Organophosphates

The primary toxicologic effects of OP insecticides relate to their ability to phosphorylate acetylcholinesterase (AChE), thereby forming an irreversible covalent phosphate linkage with a serine residue at the active site. This inhibition effectively allows unopposed action of acetylcholine at the nerve synapse, resulting in sustained depolarization of the postsynaptic neuron. This action occurs both in the central nervous system (CNS) and at muscarinic sites in the peripheral nervous system, nicotinic sites in the sympathetic and parasympathetic ganglia, and nicotinic sites at the neuromuscular junction. Although OP insecticides registered by the EPA are relatively more selective in acting on insect cholinesterase, they also affect mammalian AChE in the event of excessive exposure.

The rate of spontaneous reactivation of AChE is dependent on the chemical structure of the agent involved. The most commonly encountered agents carry either two methyl or two ethyl ester groups attached to the phosphorus atom. The significance of this structural finding relates to the fact that poisoning with dimethyl agents (e.g., demeton-S-methyl, dichlorvos, dimethoate, or malathion) results in rapid and spontaneous reactivation of AChE, whereas poisoning with diethyl agents (e.g., chlorpyrifos, diazinon, or parathion) is associated with slower reactivation of AChE. The differences among the OP insecticides can create therapeutic dilemmas in determining appropriate courses of treatment.⁸

Patients acutely poisoned with OP insecticides present with a range of signs and symptoms, depending on the dose and potency of the agent involved. Significant poisoning exposures result in respiratory failure due to muscle weakness, excessive mucous secretion, and noncardiogenic pulmonary edema, which may be an immediate cause of death. Severe poisoning also can cause neurologic effects including seizures, coma, or delirium, which result from cholinergic input in the midbrain and medulla. Dystonias, choreoathetoid movements, and fasciculations also can be noted.

Varieties of arrhythmias have been reported, including tachyarrhythmias, bradyarrhythmias, and torsades de pointes ventricular tachycardia. Diarrhea and vomiting are almost universally seen in severe poisoning, along with excessive secretions of tears, saliva, and sweat. This constellation of symptoms has given rise to a number of mnemonics to describe the cholinergic excesses, such as DUMBELS (diarrhea, urination, miosis, bronchospasm, emesis, lacrimation, salivation) and SLUDGE (salivation, lacrimation, urination, defecation, emesis).

An intermediate syndrome or type II toxicity also has been described. In this syndrome, patients exhibit paralysis of proximal limb muscles, neck flexor muscles, motor cranial nerves, and respiratory muscles, without significant muscarinic symptoms. These effects are noted 24 to 96 hours after initial signs and symptoms and are thought by some to be a result of initial underdosing with the antidote.^9–12

Some OPs such as the triaryl phosphates can produce a delayed peripheral neuropathy known as organophosphate-induced delayed neuropathy (OPIDN), which manifests 2 to 3 weeks after a single acute poisoning. After abatement of acute cholinergic effects and symptoms associated with the intermediate syndrome (see later), patients with OPIDN develop signs and symptoms including tingling of the extremities, sensory loss, progressive muscle weakness and flaccidity of the distal skeletal muscles of the lower and upper extremities, and ataxia. The mechanisms leading to OPIDN are not fully understood and may not be directly related to inhibition of AChE, since some of the agents involved are poor AChE inhibitors.^13–15

Diagnosis of OP poisoning typically requires a clinical picture of cholinergic symptoms, onset of symptoms within 12 hours of exposure, a 50% or more reduction of plasma and red blood cell (RBC) cholinesterase below baseline, and clinical improvement of muscarinic signs and symptoms with the administration of atropine.

The most severe cases of poisoning can be rapidly fatal if not aggressively treated. Atropine is the mainstay of treatment, and in some cases extremely large doses (>100 mg/d) may be required to reverse muscarinic symptoms. Critical care clinicians often will be faced with the decision to administer an oxime such as pralidoxime (2-PAM), which regenerates AChE by reversing phosphorylation of the active site on the enzyme before the phosphorylated AChE has undergone aging. Although animal data consistently have shown a positive effect of oxime therapy, a number of authors have questioned their utility, and reviews of the clinical effectiveness of oxime therapy have produced mixed results.^16,17 Still other work has demonstrated a more convincing benefit associated with the use of 2-PAM and provides a rationale for appropriate dosing that includes continuous pralidoxime infusion, as compared to repeated bolus injection.¹⁸ Although various studies have lead the World Health Organization to recommend standard doses of 2-PAM, including an intravenous (IV) bolus of 30 mg/kg as a loading dose followed by infusion of at least 8 mg/kg/h, a modified administration schedule of a 2-g IV bolus dose followed by a continuous infusion of 1 g over an hour for 48 hours demonstrated reduction in both morbidity and mortality of moderately severe cases of acute OP poisoning.^18,19–21

As such, 2-PAM administration is warranted in moderate to severe poisoning in patients with respiratory compromise, seizures, or coma. Furthermore, 2-PAM is typically used in combination with atropine, as atropine blocks only the effects of acetylcholine at the postsynaptic neuron but does not regenerate AChE.

