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Editor-In-Chief: C. Michael Gibson, M.S., M.D. ; Associate Editor(s)-in-Chief:
Synonyms and Keywords: Pesticide intoxication; pesticide exposure; insecticide poisoning; insecticide intoxication; insecticide exposure; suicide
Pesticides are chemicals, either naturally occurring or synthetically produced, which may be used to eliminate unwanted plants, animals, or other organisms. They are used extensively in the agriculture industry as well as in the household and can be classified into five categories, namely: insecticides, rodenticides & avicides, fungicides, herbicides, and cross-classified pesticides. While pesticides are meant to be lethal to various unwanted organisms, they are also generally toxic to humans as well. Roughly 7 million people are poisoned by pesticides annually causing more than 350,000 deaths each year, making it a major issue to be considered for emergency physicians. . This article covers the mechanism of toxicity, clinical presentation and diagnosis, and treatment of intoxicated patients for the major pesticides within each category of pesticide.
Pesticides are classified into groups based on their targets. While some texts may discuss anti-bacterial and other anti-microbial agents, article will focus on the five major categories of pesticides. These are as follows:
- Rodenticides & Avicides
- Major Cross-classified Pesticides
The mechanism of toxicity of various pesticides which patients may be poisoned with vary considerably between different categories of pesticides and among the agents within each category. This section will be divided into each category and will discuss the mechanisms of toxicity for the most common agents within each category.
While commercially produced glyphosate herbicides are generally highly toxic, the active ingredient, glyphosate, has been engineered to be relatively non-toxic to humans. Unfortunately, most commercially produced glyphosate herbicides are packaged with surfactants to increase the effectiveness of the product. Polyethoxylated tallow amine (POETA) is one such surfactant, which is understood to be a primary factor in the toxicity of glyphosate herbicides.
POETA has been shown to cause membrane disruption and inhibition of cellular respiration leading to cell necrosis in patients poisoned by glyphosate herbicides.
2,4-Dichlorophenoxyacetic acid has been studied and observed to act in a myriad of pathological mechanisms.
2,4-Dichlorophenoxyacetic acid has been shown in animal studies to uncouple the mitochondrial electron transport chain with inhibition of cytochrome c reductase and succinate dehydrogenase resulting in damage to hepatocyte respiration.
It has also been shown to cause damage to cell membranes by means of significant disturbances to the structure of the hydrophobic phospholipid bilayer resulting in echinocyte formation within erythrocytes and disorganization of the Golgi apparatus.
Further dysfunction of mycrotubules and inhibition of synthesis of complex gangliosides has been demonstrated in animal studies.
Finally, it has also been observed to act as a competitive inhibitor for acetylcholine by acting as a false neurotransmitter binding to acetylcholine receptors.
Paraquats and Diquats
Paraquats and diquats corrosive agents that are rapidly and efficiently absorbed through the mucosa when ingested, however they are not able to be absorbed through intact skin. Paraquats and diquats alike are bipyridyl herbicides which generate reactive oxygen species through successive redox reactions culminating in the generation of superoxide and hydroxyl radicals which are able to rapidly damage various tissue cells by means of lipid peroxidation. They are highly toxic to the liver, lungs, kidney and heart. The lungs are particularly vulnerable to paraquats which tend to accumulate within pneumocytes leading to pulmonary fibrosis.
Organophosphates are ester derivatives of phosphoric acid which function as insecticides by means of binding to a serine moiety in acetylcholine esterases and neuropathy target esterases (NTEs) preventing acetylcholine from binding. As these esterases serve to break down acetylcholine into acetate and choline, preventing of binding of acetylcholine results in the accumulation of excessive amounts of acetylcholine. This causes excessive stimulation of cholinergic receptors. Over time, the organophosphate-esterase complex may undergo a process called ageing during which nucleophilic attack leads to reinforcement of the bond between the serine moiety and the now aged organophosphate. Once aged, the binding becomes irreversible rendering the esterase inoperable.
Carbamates are ester derivatives of carbamic acid which function as insecticides by means of a mechanism nearly identical to that of organophosphates (see organophosphates). Carbamates differ from organophosphates in that they only transiently inhibit the esterase, which after time regain full functionality.
