A narrative review of contemporary lethal pesticides: unveiling the ongoing threat of pesticide poisoning

Contemporary lethal pesticides

Article information

Clin Exp Emerg Med. 2024;11(4):335-348

Publication date (electronic) : 2024 January 29

doi : https://doi.org/10.15441/ceem.23.167

Sangchun Choi

, Gi Woon Kim

, Hoon Lim

Department of Emergency Medicine, Soonchunhyang University Bucheon Hospital, Soonchunhyang University College of Medicine, Bucheon, Korea

Correspondence to: Sangchun Choi Department of Emergency Medicine, Soonchunhyang University Bucheon Hospital, Soonchunhyang University College of Medicine, 170 Jomaru-ro, Wonmi-gu, Bucheon 14584, Korea Email: avenue59@schmc.ac.kr

Received 2023 November 27; Revised 2023 December 29; Accepted 2024 January 2.

Abstract

Following the 2011 ban on paraquat sales, Korea has witnessed a significant reduction in the mortality rate associated with acute pesticide poisoning. Traditionally, paraquat and diquat, alongside several highly toxic organophosphates, carbamates, and organochlorine insecticides, have been recognized as culprits in causing fatalities among patients with acute pesticide poisoning. However, despite global efforts to curtail the use of these highly toxic pesticides, certain pesticides still exhibit a level of lethality surpassing their established clinical toxicity profiles. Understanding the clinical progression of these pesticides is paramount for physicians and toxicologists, as it holds the potential to enhance patient prognoses in cases of acute poisoning. This review aims to address the persistence of highly lethal pesticides, which continue to pose a grave threat to victims of acute poisoning.

Keywords: Insecticides; Herbicides; Poisoning; Mortality

INTRODUCTION

Following the 2011 ban on paraquat sales, Korea witnessed a significant reduction in the mortality rate associated with acute pesticide poisoning [1]. Traditionally, paraquat and diquat, alongside several highly toxic organophosphates, carbamates, and organochlorine insecticides, have been recognized as major causes of fatalities among patients with acute pesticide poisoning [2,3]. However, despite global efforts to curtail the use of highly toxic pesticides, certain pesticides still exhibit a level of lethality surpassing their established clinical toxicity profiles [1–6].

Understanding the clinical progression of acute poisoning with these pesticides is paramount for physicians and toxicologists in order to enhance patient care and improve the prognosis. This review aims to address the persistence of such highly lethal pesticides, which continue to pose a grave threat to victims of acute poisoning.

CHLORFENAPYR

Chlorfenapyr is an insecticide, derived from halogenated pyrroles produced by Streptomyces spp. According to the US Environmental Protection Agency, toxicity categories for acute hazards of pesticide products, the acute toxicity of chlorfenapyr following ingestion is considered toxicity category I (mild toxicity) in mice (lethal dose [LD₅₀] of 45 mg/kg) and category II (moderate toxicity) in rats (LD₅₀ of 441 mg/kg) [7,8]. In humans, chlorfenapyr intoxication can be fatal and is associated with distinctive clinical and neuroradiological features [9–15].

Mechanisms of toxicity

Chlorfenapyr acts as a pro-insecticide that must undergo conversion through oxidative removal of the N-ethoxymethyl group by the microsomal monooxygenase system of target insects to produce the toxic metabolite tralopyril [16]. Tralopyril, identified as the most toxic metabolite in animal studies, has an oral LD₅₀ of 27 mg/kg in male rats [17]. Possessing both lipophilic and acidic properties, tralopyril exerts its lethal effects on insects and rodent cells by causing uncoupling of oxidative phosphorylation [8,18]. In insect studies, inhibition of microsomal monooxygenases by the specific inhibitor pyperonyl butoxide significantly reduces the potency of chlorfenapyr, but not tralopyril [19,20]. Animal studies indicate the detergents in pesticides may enhance gastrointestinal absorption of chlorfenapyr [21]; however, knowledge regarding the most other aspects of the pharmacokinetics of chlorfenapyr and tralopyril in mammals remains limited.

Radiologically, the involvement of the entire white matter tract is a characteristic finding, consistent with previous reports [9–11]. Rats with chlorfenapyr intoxication revealed vacuolar myelinopathy and myelin sheath swelling [7]. Similar pathological changes in myelin and white matter necrosis have been observed in autopsies of patients with toxic leukoencephalopathy [11,14]. These findings suggest that chlorfenapyr may damage the white matter of the central nervous system (CNS), resulting in neurological symptoms and signs such as blurred vision, optic neuropathy, urinary incontinence, altered mental status, seizure, and paraplegia [10–13].

