated spiritual (music), spirituals, work songs, field hollers, Ring shout, shouts, cha ...

music of the period. Europe and

Morocco Morocco, officially the Kingdom of Morocco, is a country in the Maghreb region of North Africa. It has coastlines on the Mediterranean Sea to the north and the Atlantic Ocean to the west, and has land borders with Algeria to Algeria–Morocc ...

both experienced outbreaks of TOCP poisoning from contaminated

abortifacient An abortifacient ("that which will cause a miscarriage" from Latin: '' abortus'' "miscarriage" and '' faciens'' "making") is a substance that induces abortion. This is a nonspecific term which may refer to any number of substances or medications, ...

s and

cooking oil Cooking oil (also known as edible oil) is a plant or animal liquid fat used in frying, baking, and other types of cooking. Oil allows higher cooking temperatures than water, making cooking faster and more flavorful, while likewise distributing h ...

, respectively.

Gulf War syndrome

Research has linked the neurological abnormalities found in

Persian Gulf War , combatant2 = , commander1 = , commander2 = , strength1 = Over 950,000 soldiers3,113 tanks1,800 aircraft2,200 artillery systems , page = https://www.govinfo.gov/content/pkg/GAOREPORTS-PEMD-96- ...

veteran A veteran () is a person who has significant experience (and is usually adept and esteemed) and expertise in an job, occupation or Craft, field. A military veteran is a person who is no longer serving in the military, armed forces. A topic o ...

s who have chronic multisymptom illnesses to exposure to wartime combinations of organophosphate chemical nerve agents. Before, it was believed that veterans had a psychologically based disorder or depression, most likely

post-traumatic stress disorder Post-traumatic stress disorder (PTSD) is a mental disorder that develops from experiencing a Psychological trauma, traumatic event, such as sexual assault, domestic violence, child abuse, warfare and its associated traumas, natural disaster ...

(PTSD). Many veterans were given pyridostigmine bromide (PB) pills to protect against nerve gas agents such as

sarin Sarin (NATO designation GB nerve_agent#G-series.html" ;"title="hort for nerve agent#G-series">G-series, "B" is an extremely toxic organophosphorus compound.soman. During the war veterans were exposed to combinations of organophosphate pesticides and nerve agents, which produced symptoms associated with chronic organophosphate-induced delayed polyneuropathy (OPIDP) syndrome. Similar symptoms found in the veterans were the same symptoms reported for individuals in occupational settings who were acutely poisoned by organophosphates, such as

. Studies found veterans experienced deficits in intellectual and academic abilities, simple motor skills, memory impairment, and impaired emotional function. These symptoms indicate brain damage, not a psychologically based disorder.

Society and culture

United States

Under a 1988 amendment to the Federal Insecticide, Fungicide and Rodenticide Act (FIFRA), the U.S.

(EPA) regulates organophosphate pesticides Its focus was initially on registering pesticides for use on food crops. No pesticide can be sold in the United States before the EPA has reviewed the manufacturer's application for registration and determined that the use of the product will not present an unreasonable risk to the public or the environment. In 1996, with the passage of the Food Quality Protection Act, Congress required the EPA to reassess all existing pesticide tolerances with specific consideration for children. This resulted in a 10-year review process of the health and environmental effects of all pesticides, beginning with the organophosphates. As part of that process, in 1999 the EPA announced a ban the use of organophosphate pesticide methyl parathion and significant restrictions on the use of another OP, azinphos methyl, in what they called "kid's food". The review process was concluded in 2006 and eliminated or modified thousands of other uses of pesticides.Janofsky, Michael
"E.P.A. Recommends Limits On Thousands of Pesticides"
, ''

The New York Times ''The New York Times'' (''NYT'') is an American daily newspaper based in New York City. ''The New York Times'' covers domestic, national, and international news, and publishes opinion pieces, investigative reports, and reviews. As one of ...

