Acute Toxicity–Organic Phosphorus Compounds
Clinical findings of acute toxicity from OPs derive from excessive stimulation of muscarinic and nicotinic cholinergic receptors by ACh in the central and autonomic nervous systems, and at skeletal neuromuscular junctions (Fig. 113–5). The classically described patient with severe OP poisoning is one who is unresponsive, with pinpoint pupils, muscle fasciculations, diaphoresis, emesis, diarrhea, salivation, lacrimation, urinary incontinence, and an odor of garlic or solvents. Less severe poisoning is often not so typical.
The timing of onset of symptoms varies according to the route, the degree of exposure, and particularly the OP. This is important since more rapid onset of poisoning will reduce the likelihood of the patient reaching health care safely, before need for intubation and ventilation, or onset of complications such as aspiration. Onset of respiratory failure outside of a hospital in most parts of the world will result in the patient’s death.
Patients suffering massive ingestions can become symptomatic as quickly as 5 minutes following ingestion. Most patients with acute poisoning become symptomatic within a few hours of exposure, and practically all who will become ill show some features within 24 hours.
Oxon OPs (such as mevinphos and monocrotophos) are already active on exposure, and patients become symptomatic very soon after ingestion. One man was reported to have died within 15 minutes of mevinphos ingestion.138 Some thion OPs are very rapidly converted to oxons and can similarly produce symptoms rapidly—patients ingesting parathion can be unconscious within minutes.79 In contrast, patients ingesting thions that are slowly converted to active oxons (such as fenthion) may not show symptoms for hours.
The speed of onset will also be affected by the quantity ingested and the toxicity81 of the OP. Patients ingesting very large doses or less toxic pesticides or small doses of highly toxic pesticides will rapidly inhibit a clinically significant proportion of their AChE and exhibit features earlier.
Lipid solubility also likely affects time to onset. Fat soluble OPs (with log P of >3–4) will rapidly distribute to fat stores, in the process reducing their concentration in extracellular fluid where they impart their clinical effect (eg, fenthion69). Significant poisoning with such OPs is commonly delayed as respiratory failure with fenthion, for example, typically occurs after 24 hours, in contrast to less fat soluble OPs.73
Symptoms following OP exposure may last for variable lengths of time, again based on the compound and the circumstances of the poisoning. For example, the more lipophilic compounds, such as dichlofenthion or fenthion, can cause recurrent cholinergic effects for many days following oral ingestion as they are released from fat stores.49,148,172
A variety of CNS findings are reported after exposure. Many patients present awake and alert, complaining of anxiety, restlessness, insomnia, headache, dizziness, blurred vision, depression, tremors, or other nonspecific symptoms.17,158 The level of consciousness may deteriorate rapidly to confusion, lethargy, and coma, and patients may display inappropriate behavior. Where careful observational studies have been done, convulsions appear to be uncommon in OP pesticide poisoning compared to OP nerve agent poisoning.69,122 The few convulsions that do occur may be due to hypoxia as a complication of acute cholinergic poisoning.
The effects of excessive ACh on the autonomic nervous system may be variable because cholinergic receptors are found in both the sympathetic and parasympathetic nervous systems (Fig. 113–5). Excessive muscarinic activity can be characterized by several mnemonics, including “SLUD” (salivation, lacrimation, urination, defecation) and “DUMBBELS” (defecation, urination, miosis, bronchospasm or bronchorrhea, emesis, lacrimation, salivation). Of these, miosis may be the most consistently encountered sign. Bronchorrhea can be so profuse that it mimics pulmonary edema.158
Although muscarinic findings are emphasized in these mnemonics, muscarinic signs may not always be clinically dramatic or initially predominant. Parasympathetic effects can be offset by excessive autonomic activity from stimulation of nicotinic adrenal receptors (resulting in catecholamine release) and postganglionic sympathetic fibers.207 Mydriasis, bronchodilation, and urinary retention can occur as a result of sympathetic activity. Increased sympathetic activity usually precipitates white blood cell demargination, resulting in leukocytosis.156,158
Excessive adrenergic influences on metabolism cause glycogenolysis208 with hyperglycemia and ketosis that have been mistaken for diabetic ketoacidosis.146,238 Hypoglycemia can also occur, although the mechanism is unclear.114 Disturbances of glucose metabolism do not seem to be common. Two studies of patients with OP or carbamate poisoning showed hyperglycemia in 6% to 8%.105,195 It is possible that effects on glucose metabolism may be associated with specific OPs, such as the malathion114 and diazinon,188 rather than all OPs. Larger cohorts of patients exposed to single OPs are required to determine whether such associations exist.