Pyrethroid compounds are derivatives of the East African chrysanthemum flower and are one of the most widely used insecticides in both developed and developing nations alike. Their toxicity results from a number of mechanisms.
Pyrethroid compounds have been shown to cause delayed closure of the sodium ion channels during repolarization in excitable neurological tissue. This delayed closing results in the generation of an inward sodium tail current that serves to lower the action potential threshold. This causes repetitive action potentials to fire resulting in excessive neurostimulation.
Additionally, pyrethroids may act on protein kinases causing excessive calcium and neurotransmitter release inside cells.
At very high levels, pyrethroids have also been shown to be neurotoxic. Animal studies have shown damage consistent with Wallerian degeneration in posterior tibial and sciatic nerves of laboratory animals when treated with near lethal doses.
Finally, pyrethroids are also thought to act on GABAergic neurons, which may explain seizure activity see with severe intoxication.
Organochlorides are thought to inhibit Ca/Mg ATPases antagonizing GABAergic chloride transport. This results in over-stimulation of the central nervous system.
Rodenticides & Avicides
Thallium is an elemental metal absorbed extremely efficiently through the mucousa. It is easily distributed to bones, liver, muscle, lungs, and brain. It's toxicity is derived from the fact possesses a similar atomic radius to potassium allowing it compete for binding to various proteins, including membrane transport proteins and intracellular proteins which bind potassium. Thallium substitutes for potassium in Na-K-ATPases with considerably stronger affinity than potassium. This results in a loss of sodium potassium homeostasis and disruption of various dependent intracellular activities.
Thallium's toxicity has also been shown to result from a number of additional mechanisms.
Thallium has been observed to be directly neurotoxic and has been shown to cause central, cranial, and peripheral nerve dysfunction.
Disruption of sulfhydryl groups within the mitochondria is by thallium thought to result in mitochondrial damage.
Finally, it is thought that thallium may generate insoluble riboflavin complexes causing riboflavin deficiency in patients, which may explain some of the dermatological effects of thallium.
Coumarins include Warfarin and its derivatives. These chemicals are used therapeutically in patients to control activation of coagulation cascade. They are also used as rodenticides because excessive levels can cause coagulopathies in target organisms.
Conversion of coagulation factors II, VII, IX, and X, along with Factors S and C to their active forms requires a cofactor, vitamin K. Upon activation, however, vitamin K is converted to an unusable form. An enzyme, vitamin K1-2,3-reductase, is necessary to replenish vitamin K levels by converting the unusable form of vitamin K back to its functional form. Warfarin and its derivatives function by inhibiting vitamin K1-2,3-reductase, depleting vitamin K and preventing the conversion of factors II, VII, IX, X, S, and C to their active forms and disrupting normal coagulation.
Calciferol is necessary for proper phosphate and calcium homeostasis and is responsible for activating calcium absorption from the gut. It also results in stimulation of reabsorption of phosphate in the renal tubule and secretion of calcium from bone. Excess levels of calciferol as may occur in calciferol intoxication results in hypercalcemia.
Chloralose is thought to bind to distinct allosteric site within GABAergic neurons resulting in potentiation of GABA's binding to its receptor. This results in depression of the central nervous system.
Sodium fluoroacetate is a salt which interferes with a number of metabolic pathways in cells. Flouroacetate structurally resembles acetate and can therefore react with co-enzyme A. As a result, mechanisms requiring acetyl-CoA cannot properly proceed, thereby inhibiting the citric acid cycle, fatty acid metabolism, and the urea cycle, among other metabolic pathways.
Pentachloraphenol uncouples the electron transport chain in mitochondria and prevents uptake of phosphate during alpha-ketoglutarate oxidation.
Organomercury compounds are absorbed in the lungs, the gastrointestinal mucosa, and even the skin. They are extraordinarily toxic and absorption results in the inactivation of thioredoxin reductase and other selenoenzymes. As a result vitamins C & E cannot be restored to their functional states resulting in accumulation of reactive oxygen species and cellular damage.
