Organophosphates (OPs) are chemical substances originally produced by the reaction of alcohols and phosphoric acid. In the 1930s, organophosphates were used as insecticides, but the German military developed these substances as neurotoxins in World War II. They function as cholinesterase inhibitors, thereby affecting neuromuscular transmission.
Organophosphate insecticides, such as diazinon, chlorpyrifos, disulfoton, azinphos-methyl, and fonofos, have been used widely in agriculture and in household applications as pesticides. Over 25,000 brands of pesticides are available in the United States, and their use is monitored by the Environmental Protection Agency (EPA).
Diazinon was sold in the United States for 48 years with 14.7 million pounds sold annually. It was the most widely used ingredient in lawn and garden sprays in the United States. Diazinon was found under the brand names Real Kill, Ortho, and Spectracide. In the past decade, the EPA reached an agreement with the pesticide industry to end the production of diazinon by March 2001 for indoor use and June 2003 for lawn and garden use. Chlorpyrifos (Dursban) was involved in a negotiated phaseout in June 2000. These phaseouts resulted from recognition of the special risk that these substances posed for children. Four percent of patients presenting to poison control centers report pesticide exposure. Of those patients, 34% are children younger than 6 years.
Toxic nerve agents used by the military are often of the organophosphate group; an example is sarin, the nerve gas used in a terrorist action in Tokyo in 1995. In anticipation of military use of OP neurotoxins during the Gulf War, the US military was given prophylactic agents which some believe caused some of the symptoms of Gulf War syndrome.
With the emergence of the West Nile virus in the northeastern United States, programs of spraying have been implemented in large urban areas, in particular New York's Central Park.
Controversy exists regarding the long-term effects of exposure to low levels of potentially neurotoxic substances.[1]
Therapeutic uses of organophosphates
Several organophosphate agents are being tried therapeutically. Cholinesterase inhibition, which in large doses makes these agents effective pesticides, also may be useful in other doses for treating dementia. Metrifonate has been used to treat schistosomiasis and is undergoing trials for the treatment of primary degenerative dementia.
The organophosphates pyridostigmine and physostigmine are carbamate anticholinesterases that have been used for many years for the treatment of myasthenia gravis. Although the short-duration anticholinesterases are generally safe, reports of their abuse are associated with a picture similar to pesticide intoxication.
One of the author's patients had been diagnosed erroneously as a myasthenic. Long-term "therapeutic" doses of physostigmine chemically altered her neuromuscular junctions to the point where she had to be slowly weaned from the drug.
Sung and others have reported on the ability of these substances to induce nicotinic receptor modulation.[2] This explains the action of these drugs and may result in development of more effective agents.
Historic and new uses of organophosphates
The first organophosphate was synthesized in 1850. Physostigmine was used to treat glaucoma in the 1870s. By the 1930s, synthetic cholinesterase inhibitors were being used for skeletal muscle and autonomic disorders. Some organophosphates were tried in the treatment of parkinsonism.
In 1986, testing began for tacrine, the first cholinesterase inhibitor to be tried for Alzheimer disease; it was released for clinical use in 1993. It is no longer in use. The blood-brain barrier has been the limiting factor in developing a cholinesterase inhibitor for use in dementia. Drugs such as rivastigmine are now widely used. Reported adverse effects are nausea and vomiting, with resultant weight loss because of the increase in cholinergic activity. It has been shown to be useful in mild to moderately severe Alzheimer disease.
Pyridostigmine has been tried for the fatigue of postpolio syndrome but showed no benefit.[3]
The mechanism of action, on both target and nontarget species, is irreversible inhibition of acetylcholinesterase (AchE). Acetylcholinesterase is found in red blood cells and in nicotinic and muscarinic receptors in nerve, muscle, and gray matter of the brain. Plasma acetylcholinesterase is found in CNS white matter, pancreas, and heart. It is a hepatic acute phase protein that often is decreased in liver dysfunction, malnutrition, neoplastic disease, pregnancy, and infectious processes as well as in narcotic or cocaine use. Decrease in plasma cholinesterase results in a decrease of cholinesterase activity in the central, parasympathetic, and sympathetic nervous systems.
Organophosphates phosphorylate the serine hydroxyl group at the site of action of acetylcholine. They bind irreversibly, deactivating the esterase, resulting in accumulation of acetylcholine at the endplate. Accumulation of acetylcholine at the neuromuscular junction causes persistent depolarization of skeletal muscle, resulting in weakness and fasciculations. In the central nervous system, neural transmission is disrupted. If this block is not reversed by a strong nucleophile such as pralidoxime (2-PAM) within 24 hours, large amounts of acetylcholinesterase are destroyed. RBC cholinesterase levels rise slowly; about 0.5-1% a day.