Hyperamylasemia appears to be relatively common in OP poisoning, occurring in 4/47 (9%) adults in one series186 and 5/17 (29%) children in a second.225 However, both included various anticholinesterase pesticides; a series of only malathion poisoned patients reported hyperamylasemia in 47/75 (63%).46 The amylase likely comes from the pancreas since animal studies show OP-induced damage115 and human poisoning cases show associated pancreatic edema and, rarely, necrotizing pancreatitis.29,103,165 The incidence of subclinical and clinical pancreatitis probably varies according to the OP ingested and perhaps the co-formulants. Elevations of hepatic enzymes can also occur following OP pesticide exposures.161,174,239
Cardiovascular manifestations reflect mixed effects on the autonomic nervous system (including increased sympathetic tone), together with the consequences of OP-induced hypoxia and hypovolemia. Admission heart rate is usually normal, with relatively few patients expressing a tachycardia or bradycardia. Patients who have received atropine before admission may be tachycardic. The literature is filled with reports of QT prolongation and ventricular dysrhythmias.15,95,128,183,185 However, these reports are complicated by the fact that most patients had an ECG done before they received any atropine to counter the cholinergic syndrome or were so ill that atropine was ineffective. The first is illustrated by a description of 46 patients with OP or carbamate poisoning in which “ECG recordings [were] taken on arrival … before the start of atropine treatment.”185 The reported cardiac rhythms may be confounded by the hypoxia and hypovolemia that characterize the cholinergic syndrome. In another study, 29 of the 35 patients with such dysrhythmias died.140 In contrast, when more than 1000 patients poisoned with WHO Class II OPs were evaluated, serious dysrhythmias were very rare in patients adequately resuscitated with oxygen, atropine, and fluids (Eddleston, unpublished data).
Hypotension may occur because of stimulation of vascular receptors by excessive circulating Ach, severe volume loss, or myocardial dysfunction.11,124 Severe hypotension is a particularly significant problem in poisoning with the unusually fat-insoluble OP dimethoate.50,69 Fatal poisoning is characterized by early respiratory failure followed by hypotension that can be treated only transiently with vasopressors. Such a syndrome was not found in poisoning with fat-soluble OPs such as chlorpyrifos and fenthion.69 The exact role of direct cardiotoxicity and peripheral vasodilation is not yet clear, or whether this syndrome occurs with other fat-insoluble OPs, such as methamidophos and oxydemeton methyl.50 Recent studies indicate that the solvent in branded dimethoate EC40, cyclohexanone, is partially responsible for this severe hypotension.74
Respiratory complications of OP poisoning include the direct pulmonary effects of bronchorrhea and bronchoconstriction, neuromuscular junction failure in the diaphragm and intercostal muscles, and loss of central respiratory drive.53 If severe and occurring before patients reach medical care, these effects will lead to hypoxemia and respiratory arrest, the most common cause of death after OP poisoning.88 Both bronchorrhea and bronchoconstriction respond to adequate atropine therapy. Unfortunately, neither neuromuscular junction failure nor loss of central respiratory drive respond to atropine, and patients must be intubated and ventilated until respiratory function returns.
An additional early respiratory complication is hydrocarbon aspiration that may occur after ingestion of commercially formulated pesticides. The incidence of aspiration and the consequences of aspiration—whether chemical pneumonitis, pneumonia, or acute respiratory distress syndrome—are not yet known and likely differ according to the OP and formulation ingested.
Acetylcholine stimulation of nicotinic receptors also governs skeletal muscle activity. The effects of excessive cholinergic stimulation at these sites are similar to that of a depolarizing neuromuscular blocker (succinylcholine) and initially result in fasciculations or weakness. Although this effect is often considered to be the most reliable sign of parathion toxicity,158 it is the author’s clinical experience that many patients severely poisoned with other OP insecticides do not display this sign. Acute cranial nerve abnormalities are uncommon.
Severe poisoning results in paralysis.223 Rarely, patients may present with paralysis from nicotinic effects without any other initial signs and symptoms suggestive of OP toxicity.84,92 Extrapyramidal effects such as rigidity and choreoathetosis occur uncommonly after severe anticholinesterase poisoning but can persist for several days after cholinergic features have resolved.9,25,134,153
The acute effects of poisoning from carbamate insecticides appear identical to those of OP insecticides except for the relative short duration of cholinergic features due to rapid hydroxylation of the carbamate-AChE bond. Persistent cholinergic features are not reported for carbamate poisoning.