Organotin compounds cause irritation to the skin and mucus membranes and can cause damage to the respiratory tract and eyes. They are also neurotoxic.
Thiocarbamates force the release of glutamate from cells by distorting vesicular transport. It is thought that release of glutamate for prolonged periods may play a role in the formation of basal ganglia lesions.
Further, thiocarbamates have been known to induce copper accumulation within the cerebellum and hippocampus. This accumulation has been shown to be directly neurotoxic.
In addition, thiocarbamates have been shown to cause inhibition of cellular respiration in GABAergic and dopaminergic cells through mitochondrial uncoupling. It has also been shown that thiocarbamates produce destructive reactive oxygen species which result in damage to dopaminergic neurons seen in animal studies.
Chloropicrin is thought to exert a number of toxic effects on those exposed to it. It reacts with sulfhydryl groups in a number of proteins causing dysfunction. It is thought that its interaction with these groups may result in misfiling of sulfhydryl containing proteins. This is observed in the activation of certain chaperone proteins within the endoplasmic reticulum.
Chloropicrin has been observed to inhibit succinate dehydrogenase and pyruvate dehydrogenase, and damage hemoglobin resulting in decreased oxygen transport.
Additionally, it has been observed to generate reactive oxygen species which cause oxidative damage to exposed tissue. It is speculated that this may be a mechanism responsible for its affect on sulfhydryl groups.
This effect results in widespread irritation and damage to epithelial surfaces, and in the case of inhalation, can cause pulmonary edema.
Metal phosphides, including zinc, magnesium, and aluminum phosphide, generate phosphine upon exposure. Phosphine perturbs the mitochondrial membrane potential and inhibits complex IV of oxidative phosphorylation. This directly inhibits mitochondrial respiration.
Arsenic containing compounds are toxic to a number of processes. Arsenic can bind to red blood cells allowing for wide disbursement to various tissues. It binds to sulfhydryl groups causing dysfunction of various metabolic processes. It directly inhibits pyruvate dehydrogenase and impedes gluconeogenesis, fatty acid oxidation, and glutathione metabolism. It also crosses various barriers such as the blood brain barrier and the blood placental barrier.
The clinical presentation of pesticide intoxication varies significantly with the particular agent a patient may be poisoned with. This section will discuss the clinical presentation of each of the pesticides discussed in previous sections.
One of the most common manifestations of glyphosate poisoning is gastrointestinal disturbances. Patients often experience nausea, vomiting, and diarrhea. In addition, patients poisoned with glyphosate also frequently experience hypotension. Other common signs and symptoms of acute poisoning with glyphosate pesticides include acute kidney injury, respiratory failure, and cardiac arrhythmias. In cases in which the glyphosate containing pesticide product is found to be caustic, erosion of the gastrointestinal tract, dysphagia, pharyngeal pain, and hemorrhage have been observed. Diagnosis should be made on the basis of clinical presentation, however gas/liquid chromatography is available for identification of glyphosate in plasma. In addition, hyperkalemic, metabolic acidosis is also observed.
Presentation of patients with cutaneous exposure and inhalation of small quantities may not be obvious, however chloracne has been observed in some cases. Patients who have been poisoned with 2,4-D may experience nausea and vomiting, accompanied by confusion and sometimes aggression, when large quantities have been ingested. Some patients may also present with prolongation of the QT interval and T wave inversion on ECG. While some patient may exhibit metabolic acidosis others may show an alkalosis making blood gas analysis inconsistent. Isolated urea elevation has been observed in cases of poisoning, and elevations in hepatic transaminases have been seen frequently in cases of 2,4-D poisoning. 2,4-D can be identified effectively in blood as well as urine by means of gas chromatography, but diagnosis should be made on the basis of clinical presentation and thorough history, as gas chromatography may not be practical in the acute setting.