Animal studies suggest that other new treatment approaches such as alkalinization hold promise in the effective management of OP intoxication, but there is insufficient evidence supporting their role in the routine care of these patients.^22,23 If the patient receives appropriate treatment and survives the first few hours, prognosis is good, even in severe cases of poisoning.

N-Methyl Carbamates

Carbamate insecticides are derivatives of N-methyl carbamic acid and share similar toxicologic effects with OP insecticides in that both inhibit AChE. These insecticides differ from the OPs in that they cause a reversible carbamylation of the AChE enzyme. This carbamyl-AChE combination dissociates more readily than the OP phosphoryl-AChE complex, resulting in a shorter duration of clinical effects, a wider range between doses causing clinical effects and fatality, and diminished usefulness of blood cholinesterase measurements.

In cases of serious poisoning, patients demonstrate CNS depression with coma, seizures, and hypotonicity. Nicotinic effects including hypertension and cardiorespiratory depression are also common. Respiratory effects such as dyspnea, bronchospasm, bronchorrhea, and pulmonary edema are also likely to be present.²⁴

As in severe cases of OP poisoning, treatment should be based on a high index of suspicion or history suggestive of either OP or carbamate exposure and presence of characteristic symptomatology and should not be delayed pending confirmation by blood cholinesterase testing. Although clinical presentation is quite similar to OP intoxication, seizures as a presenting symptom are uncommon because many carbamates do not cross the blood-brain barrier.

Cholinesterase testing may be of more limited value in carbamate poisoning, depending on the timing of sampling; in vitro regeneration of AChE may render the results unreliable in confirming exposure.^25,26

Initial treatment of choice is atropine, and as in severe cases of OP poisoning, large doses may be required to reverse symptoms of cholinergic crisis. Although pralidoxime has been suggested to be relatively contraindicated in cases of carbamate poisoning and may serve as an additional competitive inhibitor of AChE, the risk of adverse effects is small in comparison to potential benefit when faced with poisoning from an unknown cholinesterase inhibitor.

Prognosis in cases of carbamate poisoning is typically excellent when treatment is prompt and appropriate, with most cholinergic symptoms resolving within 24 hours. Contrary to OP poisoning, delayed or prolonged symptoms are not expected.

Solid Organochlorines

The use of solid organochlorine compounds as insecticides has been sharply curtailed worldwide in recent years, and almost all EPA registrations for compounds such as aldrin, dieldrin, benzene hexachloride, chlordane, and DDT have been cancelled. The EPA is currently banning endosulfan, leaving dicofol as essentially the last organochlorine compound that is a restricted-use insecticide. Lindane was banned by the EPA for use as a pesticide in 1996 but remains on the market under FDA jurisdiction as a second-line therapy for scabies. Still, a variety of agents remain in other international markets. Although poisoning from banned toxic agents is less likely, occasionally exposures to some residual products occur.

Cases of mild acute poisoning often result in CNS effects including headache, dizziness, nausea, vomiting, incoordination, tremor, and mental confusion. Even in more severe cases of poisoning, neurologic toxicity predominates, with myoclonic jerking progressing to generalized seizures, including status epilepticus.^27,28 Symptoms may progress to coma and respiratory depression, and cardiac irritability may result in arrhythmias.

Confirmation of poisoning is more likely to be made from a strong history of exposure, since laboratory analysis is not routinely available and difficult to interpret. Although severe cases of exposures may demonstrate correspondingly high blood levels, measurable low levels do not necessarily confirm poisoning.

Treatment of severe poisoning is aimed at controlling convulsions and monitoring for respiratory compromise. Atropine, epinephrine, and other adrenergic amines in standard Advanced Cardiac Life Support (ACLS) protocols should be used only if absolutely necessary, as enhanced myocardial irritability predisposes to ventricular fibrillation. Despite the fact that serious and life-threatening effects can occur, especially in instances of intentional ingestion, advances in critical care medicine have significantly reduced the mortality in those patients receiving early and well-managed supportive care.

