Pesticide poisoning

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Historical Perspective

Pathophysiology

Classification

Causes

Differentiating Pesticide poisoning from other Diseases

Epidemiology and Demographics

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Natural History, Complications and Prognosis

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History and Symptoms

Physical Examination

Laboratory Findings

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-In-Chief:
Synonyms and Keywords: Pesticide intoxication; pesticide exposure; insecticide poisoning; insecticide intoxication; insecticide exposure; suicide

Overview

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.[1] . 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.

Historical Perspective

Classification

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:

  • Herbicides
  • Insecticides
  • Rodenticides & Avicides
  • Fungicides
  • Major Cross-classified Pesticides

Pathophysiology

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.

Herbicides

Glyphosate

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

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.

Insecticides

Organophosphates

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

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

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

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

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

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

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

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

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.

Fungicides

Pentachloraphenol

Pentachloraphenol uncouples the electron transport chain in mitochondria and prevents uptake of phosphate during alpha-ketoglutarate oxidation.

Orgnaomercury Compounds

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

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

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.

Cross-classified Pesticides

Chloropicrin

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

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

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.

Causes

Differentiating Pesticide poisoning from other Diseases

Epidemiology and Demographics

Risk Factors

Natural History, Complications and Prognosis

Diagnosis

History and Symptoms | Physical Examination | Laboratory Findings | Other Diagnostic Studies

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.

Herbicides

Glyphosate

2,4-Dichlorophenoxyacetic acid

Paraquats and Diquats

Insecticides

Organophosphates

Carbamates

Pyrethroid Compounds

Organochlorides

Rodenticides & Avicides

Thallium

Coumarins

Calciferol

Chloralose

Sodium Fluoroacetate

Fungicides

Pentachloraphenol

Orgnaomercury Compounds

Organotin Compounds

Thiocarbamates

Cross-classified Pesticides

Chloropicrin

Metal Phosphides

Arsenic

Treatment

Medical Therapy | Primary Prevention | Secondary Prevention | Cost-Effectiveness of Therapy | Future or Investigational Therapies

Case Studies

Case #1

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