Paraquats and Diquats
Symptoms present rapidly in acute poisoning cases involving paraquats or diquats. Initial symptoms may be seen within 12 hours of poisoning. Patients who have skin exposure to these pesticides typically present with erythema, skin ulceration, and/or blistering. Eye exposure may result in eye irritation and ulceration. Patients with inhalation exposure may experience damage to the mucosa resulting in epistaxis and burns to the throat. Deep lung injury may also occur resulting in lung damage. Ingestion of paraquats and diquats results in a dose dependent presentation. Large quantity ingestion results from intake of more than 15mL (10% solution) and generally results in severe manifestations: shock, respiratory failure, multi-system organ failure, acute kidney injury, abdominal pain and dysphagia, hematemesis, and neurological involvement including seizures, confusion, and coma. Hollow organ perforation has been observed. Smaller doses (less than 15mL of 10% solution) have been observed to manifest with diarrhea, nausea and vomiting, pulmonary fibrosis, and liver, heart, and renal failure within days to weeks of ingestion. Urine and serum levels of paraquats or diquats may be obtained every 6-12 hours, however, diagnosis may be made by means of a proper history and physical examination.
The clinical feature of organophosphates have been well studied and significant effort has been made to ensure awareness of these features. As a result there are multiple mnemonics which serve to identify the manifestations of organophospate poisoning. One such mnemonic is the acronym SLUDGE which identifies 6 features of acute poisoning, namely: Salivation, Lacrimation, Urination, Defecation/Diarrhea, Gastrointestinal distress, and Emesis. Another frequently used, and more informative mnemonic is DUMBELS: Defecation/Diarrhea,Urination, Miosis, Bradycardia/Bronchorrhea/Bronchospasm, Emesis, Lacrimation, and Salivation. Other effects typically seen in patients exposed to organophosphate pesticides include neuromuscular involvement: weakness, fasciculation, tremors, and paralysis, and CNS involvement: altered mental status, respiratory depression/failure, seizures, and coma. Delayed symptoms include neuropathy and parasthesias. Additionally, many patients experience depressed or absent deep tendon reflexes. Because of the limited time to administer antidote, high index of clinical suspicion is vital to the diagnosis of organophosphate poisoning. Red blood cell acetylcholinesterase levels are useful in serving as a marker for exposure, though plasma acetylcholinesterase levels may be obtained n facilities where red blood cell acetylcholinesterase levels may be unavailable.
Because of the similar mechanism of action of carbamates, their clinical manifestations are similar to those of organophosphates. Like organophosphates, patients present with the DUMBELS cholinergic manifestations: Defecation/Diarrhea, Urination, Miosis, Bradycardia/Bronchorrhea/Bronchospasm, Emesis, Lacrimation, and Salivation. Diagnosis is also similar to that of organophosphates.
Pyrethroid compounds are some of the most widely used insecticides by individual consumers, and as a result, the clinical manifestations are well known. Most frequently, patients experience low level exposure to the skin and low level inhalation. In such cases, patients generally experience headache, fatigue, dizziness, and anorexia. Patients exposed to greater levels may also experience listlessness and muscle fasciculations. Seizures, comas and altered mentation may be seen in patients who have experienced high level intoxication. Ingestion of large volumes of pyrethroids may result in injury to the mucosal surfaces resulting in dysphagia, and epigastric pain, as well as ulcerations of the mouth and throat, and emesis. Nurological manifestations similar to those seen in inhalation and cutaneous exposure are generally absent. A common complication of ingestion and emesis is aspiration pneumonitis; pulmonary edema has also been observed. Laboratory studies of patients who have been poisoned have frequently shown leukocytosis. In some rare cases, ECGs have demonstrated persistent sinus arrest with escape junctional rhythms. While gas chromatography is available in some facilities for testing blood and urine for pyrathroid compounds, it is generally only useful as confirmatory testing. Diagnosis is best made by means of a proper history and physical examination. Anion gap metabolic acidosis may raise suspicion of pyrethroid poisoning.
Oral intoxication with organochlorides typically results in abdominal discomfort, nausea and vomiting, headaches, dizziness, hyperasthesias, and if severe, seizures, confusion, and dyscordination. Diagnosis may be made on the basis of thorough history and physical examination. Since organochlorides have been shown to be toxic to the kidneys, liver, and lungs, signs and laboratory analysis indicating end-organ damage to these systems are also useful in diagnosis of organochloride poisoning.