Delayed neurotoxicity
Delayed neurotoxicity is produced by certain organophosphorus esters classified as axonopathic. Few of the thousands of organophosphorus agents in the market have been associated with delayed onset of neuropathy. In those that produce neuropathy, effects may result from a single large dose or cumulative doses. Organophosphorus ester-induced delayed neuropathy (OPIDN) takes at least 10 days to develop following a single acute exposure. The effects of cumulative doses occur over a period of weeks following exposure.
Pathologic examination reveals central-peripheral distal axonopathy. Typically, the spinal cord tracts and distal axons of the lower extremities are involved more than the upper extremities. Primary axonopathy is accompanied by secondary demyelination. Sensory and motor fibers are involved. Interestingly, this late toxicity is not a result of acetylcholinesterase inhibition but rather a result of phosphorylation of a receptor protein, neurotoxic esterase, also called neuropathy target esterase (NTE). The exact mechanism is not known.[4]
Lotti et al described a second step, an "aging" of the phosphoryl-enzyme complex, that is required to produce the neurotoxic effect.[1] Not all organophosphates cause delayed neuropathy. An in vitro test measuring the catalytic activity of this neuron-specific enolase (ie, neuropathy target esterase) may be able to determine the risk of development of delayed neuropathy. Studies in hens given single doses of diazinon or triorthocresyl phosphate (TOCP), showed a "dying back" type of lesion that developed in hens exposed to TOCP but not those exposed to diazinon. Peripheral nerves were affected, and researchers noted moderately severe to marked degeneration of the folia of the cerebellum, the medulla, and spinal cord (the dorsolateral and dorsal columns). TOCP is not a cholinesterase inhibitor.[4]
In 1983, the rate of mortality from unintentional pesticide poisoning was 2.7 per 10 million men and 0.5 per 10 million women. Generally, about 20,000 cases of organophosphate intoxication are reported yearly. About 2.3-2.6 per 10 million of the cases represent suicidal ingestion. In 1998, American Association of Poison Control Centers reported 16,392 exposures to organophosphates, with 11 reported deaths. The true number of exposures is likely to be underestimated. Most cases of cumulative exposure in agricultural workers go unreported.
International
Estimating the number of individuals exposed to organophosphates internationally is virtually impossible. Many agents considered too toxic to market in the United States still may be available in developing nations. Thirty percent of the pesticides exported from the United States are banned for use in the United States. Awareness of the dangers of pesticides is less in developing countries. The number of children exposed is likely to be greater in developing countries where children are expected to work on the family farm or may be hired out as laborers. The use of pesticides as agents of suicide is far more common in developing nations. Eddleston et al (2008) estimate that in the developing world, organophosphorus pesticide self-poisoning kills 200,000 people a year.[5]
Mortality/Morbidity
Mortality rate is generally low in patients treated promptly. Morbidity involves the late onset of neuropathy and tremor, and in large doses, convulsions and delirium. Other late effects are less expected. Compston et al reported reduced bone formation after exposure to organophosphates in 80 male agricultural workers. The mechanism of action was thought to be inhibition of acetylcholinesterase in bone matrix. Acetylcholinesterase is expressed by osteoblasts; it is present along cement lines and in osteoid. The author believes that acetylcholinesterase may have a role in the regulation of cell-matrix interactions and in the coupling of bone resorption and formation.[6]
Frequently, the cumulative effects of low doses of organophosphates are neuropsychological. A joint report by the UK Royal College of Physicians and Psychiatrists concluded that a wide range of often-severe symptoms such as excessive fatigue, poor concentration, and suicidal thoughts are reported more frequently in populations exposed repeatedly. Exposed individuals often have a chronic flulike state that improves when exposure ceases. A patient the author saw 3 years after exposure to a single high dose of diazinon was left with significant cognitive impairment and episodes of generalized muscle hypertonia, initially thought to be seizural. Chronic neuropsychological effects have been seen in 4-9% of patients exposed in occupation-related use.[7, 8, 9]
Race
No particular racial susceptibility to organophosphate toxicity has been noted, but the reported incidence is 3-fold greater in African Americans. This may be a result of the predominance of African Americans in the at-risk population.
