Background
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. More than 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]
Pathophysiology
The mechanism of action of organophosphates, 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]
Etiology
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.
Epidemiology
Frequency
In 2022, the American Association of Poison Control Centers reported 1529 single exposures to organophosphate insecticides alone, with 18 major outcomes and six deaths. In addition, 369 single exposures to organophosphate insecticides in combination with carbamate or non-carbamate insecticides were reported, with one major outcome but no deaths. [5] Many more exposures probably occur, but patients with minor symptoms often do not seek medical care.
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.
A 2020 systematic review estimated that globally 385 million unintentional pesticide poisonings occur annually, resulting in 11,0000 deaths. Data was not available to determine rates for organophosphates alone. The highest rates of exposure were in Asia and East Africa. [6]
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. [7]
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. [8]
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.
Prognosis
Promptly treated organophosphate toxicity carries a favorable prognosis. Individuals with long-term exposure need to be monitored for the late complication of neuropathy and development of cognitive abnormalities.
The majority of deaths are attributed to respiratory failure. In a study of 60 patients with organophosphate exposure, 47 were deemed to have mild toxicity and 13 were deemed to have moderate toxicity after receiving received atropine and/or pralidoxime prior to arrival at the emergency department. All 13 patients with moderate toxicity and 29 of the patients with mild toxicity were admitted to the ICU and required mechanical ventilation. There were 11 deaths, 7 with mild toxicity (15%) and 4 with moderate toxicity (31%). [9]
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. [10]
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. [11, 12, 13]
Patient Education
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.