Clinical features

Toxic symptoms and signs of acute chlorfenapyr poisoning include fever, diaphoresis, general fatigue, blurred vision, psychological effects, pancreatitis, and rhabdomyolysis [10,22–25]. Following chlorfenapyr ingestion, patients typically exhibit self-limited vomiting, diarrhea, a subjective feeling of heat, and diaphoresis within 1 to 14 days post-exposure [10,26,27]. Restlessness and confusion may appear 4 to 18 days after exposure [25,28,29]. The appearance of high body temperature or hyperthermia (>39 °C) 5 to 19 days post-exposure,, often indicates a poor prognosis [15,30–32]. Hence, heightened vigilance is essential in cases of hyperthermia (>39 °C) associated with acute chlorfenapyr poisoning, irrespective of the onset timing. The reported minimal lethal dose for oral administration was estimated to be 10 mL of 10% chlorfenapyr based on the poisoning of a 13-year-old girl, and the median time to death is reported to be 10 days (ranging from 5 to 20 days) [26,32,33]. Notably, inhalation and skin contact exposure can also result in severe poisoning. For instance, a 55-year-old man involved in farming work developed fever and seizures shortly after spraying a diluted chlorfenapyr solution (125 mL at 10% in 500 L of water) and died 7 days later [34]. A 49-year-old man developed various neurotoxic symptoms and signs beginning 1 day after exposure of the skin on the arms, chest, and abdomen to a 10% chlorfenapyr solution [28]. Lee et al. [35] reported a 74-year-old man passed away 12 days after self-injection with 20 mL of chlorfenapyr into his abdomen. The main toxic symptoms and signs and the progression clinical toxicity are summarized in Fig. 1.

Fig. 1.

Clinical course of acute chlorfenapyr poisoning. In the clinical course of acute chlorfenapyr poisoning, the following should be noted: (1) the potential for fatality even with minimal exposure; (2) the possibility of “life-threatening delayed injury” occurring after the resolution of nonspecific acute poisoning; and (3) the extension of this “latent period” to approximately 14 days post-exposure.

Management

All personnel encountering patients exposed to chlorfenapyr should exercise caution given the potential for secondary poisoning. There are no well-established specific treatments for acute chlorfenapyr poisoning and conservative treatment should be tailored to the patient's symptoms and clinical signs. Basic detoxification and supportive measures, may include administering activated charcoal and, if necessary, performing gastric lavage. Regarding the management of significant hyperthermia, a standardized treatment protocol for effectively managing significant hyperthermia has not been explicitly reported. Muscle relaxants, such as benzodiazepines, and neuroleptic agents like chlorpromazine, have been utilized to mitigate shivering and act as a preventive measure against seizures; however, clinical trials demonstrating their efficacy are lacking. Dantrolene sodium has not proven effective in reducing core temperature. Although antipyretic agents theoretically hold promise in addressing the acute-phase reactant response, they have not been adequately evaluated for this purpose. Active cooling methods, encompassing cold packs or ice packs, cooling blankets, evaporative cooling, and intravenous cold saline, are considered potential strategies to facilitate temperature reduction. In exigent circumstances, the contemplation of therapeutic hypothermia (target temperature management) may also be warranted.

Extracorporeal removal methods may be considered due to the small molecular weight of chlorfenapyr (407.6 Da), allowing it to readily cross cellular membranes [19,20]. However, the lack of comprehensive data regarding other toxicokinetic parameters of chlorfenapyr in humans, such as protein binding, volume of distribution, and lipid solubility, hinders the use of extracorporeal removal methods. Nevertheless, the latest clinical reports indicate timely elimination of the toxicant and early organ-function support can significantly enhance the prognosis; intermittent hemodialysis (IHD) or continuous renal replacement therapy (CRRT) may therefore be undertaken at the attending physician’s discretion [27,36]. It is important for healthcare providers to recognize that while the clinical course among patients may vary, with potential occurrence of delayed toxic symptoms following the initial alleviation of acute poisoning symptoms, and all patients exposed to chlorfenapyr, even in cases of dermal exposure, carry a potential risk of a relentless course and mortality [28]. Therefore, proactive treatment to prevent delayed toxic symptoms is strongly recommended, as is extended in-hospital observation of individuals with chlorfenapyr intoxication.