Menegon et al studied the possibility of genetic predisposition in patients who developed Parkinson disease after pesticide exposure. Glutathione transferase polymorphism was investigated. Glutathione transferase polymorphism 1 (GSTP1) genotypes appeared to be associated with the risk.[10]
Studies by Bhatt et al may confirm the existence of genetic susceptibility. The risk of developing Parkinson disease after long-term pesticide exposure has been reported. Bhatt et al reported 5 cases of acute and reversible parkinsonism due to organophosphate pesticide exposure in India. One patient was a 31-year-old woman who ingested an organophosphate pesticide in a suicide attempt. The other 4 were exposed following household use of pesticides. Typical features of parkinsonism developed in all cases; however, the patients did not respond to levodopa-carbidopa administration. All patients improved when they were removed from the source of the toxin. Surprisingly, atropine, which is used to provide protection against the effect of organophosphates, was used to treat parkinsonism prior to the development of more effective agents.[11]
Sex
Most cases of exposure involve agricultural workers or those involved in pest control; therefore, most reported cases are males.
Susceptibility apparently is not increased inherently among males or females.
Inhibition of RBC cholinesterase activity is greater in females than in males.
Age
Age does not appear to be a significant factor, although children exposed to pesticides may absorb relatively more chemical with respect to surface area. Children are also more likely to be exposed to pesticides used in lawn care in the course of play. Exposure to vaporized pesticide in the air, dermal exposure, and placing of pesticide-covered fingers in the mouth increase the routes of exposure.
Typically, the patient with acute toxic effects of exposure reports being involved in agricultural spraying of crops or the use of pesticides in an enclosed space. Children become ill after playing in areas that have been treated. In the United States, suicidal ingestion is unusual but accidental ingestion by children may result in acute effects. The antihelminthic trichlorfon is used infrequently but may produce symptoms.
Acute effects
Onset of symptoms occurs within hours of exposure. The acronym SLUDGE is used to describe the muscarinic manifestations of salivation, lacrimation, urination, defecation, GI distress, and emesis.
Signs and symptoms of mild to moderately severe toxicity include tightness in the chest, wheezing, increased sweating, salivation, and lacrimation, as well as GI effects including nausea, vomiting, cramps, watery diarrhea, and involuntary defecation/urination.
Pupils are constricted.
Patients are anxious, restless, emotionally labile, and confused; they typically have insomnia and headache.
Speech may be slurred and the patient may have ataxia, tremor, muscle weakness with cramping, and fasciculations.
Seizures may occur secondary to anoxia.
Death in organophosphate toxicity usually results from cardiac or respiratory failure.
Delayed effects
Organophosphorus ester-induced delayed neuropathy takes at least 10 days to develop following a single acute exposure. The effects of cumulative doses occur over a period of weeks following exposure.
Cramping, tingling, ataxia, and weakness in the lower extremities, progressing to generalized weakness, may be seen in severe cases. Occasionally, a picture resembling amyotrophic lateral sclerosis may be seen in long-term exposure.
Himuro et al described neuropathologic changes seen in a 51-year-old man exposed to the nerve gas sarin in a terrorist attack in Tokyo in 1995. He died 15 months after exposure. He was in cardiopulmonary arrest when seen in the emergency room and remained on a ventilator during hospitalization. He was found to have severe sensory and motor fiber loss in the sampled peripheral nerves. Myelinated fibers in the white matter of the spinal cord were totally lost except for well-preserved posterior columns. Brain changes were described as being consistent with hypoxic-ischemic encephalopathy.[12]
Tricresyl phosphate (TCP), in an isomeric combination, was involved in the notorious ginger jake paralysis, which affected about 50,000 people in the United States in the 1930s and has caused outbreaks in India and South Africa.[13, 14, 15] Senenayake and Jeyaratnam reported a group of more than 20 Sri Lankan women affected by neuropathy associated with the intake of gingili oil contaminated with TCP. The occurrence of neuropathic complaints, 2-4 weeks after menarche, was the result of traditional ingestion of raw eggs and gingili oil (made from a type of sesame seed) to strengthen a woman after her first menstruation or in the case of 3 Moslem women, to strengthen them after childbirth. Paralysis involved distal limb muscles. Electrodiagnostic studies confirmed an axonal polyneuropathy.[13]
The physical features of short-term and long-term exposure are detailed in History.
In mild exposure, the picture is that of acetylcholine overload. The patient shows restlessness, has very active bowel sounds, and may have diarrhea and frequent urination.
In more severe exposure, patients may exhibit muscle twitching and cramping, hypertension, and tachycardia, with an abdominal examination consistent with cramping and watery diarrhea. The patient is usually confused but may be drowsy.