Rodenticides & Avicides
Thallium pesticide poisoning presents similarly to poisoning from other thallium sources such as glass manufacturing or lead smelting, etc. Patients who become poisoned with thallium, either through ingestion or exposure through the skin or mucosal surfaces, initially experience gastrointestinal symptoms including nausea and vomiting, diarrhea, constipation and abdominal pain. Patients also exhibit neurological dysfunction. Patients may experience changes in color perception, diplopia, nystagmous, and blindness. Also, patients may feel parasthesias or hyperalgesia of the skin and experience weakness in the extremities. Psychiatric disturbances have also been observed, primarily in children. Patients with severe poisoning may experience seizures, and thallium is known to be cardiotoxic, hepatotoxic, and nephrotoxic.
Late sequelae of intoxication with thallium include an acenform rash of the face and hyperkeratosis of the soles and palms. These typically occur about two weeks following exposure. In addition, alopecia occurs around the same timeframe, and is characteristic of thallium poisoning. Patients may also experience icthyotic lesions of the hands and feet.
Diagnosis should be made by means of a careful history and physical examination, but clinicians should be suspicious of thallium poisoning in patients with alopecia, characteristic skin signs and/or unexplained neuropathy. Laboratory assay is available to test for thallium directly in blood and urine. Due to the high propensity for end-organ damage, specific organ function tests should also be performed.
Clinicians should be familiar with the presentation of coumarin poisoning in patients due to the widespread use of warfarin as a therapeutic anti-coagulant in patients. Being an anti-coagulant, coumarin poisoning will result in a hypocoagulable state in most patients, though some may experience a paradoxical hypercoagulable state due to depletion of functional Proteins S and C. Thus patients may experience epistaxis, gingival bleeding, hematuria, GI bleeding, hemoptysis, and menorrhagia in females, among other manifestations. One severe manifestation is the possibility of in intracranial bleed. Effects typically may be seen within 12-48 hours of intoxication. Diagnosis may be achieved through careful history and physical examination, looking for signs of bleeding such as easy bruising, or in rare cases, coagulative skin necrosis. Laboratory investigations include prothrombin time with international normalized ratio which will generally be elevated in coumarin poisoning. In addition, activated partial thomboplastin (aPTT) should also be obtained. Vitamin K levels, factor levels, and mixing studies may be useful for further clarification.
Calciferol, like warfarin, is also an agent used therapeutically in patients. Individuals suffering from toxicity from calciferol based pesticides will present with signs and symptoms of D hypervitaminosis. These include hypercalcemia, abdominal pain, anorexia, nausea, and vomiting, renal insufficiency and renal stones, confusion, lethargy, cardiac arrhythmias, and systemic metastatic calcification, among other features. Clinicians may diagnose calciferol rodenticide poisoning by means of history of exposure to rodenticides in conjunction with high levels of vitamin D or calcium in the patient's plasma and clinical features of D hypervitaminosis.
In addition to sedation, chloralose intoxication may present with neurological manifestations including extremity myoclonus, seizures, and coma, heart failure consistent with ischemia, and tracheobronchiolar hypersecretion. Diagnosis should be made by means of a proper history and physical examination, but may be confirmed by means of gas chromatography mass spectroscopy (GCMS) or 1H Nuclear Magnetic Resonance (1H-NMR) of urine or plasma to detect presence of chloralose.
Patients with sodium fluoroacetate poisoning typically present nausea and vomiting, abdominal pain, hypocalcaemia, lactic acid metabolic acidosis, acute kidney injury, hypotension, respiratory depression, and neurological manifestations, including seizures, altered mentation, and coma. Patients may also exhibit non-specific ST changes or prolongation of the corrected QT interval, atrial fibrillation, and ventricular dysrhythmias including ventricular tachycardia and ventricular fibrillation. There is no specific testing for sodium fluoroacetate poisoning, so a high index of clinical suspicion is necessary to diagnose sodium fluoroacetate poisoning from the history and physical examination.