BENTAZONE

Bentazone is a selective contact herbicide and is classified as a moderately hazardous (class II) herbicide by the World Health Organization [37,38].

Mechanisms of toxicity

In a rat model, bentazone was rapidly absorbed and mostly excreted in the urine [37]. An hour after its oral administration, it was distributed to the stomach, liver, kidneys, and heart of the rat, but not to the brain or spinal cord [37,38]. The substance was metabolized to 6-OH bentazone and 8-OH bentazone through hydroxylation [38,39]. The LD₅₀ was 1,100 mg/kg in rats and 2,918 mg/kg in pheasants [38,39]. Bentazone was rapidly absorbed in and distributed to the stomach, liver, kidneys, and heart. Limited information regarding the toxicokinetics of bentazone in humans suggests rapid and extensive absorption following oral administration, with significant excretion in the urine, primarily in its unchanged form [37]. Although bentazone is not thought to easily cross the blood-brain barrier (BBB) in rats, neurological toxic signs and symptoms in acute bentazone poisoning suggest that it may do so after consumption of large amounts. Its mechanism of action in humans is unknown, although the clinical features of poisoning suggest that bentazone may uncouple oxidative phosphorylation. It is likely that co-formulants are responsible for some of the toxic effects of some products.

Clinical features

The toxic symptoms and signs of acute bentazone poisoning include sweating, hyperpyrexia, nausea, vomiting, diarrhea, abdominal pain, cough, tachypnea, dyspnea, apnea, tachycardia, mental change, neurological abnormalities including agitation, talking nonsense, and loss of consciousness, muscle rigidity, rigor mortis, and cardiac arrest [39–45]. Limb rigidity was a prominent feature in severely intoxicated patients. Limb rigidity, rhabdomyolysis, hyperpyrexia, and elevated levels of aspartate and alanine aminotransferase may lead to misdiagnosis of acute bentazone poisoning as neuroleptic malignant syndrome [40]. Fatal cases involving liver failure, kidney injury, and muscle rigidity, often accompanied by failed or delayed airway access, have been reported [39-42]. Of note, the emerging pattern of acute bentazon poisoning indicates that the onset of symptoms may occur in less than 1 hour, with death occurring within as little as 2 hours. Jaw rigidity commonly occurs in such cases. The acute symptoms associated with acute bentazon poisoning may resemble those of malignant hyperthermia, suggesting that lethality from acute poisoning might be further delayed.

In the clinical course of acute bentazone poisoning, the following should be noted: (1) the occurrence of musculoskeletal rigidity; (2) a very rapid progression to deterioration in cases of severe, life-threatening poisoning; and (3) the development of jaw rigidity unresponsive to muscle relaxants in severely poisoned patients. The main toxic symptoms and signs and clinical progression are summarized in Fig. 2.

Fig. 2.

Clinical course of acute bentazone poisoning. In the clinical course of acute bentazone poisoning, the following should be noted: (1) the occurrence of musculoskeletal rigidity; (2) a very rapid progression to deterioration in cases of severe, life-threatening poisoning; and (3) the development of jaw rigidity unresponsive to muscle relaxants in severely poisoned patients. CNS, central nervous system.

Management

All personnel encountering patients exposed to bentazone should exercise caution given the potential for secondary poisoning. If the patient seeks medical attention within 1 hour of ingestion, gastric lavage should be performed, and activated charcoal administered. Activated charcoal administration may be helpful for several hours after exposure. There is no specific antidote for acute bentazone poisoning. The management of acute bentazone poisoning is symptomatic and supportive. As illustrated in Fig. 2, severe poisoning advances rapidly and is frequently accompanied by trismus. Thus, in scenarios where severe poisoning is anticipated, proactive preparation for airway management is crucial. Laboratory work-up and the electrocardiogram results should be monitored. While dantrolene sodium hasn't been commonly used in treating this type of poisoning, it could be administered if muscle rigidity is expected to worsen significantly. In cases of hypotension and loss of consciousness, fluid resuscitation with vasopressor administration and respiratory support, including endotracheal intubation are crucial. The muscle relaxant succinylcholine may be ineffective against muscle rigidity in acute bentazone poisoning; in such cases, cricothyroidotomy will be needed to keep the airway open [44].