In more severe exposure, the patient may need ventilatory support with active pulmonary toilet because of respiratory failure and excessive secretions.
Job-related exposure to organophosphates is the most common cause of toxicity, particularly when care is not taken to use personal protective equipment. Domestic exposure occurs when spraying takes place in an enclosed, unventilated space or skin is exposed during application of a pesticide.
In the acute care setting, laboratory studies should include glucose, BUN, electrolytes, prothrombin time, liver function studies, and cholinesterase measurements.
Levels of plasma and/or RBC cholinesterase enzyme may be measured by any of several existing methods. Most frequently used, because it is most readily available, is the test for plasma (or pseudo) cholinesterase (PChE). Because this can be affected by other disorders, it does not confirm the diagnosis. Mild intoxication is diagnosed when RBC cholinesterase inhibition is less than 50% of normal. Depression of this value by 25% or more is confirmatory; this test may be used to follow progress. Workers exposed to organophosphates used in agriculture should have a baseline level recorded.
The Test-mate ChE 400 is a portable field kit used to detect occupational organophosphorus exposure. The test measures RBC AChE and plasma cholinesterase (PChE) within 4 minutes. A study of patients with acute organophosphorus self-poisoning compared Test-mate ChE results to reference laboratory tests and found good agreement between the two. The Test-mate ChE kit provides rapid and reliable measurement of RBC AChE levels.[16]
The only imaging study that may be useful in acute management is a chest radiograph because of the danger of aspiration pneumonia in a confused patient with vomiting and compromised respiration.
Electrocardiography should be done on admission, since many patients develop cardiac irregularities following acute exposure.
Electrophysiologic studies
Acute organophosphate toxicity producing weakness is due to sustained endplate depolarization. In vivo microelectrode studies reported by Maselli and Soliven demonstrated no reduction in the amplitude of miniature endplate potentials or of the quantal content of the endplate potentials. Repetitive stimulation produced a decremental response as the endplate was "flooded" with acetylcholine.[17]
Rutchik and Rutkove found a temperature-dependent response; cooling to 32°C produced a normal-amplitude compound action potential (CMAP). A smaller spontaneous repetitive response was elicited in a man with organophosphate intoxication. Warming the limb to 39°C caused these responses to decrease in amplitude; the authors likened the effect to that seen in myasthenia gravis.[18]
De Luca et al have described a technique for evaluating neuromuscular involvement by measuring changes in the firing pattern of surface electromyography. Studies in rhesus monkeys showed gaps in the motor unit recruitment following a dose of OP. This pattern may reflect the tremor related to the degree of OP exposure.[19]
Singh et al examined the phrenic nerve conduction of 29 patients with organophosphate toxicity admitted to the hospital in 1997, 14 of whom required mechanical ventilation. They found that reduction in CMAP correlated with need for ventilatory assistance. By following patients with daily studies, they were able to predict successful weaning.[20]
Neuropsychological testing: Workers exposed over a long period to pesticides have been reported to manifest irritability, fatigue, headache, and difficulties with memory and concentration.
Evidence of neuropsychological abnormalities has been found in 4-9% of those who have had long-term exposure.[8, 9]
The patient exposed to organophosphates often arrives at the hospital with cutaneous contamination. The clothing should be removed and discarded. All traces of residue must be removed by careful washing with alkaline soap or bleach solution.
Laboratory studies should be drawn and a baseline ECG done.
Patients who have had a high level of exposure and are obtunded should be intubated; those having seizures or severe spasms should be given diazepam.
Volume depletion may be a problem if the patient is having diarrhea. Intravenous infusion with 5% dextrose in water should be started.
Surgical care such as tracheotomy and ventilatory assistance generally is not needed unless toxic effects are severe. In late-onset neuropathy, phrenic nerve function may be compromised and the patient may need ventilatory assistance.
Consultation should be sought from pulmonary medicine, neurology, and if possible, psychiatry. An agitated patient requiring intubation in the acute phase of treatment can be difficult to control because sedatives may worsen the condition.
Patients in the acute phase of organophosphate toxicity may be agitated and should be kept in a quiet environment. As weakness and respiratory difficulties resolve, normal physical activity can resume.
The patient should be monitored closely during the first 24-48 hours.
The patient may respond initially to therapy and then become confused or agitated, requiring repeat doses of medication.
Atropine was used as the sole treatment until oximes were developed; it is still used as the sole treatment in developing countries where oximes are not available. In the United States, oximes are used in mild cases; in more severe cases oximes are augmented by the use of atropine.