Pyrethrin/Pyrethroid

Pyrethrins (e.g., jasmolin, cinerin, pyrethrin) are naturally occurring esters of chrysanthemic and pyrethric acid, extracts of the Chrysanthemum cinerariaefolium flower. Pyrethroids (e.g., allethrin, bifenthrin, bioresmethrin, cypermethrin, deltamethrin, fenvalerate, permethrin, phenothrin, resmethrin, tetramethrin) are synthetic pyrethrins which have been chemically modified to increase stability in the natural environment. A variety of different types of formulations are used for the control of insects on animals, in the house and garden, and in agriculture. Pyrethroids and pyrethrins interact with sodium channels in peripheral and central nerve cells to prolong the increase in permeability during the action potential excitatory phase of impulse transmission, resulting in failure of the cell to depolarize. In humans, rapid cleavage of the acid/alcohol ester along with oxidation to nontoxic metabolites limits toxicity. Pyrethrins and pyrethroids in their diluted form are poorly absorbed across intact skin and rarely result in toxicity. Despite limited absorption, an additional reason for low toxicity relates to rapid biodegradation by mammalian liver enzymes (ester hydrolysis and oxidation). Pyrethroids are differentiated by the absence (type I) or presence (type II) of an α-cyano group. Type I pyrethroids cause a tremor syndrome, and type II agents demonstrate a choreoathetosis/salivation syndrome.²⁹ Most human case reports of toxicity involve type II agents. Despite extensive use and frequent exposure, a review of national poison center data revealed that moderate or major adverse effects were relatively rare based on review of 3 consecutive years of data (717 moderate and 23 major outcomes out of 17,873 exposures reported to poison centers nationwide).³⁰

Unless significant ingestion of more concentrated type II products occurs, serious toxicity is unlikely. In those few significant exposures, patients must be monitored for the development of neurotoxic effects such as seizures.

Other Agents

A variety of other pest-management agents registered for use in the United States include insecticides, acaricides, and repellents that have pharmacology and toxicology that are distinct from carbamates and OPs. Agents such as boric acid are commonly involved in exposure but may not necessarily result in serious exposures. Exposures to other agents including benzyl benzoate, chlordimeform, chlorobenzilate, and cyhexatin rarely result in significant poisoning. Diethyltoluamide (DEET) is used extensively as an effective insect repellent and rarely results in serious systemic poisoning unless large amounts are ingested. Anticoagulant rodenticides produce predictable and potentially life-threatening anticoagulation and poisoning, and so-called super warfarins produce long-lasting effects requiring weeks of vitamin K₁ therapy to prevent rebound anticoagulation.

Chlorophenoxy Herbicides

Chlorophenoxy compounds such as 2,4-dichlorophenoxyacetic acid (2,4-D), MCPA, MCPB, MCPP, and 2-methyl-3,6 dichlorobenzoic acid are some of the most widely used herbicides on the U.S. market today. Fortunately, as with many herbicides, except for massive suicidal ingestion, severe poisoning is rare. Typical low-level exposures result in moderate irritation to skin and mucous membranes, and inhalations of sprays cause a burning sensation in the nasopharynx and chest. In cases of large deliberate ingestion, severe poisoning involves renal failure, acidosis, electrolyte disturbances, and multiple organ failure. Hyperthermia is also a common feature in significant exposures, possibly a result of uncoupling of oxidative phosphorylation. There are no known antidotes, and management is aimed at controlling organ failure. Forced alkaline diuresis with a high urine flow has been used successfully and has produced clearance values similar to other measures such as hemodialysis.^31,32

Paraquat

Paraquat and diquat are nonselective dipyridyl contact herbicides. Paraquat is a restricted-use herbicide for most applications, although dilute solutions of 0.276% are available to consumers for spot weed killing. Of all registered herbicides, paraquat exposures are the most serious and potentially life threatening and affect the gastrointestinal tract, kidneys, liver, heart, lungs, and other organs. Ingestion of as little as 10 to 15 mL of a 20% solution is life threatening. Although inhalation toxicity is rare, ingestions result in systemic toxicity, with the lung being the target organ. Both type I and II pneumocytes appear to accumulate paraquat, where biotransformation results in the formation of free radicals, lipid peroxidation, and cell death.^33–35 Concentrated paraquat is also quite corrosive, and prolonged contact may result in erythema, blistering, abrasion, and ulceration.^36,37 Although absorption across intact skin is slow, once the skin is abraded, eroded, or otherwise damaged, much greater absorption can occur.