G-SH AND POEA

Glyphosate is a nonselective herbicide that inhibits the shikimic acid pathway and has been extensively used worldwide since its development in 1970 [46]. It is mainly sold as Roundup (Bayer AG) [47]. Glyphosate isopropylamine or ammonium salts are commonly used as active ingredients, and many products also contain polyoxyethylene amine (POEA) as one of the surfactants [4,48–50]. POEA often leads to harm in individuals who have been poisoned in the acute poisoning In rodents, the oral LD₅₀ of glyphosate is greater than 5 g/kg [50]. However, the LD₅₀ of POEA is 1 to 2 g/kg. Due to this toxicity, a notable aspect of acute glyphosate surfactant herbicide (G-SH) poisoning is that while toxicity symptoms caused by glyphosate alone are mild, the co-formulant POEA used as an adjuvant becomes the primary cause of intoxication injury [51]. Therefore, it is important to determine whether the glyphosate formulation to which a patient was exposed included POEA in order to establish treatment options and prognosis [48,50,51].

Mechanisms of toxicity

The mechanism of G-SH toxicity appears to be related to the absorption and decomposition of surfactants containing POEA. Ingestion of surfactants may result in hemodynamic changes with decreased total vascular resistance [52].

Clinical features

Immediate medical attention is crucial in cases of suspected G-SH poisoning, as symptoms can escalate swiftly. The main toxic symptoms and signs and clinical progression are summarized in Fig. 3 [46,53–63].

Fig. 3.

Clinical progression of acute glyphosate surfactant herbicide (G-SH) poisoning. The symptoms and signs of acute G-SH poisoning vary depending on the type and level of exposure, but may include involvement of the following: (1) gastrointestinal system (oropharyngeal irritation and nausea, vomiting, abdominal irritation and pain, diarrhea, hemorrhagic gastritis, elevated hepatic enzyme, esophageal perforation, and pyloric stenosis); (2) pulmonary system (dyspnea, pulmonary congestion, pulmonary edema, and aspiration pneumonia; (3) cardiovascular system (hypotension, shock, first-degree heart block, ST-T wave change, and cardiac arrest); (4) renal system (oliguria and acute kidney injury; and (5) other organs/functions (skin irritation, hyperkalemia, hemolysis, mental change, seizures, and coma in severe cases). CNS, central nervous system; FiO₂, fraction of inspired oxygen; AKI, acute kidney injury.

Given the severity of toxicity progresses based on the extent of POEA absorption, it is conjectured that the degree of systemic toxicity is closely related to the prognosis of the patient with acute G-SH poisoning. Toxic signs such as acute kidney injury, hypotension, and severe metabolic acidosis reflect the worsening of severe poisoning, and require special attention in the management of G-SH toxicity [62,64].

Ingestion of a large amount of G-SH (>250 mL) and/or the presence of seizure, coma, hypotension, cardiac arrest, PaO₂ to fraction of inspired oxygen ratio less than 100, severe metabolic acidosis, acute kidney injury, and hyperkalemia suggest severe poisoning and a poor prognosis. Additionally, although not explicitly indicated in Fig. 3, the prognosis for elderly patients is poor.

Management

All personnel encountering patients exposed to G-SH-should exercise caution given the potential for secondary poisoning. If the ingested amount is more than one sip (0.5 mL/kg) of a typical product containing 41% or higher glyphosate concentration, it is necessary to observe the patient for a minimum of 24 hours [53,65]. If the patient seeks medical attention within 1 hour of ingestion, gastric lavage should be performed, and activated charcoal should be administered. Activated charcoal administration can be beneficial for several hours after exposure. There is no specific antidote for glyphosate poisoning. Therefore, treatment typically involves provision of supportive care, including supporting breathing and cardiac function, as well as administering medications to manage symptoms. Recently, intravenous lipid emulsion has emerged as a potential antidote for moderate to severe poisoning and may be administered at the attending physician's discretion [66–68]. The mortality rate varies among reported cases but generally falls within the range of 7.5% to 16.1% [47,53]. After active rescue, due to chemical injury, scar contractures frequently occur in both the esophagus and trachea, which will require reconstruction surgery [69]. In cases involving a drop in blood pressure or loss of consciousness, essential measures include fluid resuscitation with vasopressor administration, and respiratory support, including endotracheal intubation. If renal function remains normal after ingestion, elimination through the kidneys is likely operative; however, in poisonings where a large amount of G-SH has been ingested, and/or acute kidney injury, moderate to severe metabolic acidosis, pulmonary edema, hyperkalemia, or severe cardiovascular dysfunction have occurred or are anticipated, extracorporeal removal methods such as IHD or CRRT or extracorporeal membrane oxygenation become necessary [64,70,71]. When the ingestion is attributed to a product containing glyphosate potassium, there is an increased risk of hyperkalemia, necessitating monitoring of plasma potassium concentrations [72]. Studies examining long-term complications or sequelae following recovery from acute poisoning are lacking, and caution is warranted regarding potential complications, including esophageal stricture, and cancer of the esophagus, kidneys, and liver, and the onset of degenerative neurological disorders.