In cases of oral ingestion, activated charcoal in suspension may be used if the patient is seen within 30 minutes of ingestion.
Clinical Context:
Strong nucleophilic agent that reactivates cholinesterase by reversing phosphorylation of serine hydroxyl group at active site of receptor membrane. Should be used within first 12-24 h and may need to be repeated over 2- to 3-week period. One patient in India, who ingested OPs in suicide attempt, required 92 g of pralidoxime over 23-d period.[21] Effective against OP that is not irreversibly bound. Metabolized in liver and excreted in kidney. Early treatment most effective. Half-life 74-77 min. Not effective against carbamates. Should be used in severe OP toxicity.
Clinical Context:
Antagonizes ACh at muscarinic receptor, leaving nicotinic receptors unaffected. Continue administration until excess muscarinic symptoms improve, which can be gauged by increased ease of breathing in conscious patient or improvement in ease of ventilation of intubated patient.
Generally, after the treatment of acute effects of organophosphate exposure, no additional treatment is needed. Occasionally, the patient has residual neurophysiologic and neuropsychological sequelae.
Patients exposed to an agent suspected of producing neuropathy require monitoring and electrodiagnostic studies several weeks following acute toxicity.
Neuropsychological assessment on a periodic basis is recommended for workers with long-term exposure.
Testing should be done for patients with complaints of memory problems and cognitive deficits.
Following treatment of the acute manifestations of organophosphate poisoning, patients may develop tremor, cognitive deficits, and general debility; they may need treatment of these secondary consequences of organophosphate toxicity. In the case of the patient exposed to large amounts of diazinon, the effects initially were thought to be seizures but were in fact related to generalized nervous system hyperexcitability, which the author treated with tizanidine (Zanaflex).
Use of pesticides in enclosed spaces generally results in exposure to organophosphates. Use of proper ventilation and avoidance of cutaneous exposure reduces toxic events. Many of the more toxic substances are being phased out of production. Carbamate pesticides, for example, while not totally benign, cause a less severe type of toxicity. The carbamates are cholinesterase inhibitors with a blockade time of about 6 hours. They do not cross the blood-brain barrier well and affect primarily the peripheral receptors.
Care must be taken by those who use organophosphate pesticides commercially (eg, crop dusters, farmers); a healthy respect for the substances will help reduce cases of acute toxicity.
Children should be kept from areas where pesticides have been applied.
Complications generally are seen during the period of hospitalization and involve respiratory difficulty, requiring intubation and ventilatory assistance. Seizures occurring during the acute phase should be treated with diazepam.
Pesticides can be dangerous substances if used improperly. They must be kept in a safe place and away from children. People using pesticides should be educated in the fact that the chemicals can enter the body by several routes and to use gloves, protective clothing, and even respiratory protection. After cutaneous exposure, immediate washing is a must.
Patients exposed to pesticides at home should be cautious concerning the potential for repeat exposure. Individuals need to have proper ventilation and to use personal protective equipment such as plastic gloves and clothing that can be removed and laundered immediately after spraying is completed.
Employers are required to provide protective equipment and to instruct their workers to avoid undue exposure by not applying pesticides downwind on a windy day.
Frances M Dyro, MD, Associate Professor of Neurology, New York Medical College; (Retired) Physician, Department of Neurology, Westchester Medical Center
Disclosure: Nothing to disclose.
Specialty Editors
Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
Neil A Busis, MD, Chief of Neurology and Director of Neurodiagnostic Laboratory, UPMC Shadyside; Clinical Professor of Neurology and Director of Community Neurology, Department of Neurology, University of Pittsburgh Physicians
Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: American Academy of Neurology<br/>Serve(d) as a speaker or a member of a speakers bureau for: American Academy of Neurology<br/>Received income in an amount equal to or greater than $250 from: American Academy of Neurology.
Chief Editor
Stephen A Berman, MD, PhD, MBA, Professor of Neurology, University of Central Florida College of Medicine
Disclosure: Nothing to disclose.
Additional Contributors
Jonathan S Rutchik, MD, MPH, FACOEM, Associate Clinical Professor, Division of Occupational Medicine, Department of Medicine, University of California, San Francisco, School of Medicine; Neurology, Environmental and Occupational Medicine Associates (www.neoma.com)
Eskenazi B, Maizlish NA. Effects of Occupational Exposure to Chemicals on Neurobehavioral Functioning. Tarter RE, Thiel DHV, Edwards KL, eds. Medical Neuropsychology: The Impact of Disease on Behavior. New York, NY: Plenum Press; 1988.