Illness may result from chronic exposure to excessive amounts of OP insecticides. Chronic exposure most commonly occurs in workers who have regular contact with OPs, but may also occur in individuals who have repeated contact with excessive amounts of insecticides in their living environments. Cholinergic ophthalmic preparations can lead to toxicity in this manner.141 Although tolerance to acute cholinergic systemic effects of OP insecticides (including death in rats) may be observed with long-term exposures,88 persons who have such repeated contact may begin to describe symptoms after substantial lengths of time. These effects can range from vague neurological complaints, such as weakness and blurred vision, to miosis, nausea, vomiting, diarrhea, diaphoresis, and other cholinergic effects.6,7,141,198 Butyrylcholinesterase activity is usually the most sensitive measure of exposure, and workers in contact with these chemicals should have baseline butyrylcholinesterase testing for comparison and monitoring.88,110
Recent literature has linked Parkinson disease with chronic exposure to pesticides including OP insecticides.58,199 Some individuals may have a possible genetic susceptibility.25 Additionally, significant acute exposures to OP insecticides can lead to self-limited movement disorders resembling Parkinson disease that resolve over weeks to months (see above). Although statistics derived from some epidemiologic studies suggest the connection,77,108 other studies have failed to find an association between OP compounds and Parkinson disease.206 All studies thus far have been retrospective in nature and therefore likely confounded by recall bias.
Neuromuscular Junction Dysfunction.
A syndrome of delayed muscle weakness without cholinergic features or fasciculations resulting in respiratory failure was first reported by Wadia in 1974 as type II paralysis223 and further refined by Senanayake and Karalliedde in 1987 as the intermediate syndrome.190 The syndrome is defined as occurring 24 to 96 hours after acute OP poisoning, and after resolution of the cholinergic crisis.125,190,223 Patients develop proximal muscle weakness, especially of the neck flexors, and cranial nerve palsies and progress to respiratory failure that may last for several weeks.125 Consciousness is preserved unless complicated by hypoxia or pneumonia. The syndrome is important since apparently stable patients can suddenly develop a respiratory arrest; all patients must be evaluated for muscle weakness if deaths are to be prevented.20,166 The first sign is often weakness of neck flexion such that patients cannot lift their head off the bed.
Although the exact pathophysiology of the syndrome is unknown, it is clearly due to dysfunction of the neuromuscular junction, with respiratory failure resulting from weakness affecting the diaphragm and intercostal muscles. Preservation of consciousness suggests that the central respiratory drive is not involved. Clinicians have proposed that overwhelming NMJ stimulation causes downregulation of the NMJ synaptic machinery.52,190 This would require time to be repaired, even after the pesticide has been removed from the body, explaining the long duration of ventilation needed by many patients.73
Cases and small case series are reported from around the world, with resulting comments that the intermediate syndrome is more common with certain OPs, such as parathion, methyl parathion, malathion, and fenthion. Unfortunately, large cohorts of poisoning with specific OPs receiving standardized treatments are rarely reported, making comparisons of incidence between OPs difficult. However, two cohorts have shown that the intermediate syndrome causing respiratory failure is more common in fenthion poisoning than chlorpyrifos, malathion, or fenitrothion poisoning.73,222
Clinical examination remains the most reliable means of identifying the occurrence of intermediate syndrome.125 Electromyograms will often show tetanic fade in these patients, and suggest both pre- and postsynaptic involvement.125 Recent work has noted characteristic electrophysiological features that can be identified before onset of neurological features and respiratory paralysis.117 The majority of patients developing weakness in this series did not progress to respiratory failure, indicating that intermediate syndrome is a spectrum disorder.
Another study of severely poisoned patients suggested that the occurrence of intermediate syndrome strongly correlated with the initial degree of cholinergic crisis and seemed to be a continuum with the neuromuscular paralysis resulting from the early stages of poisoning.118 This view is supported by early work52 and a more recent study of dimethoate poisoning which showed that peripheral NMJ dysfunction can occur simultaneously with the cholinergic syndrome.73 Patients with moderate to severe dimethoate poisoning typically require intubation for respiratory failure soon after ingestion, during the acute cholinergic syndrome. However, this is relatively short-lived, and patients recover consciousness after a few days. As the cholinergic syndrome settles and the patients regain consciousness, with recovery of the central respiratory drive, they are still unable to ventilate. Similar to patients with classical intermediate syndrome, they require ventilatory support for several weeks until their NMJ recovers function. In addition, this case series showed that the classic intermediate syndrome—respiratory failure after resolution of the cholinergic syndrome—can occur before 24 hours and after 96 hours.73
These studies suggest that the original intermediate syndrome is just one important aspect of OP-induced peripheral NMJ dysfunction. It seems likely that the relative incidence and timing of the intermediate syndrome or delayed NMJ dysfunction for different OPs is determined by the rapidity and quantity of AChE inhibition. Where inhibition is intense, with fat-insoluble OPs like dimethoate that have very high plasma concentrations, NMJ dysfunction comes on early, before recovery from the cholinergic crisis. Fat-soluble OPs, such as fenthion, cause a more protracted AChE inhibition, likely explaining why fenthion-induced NMJ dysfunction and respiratory failure occur later.73
Some authors have suggested that insufficient oxime therapy explains the intermediate syndrome.22 Of note, AChE inhibited by dimethoate or fenthion responds poorly to oximes, in contrast to chlorpyrifos, which responds well to oximes and has a lower incidence of intermediate syndrome.69,73 The occurrence of NMJ dysfunction in chlorpyrifos poisoning may well be due to inadequate oxime therapy. However, adequate oxime therapy after, for example, malathion poisoning,200 may be irrelevant since this dimethyl OP responds poorly to oximes. Regardless, delayed NMJ dysfunction may be due to ineffective AChE reactivation, whether due to inadequate doses or to poisoning with OPs that do not respond to oxime therapy.