Ingestions of more concentrated paraquat solutions produce swelling, edema, and painful ulceration of the oral cavity, pharynx, esophagus, stomach, and intestine. Liver injury may be evident from centrizonal hepatocellular injury, with corresponding elevations of circulating concentrations of the enzymes aspartate aminotransferase (AST), alanine aminotransferase (ALT), and lactate dehydrogenase (LDH). Kidney damage is often seen, and evidence of early damage may suggest a grave prognosis, because impaired renal function decreases clearance of paraquat from the body.

Acute poisoning can result in severe pulmonary edema within hours of ingestion, although delayed toxicity, manifested as pulmonary fibrosis, typically results in death 7 to 10 days after exposure. Toxic concentrations of paraquat can accumulate in the lung within hours of exposure, which limits the utility of various methods of decontamination or enhanced elimination. Rough estimates of toxicity suggest that ingestions of less than 20 mg/kg body weight of paraquat typically result in recovery, while ingestions of more than 40 mg/kg body weight result in 100% mortality within 1 to 7 days.³⁷

Treatment including gastric decontamination largely has been ineffective, but theoretically, gastric lavage immediately after ingestion may be beneficial; even small returns of the substance may reduce total body burden. Administration of oral adsorbents has been recommended, but there is no conclusive evidence of value. As with gastric lavage, preventing absorption of even small quantities of paraquat may be useful. Agents that are typically recommended include activated charcoal, Robinson’s Bentonite, or Robinson’s Fuller Earth (adult dose for each is 100-150 g; dose for children is 2 g/kg) via NG tube, with or without a cathartic. In most Western medical facilities, only activated charcoal will be on hand and available for rapid administration.

Diagnosis of paraquat poisoning should be confirmed through qualitative analysis of paraquat in urine, with subsequent quantitative analysis in plasma. Manufacturers of paraquat may be able to aid in obtaining analysis of biological fluids for the presence of paraquat and interpreting results consistent with reported nomograms such as the one provided by Hart et al.³⁸ Quantitative analysis of plasma concentrations within the first 24 hours can provide an accurate assessment of survival rates. Plasma concentrations in excess of 3 mg/L, regardless of time taken, have been associated with universally fatal outcomes despite aggressive interventions including hemodialysis.

Other treatment considerations focus on organs most likely to be affected, such as the pulmonary and renal systems. Because the presence of oxygen increases free radical formation, use of supplemental oxygen should be restricted if possible.^39,40 Patients should be closely monitored for development of acute respiratory distress syndrome (ARDS) and impending respiratory failure. Varieties of other measures have been employed to increase elimination of paraquat. Although both peritoneal dialysis and hemodialysis have been used, peritoneal dialysis is largely ineffective compared to hemodialysis. Data regarding the benefits of dialysis are still inconclusive. Hemoperfusion for several consecutive days has been the most effective means of paraquat removal, and if used should be started within 24 hours—preferably within 12 hours—of ingestion. Although various antioxidants and free radical scavengers have been postulated to reduce free radical damage, no benefits have been demonstrated in animal studies.

One case reported the use of deferoxamine (100 mg/kg in 24 hours) and continuous infusion of N-acetylcysteine (300 mg/kg/d for 3 weeks) to treat an ingestion of 50 to 60 mL of a 20% solution of paraquat in an adult male.⁴¹ The patient survived without major sequelae. In another case, a 52-year-old male who ingested approximately 50 mL of a solution containing 13% paraquat and 7% diquat subsequently developed ARDS and pulmonary fibrosis. Survival prediction for the corresponding paraquat plasma levels was 30%. Treatment included oral Fuller’s earth, forced diuresis, hemofiltration, N-acetylcysteine, methylprednisolone, cyclophosphamide, vitamin E, colchicine, and delayed continuous nitric oxide inhalation. The patient recovered with subsequently normal pulmonary function. The authors were unsure which of the above interventions accounted for the successful outcome, but they were encouraged with the use of nitric oxide.⁴² Further data supporting the effectiveness of these modalities are lacking. Ultimately, there is no effective antidote.

Diquat

Diquat is also a dipyridyl compound, similar to but less toxic than paraquat. The lower toxicity may be because diquat is not selectively concentrated in the lungs. Although lung damage to type I pneumocytes does occur, type II pneumocytes are spared, and progressive fibrosis has not been reported.^43,44

Significant exposures to diquat can result in toxicity to the gastrointestinal tract, brain, and kidneys. Signs and symptoms of CNS toxicity including lethargy, seizures, and coma may be seen.^45,46 Treatment of diquat exposure is similar to treatment of paraquat poisoning, with gastric decontamination and respiratory support, but there are limited studies documenting effectiveness of most therapeutic modalities that have been employed.

Key Points