'', August 4, 2006, accessed April 1, 2008. Other legislative action has been taken to protect children from the risks of organophosphates. Many non-governmental and research groups, as well as the EPA's Office of Inspector General, have expressed 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
New studies have shown toxicity to developing organisms during certain "critical periods" at doses much lower than those previously suspected to cause harm. Even the restrictions which did successfully pass have been controversial. For example, in 1999 the EPA restricted the use of

in households (under the commercial name Dursban). However, the EPA did not limit its use in agriculture. Chlorpyrifos remains one of the most widely used pesticides. This may soon change. On February 8, 2013, the EPA requested comment on a preliminary evaluation of the potential risks to children and other bystanders from

volatilization Pesticide drift, also known as spray drift, is the unintentional diffusion of pesticides toward nontarget species. It is one of the most negative effects of pesticide application. Drift can damage human health, environment, and crops. Together ...

of chlorpyrifos from treated crops

Vulnerable groups

Some populations are more vulnerable to pesticide poisoning. In the United States, farmworkers can be exposed via direct spray, drift, spills, direct contact with treated crops or soil, or defective or missing protective equipment.Human Rights Council. Report of the Special Rapporteur on the right to food. 2017; General Assembly, 34th session, Agenda item 3. Migrant workers may be at an especially high risk of chronic exposure as over the course of a growing season, they may work at multiple farms, thus increasing their exposure to pesticides. Farmworkers in more permanent positions may receive more safety training and/or more "consistent reinforcement of safety behaviors than seasonal farmworkers or day laborers." For migrant farmworkers, language barriers and/or education level could be a barrier to understanding posted warning signs, labels and safety warnings located on the pesticides, or understanding any safety training that is provided. Other factors that may lead to greater exposure for the migrant farmworker population include: limited or no access to safety equipment, little to no control over pesticide use, cultural factors, and fear of job loss if they report potential hazards.Pesticide Safety. Studies have also shown that there are some key beliefs by farmworkers that may exacerbate pesticide exposure, including the belief that "pesticides must be felt, seen, tasted, or smelled to be present; the skin blocks absorption and body openings facilitate it; exposure occurs only when a pesticide is wet;…and acute, not low-level chronic exposure is the primary danger." This, coupled with the difficulty or uncertainty of recognizing and/or diagnosing chronic pesticide poisoning by the medical community, makes it difficult for exposed workers to receive an effective remedy. Migrant workers may also be hesitant to seek-out medical care due to lack of health insurance, language barriers, immigration status, cost, cultural factors, lack of transportation, fear of job loss, and lack of awareness of workers' compensation benefits.

Sergei and Yulia Skripal

In March 2018, Sergei Skripal and his daughter were poisoned in

Salisbury Salisbury ( , ) is a city status in the United Kingdom, cathedral city and civil parish in Wiltshire, England with a population of 41,820, at the confluence of the rivers River Avon, Hampshire, Avon, River Nadder, Nadder and River Bourne, Wi ...

, England, with an organophosphate poison known as a Novichok agent. Both fell unconscious while sitting on a park bench. A

first responder A first responder is a person with specialized training who is among the first to arrive and provide assistance or incident resolution at the scene of an emergency. First responders typically include Law enforcement, law enforcement officers (co ...

to the scene also became contaminated and had symptoms of organophosphate poisoning. All three survived after hospital treatment. Despite continually denying responsibility for the attack, Russia is suspected to be behind the poisonings.

Alexei Navalny

On 20 August 2020, Russian politician

Alexei Navalny Alexei Anatolyevich Navalny (, ; 4 June 197616 February 2024) was a Russian Opposition to Vladimir Putin in Russia, opposition leader, anti-corruption in Russia, corruption activist and political prisoner. He founded the Anti-Corruption Found ...

developed life-threatening acute poisoning symptoms on a flight. He was later transferred to

Berlin Berlin ( ; ) is the Capital of Germany, capital and largest city of Germany, by both area and List of cities in Germany by population, population. With 3.7 million inhabitants, it has the List of cities in the European Union by population withi ...

, where poisoning by a

cholinesterase inhibitor Cholinesterase inhibitors (ChEIs), also known as anti-cholinesterase, are chemicals that prevent the breakdown of the neurotransmitter acetylcholine or butyrylcholine by cholinesterase. This increases the amount of the acetylcholine or butyryl ...

was diagnosed and confirmed by multiple tests in independent laboratories.

References

{{DEFAULTSORT:Organophosphate Poisoning Toxic effects of substances chiefly nonmedicinal as to source Organophosphates Wikipedia medicine articles ready to translate Wikipedia emergency medicine articles ready to translate Medical mnemonics