Recent animal studies of dimethoate poisoning may shed further light on this condition. These studies produced NMJ dysfunction and showed that it did not occur after poisoning with dimethoate active ingredient alone. However, it did occur after poisoning with the agricultural EC40 formulation that included both the dimethoate active ingredient and its solvent, cyclohexanone.74 This raises the possibility that NMJ dysfunction is due to an interaction of solvent and active ingredient. All reported cases have occurred after poisoning with agricultural formulations of OP insecticides; further studies are required to clarify the role of solvents and the possible mechanisms of their effects.
The treatment of intermediate syndrome is supportive with airway protection and mechanical ventilation. There are no substantial data demonstrating that pralidoxime or atropine is effective in the treatment of this disorder, although patients may require these medications to control concurrent cholinergic symptoms. The weakness and paralysis commonly resolve in 5 to 18 days.73,106,117,118
Organic Phosphorous Compound-Induced Delayed Neuropathy (OPIDN).
Peripheral neuropathies can occur with chronic OP pesticide exposures days to weeks following acute exposures. OPIDN results from inhibition by phosphorylation of the enzyme neuropathy target esterase (NTE, now identified as a lysophospholipase) within nervous tissue.36,91,119,120 This enzyme catalyzes breakdown of endoplasmic reticulum-membrane phosphatidylcholine, the major phospholipid of eukaryotic cell membranes. Neuropathic OPs cause a transient loss of NTE activity, putatively disrupting membrane phospholipid homeostasis, axonal transport, and glial-axonal interactions.91
Such neuropathies may result from exposure to OPs that do not inhibit red blood cell cholinesterase or produce clinical cholinergic toxicity.39 The more commonly implicated chemicals include triaryl phosphates, such as triorthocresyl phosphate (TOCP), and dialkyl phosphates, such as mephosfolan, mipafox, and chlorpyrifos.120 Pathologic findings demonstrate effects primarily on large distal neurons, with axonal degeneration preceding demyelination.
Contaminated foods and beverages were responsible for epidemics of OP compound–induced delayed polyneuropathies and encephalopathy. In the 1930s, thousands of individuals in the United States became weak or paralyzed after drinking a supplement containing TOCP—an outbreak nicknamed “ginger Jake paralysis”10,149 (Chap. 2). Contaminated cooking and mineral oils were responsible for outbreaks of delayed polyneuropathies in Vietnam and Sri Lanka.56,189 Vague distal muscle weakness and pain are often the presenting symptoms and may progress to paralysis.97 The administration of atropine or pralidoxime does not alter the onset and clinical course of these symptoms.221 Pyramidal tract signs can appear weeks to months after acute exposures. Electromyograms and nerve conduction studies may be helpful in diagnosing this disorder by identifying the type of neuropathy (such as axonopathy, myelinopathy, or transmission neuropathy) and differentiating it from similar presentations such as Guillain-Barré syndrome.2 Recovery of these patients is variable and occurs over months to years, with residual deficits common.149,189
Delayed neuropathies are not usually associated with carbamate insecticides. One reason for this difference is presumed to be that aging of the neuropathy target esterase pesticide complex is a requirement for neuronal degeneration. Paradoxically, one study suggested that subgroups of carbamates may actually bind neuropathy target esterase and exert a protective effect against more toxic OP compounds.5 However, several cases of possible delayed neuropathy associated with carbamates have been reported.59,218,237 These cases involved ingestions of carbaryl, m-tolyl methyl carbamate, and carbofuran, included both sensory and motor tracts, and tended to resolve over 3 to 9 months. EMG findings were variable.
Behavioral changes may also occur after acute or chronic exposure to OP compounds.80 Signs and symptoms include confusion, psychosis, anxiety, drowsiness, depression, fatigue, and irritability. Electroencephalographic changes may be noted and can last for weeks.96 Single photon emission computed tomography (SPECT) scanning revealed morphologic changes in the basal ganglia of one child following poisoning.27 Recent studies have shown a deficit in cognitive processing after acute OP self-poisoning that lasts for at least 6 months and is not found in matched patients who had poisoned themselves with paracetamol.47,48 Thus far there appears to be no clear evidence for neuropsychiatric deficits resulting from subclinical exposure to OPs, although multiple small studies have suggested some effects.80,182