GLUFOSINATE AMMONIUM HERBICIDE

Glufosinate ammonium is an herbicide commonly used to control weeds and unwanted vegetation. It works by inhibiting an enzyme that is crucial for plant growth, but it can also be harmful to humans if ingested, inhaled, or comes into contact with the skin or eyes.. The LD₅₀ in rats is 1.66 g/kg, In humans, the acute oral LD₅₀ is 1.6 to 1.8 mg/kg [73]. Gastrointestinal absorption is relatively rapid, with peak blood concentrations achieved within one; however, the presence of surfactants increases absorption approximately 25% to 30% [74]. The glufosinate ammonium herbicide (GAH) that is commercially available in Korea does not contain sodium polyoxyethylene alkyl ether sulfate as the surfactant [4]. Over 90% of the absorbed compound is eliminated through the kidneys, and when renal function is maintained normally, approximately 97% of the compound is eliminated within 24 hours [73–75].

Mechanisms of toxicity

Gastrointestinal irritation and damage may occur due to the surfactants, and CNS toxicity is suspected to be attributed to N-methyl-D-aspartate (NMDA) receptor activation and a reduction in γ-aminobutyric acid (GABA) [4,76–79]. Glufosinate ammonium is a compound with high hydrophilicity and high polarity, limiting permeation through the intact BBB [74]; nonetheless, glufosinate has been detected in the brains of acute glufosinate poisoning patients at concentrations that are typically about one-third of the plasma concentration. When GAH is formulated with alkyl ether sulfate as a surfactant, caution is warranted because it can lead to significant hemodynamic changes, including vasodilation, and direct cardiac suppression at high concentrations, increasing the risk of cardiovascular complications [80].

Clinical features

Toxic symptoms and signs of acute GAH poisoning can vary depending on the route and extent of exposure, but they may include nausea, vomiting, diarrhea, abdominal pain, difficulty breathing, dizziness, headache, and in severe cases, seizures, loss of consciousness, diabetic insipidus, and apnea [81–87]. Immediate medical attention is crucial when there is suspicion of acute moderate to severe GAH poisoning, as toxic symptoms and signs can rapidly worsen in severity. It should be noted that even in cases where patients with acute GAH poisoning present with an alert mental status or a normal Glasgow Coma Scale (GCS) result upon admission to the emergency department, severe poisoning or fatality remains a possibility. Brain lesions secondary to acute poisoning are commonly found in the splenium of the corpus callosum, bilateral posterior limbs of the internal capsule, bilateral cerebellar peduncles, bilateral cerebral peduncles of the midbrain, and the hippocampus. Fig. 4 outlines the clinical progression of acute GAH poisoning.

Fig. 4.

Clinical progression of acute glufosinate ammonium herbicide (GAH) poisoning. In the clinical course of acute GAH poisoning, the following should be noted: (1) plasma ammonia concentrations are frequently elevated beginning in the early phase of poisoning; (2) various neurotoxic symptoms and signs necessitating critical care support may be present in moderate to severe poisoning; and (3) the latent period may be up to 48 hours following GAH exposure. CNS, central nervous system; EOM, extraocular muscle; AKI, acute kidney injury.

Hyperammonemia

In the process of GAH decomposition, ammonia is often produced, leading to elevated plasma ammonia concentrations in acute GAH poisoning cases. However, for CNS toxicity to occur in moderate to severe GAH poisoning, we believe that GAH or its metabolic byproducts must breach the BBB. Moderate to severe poisoning symptoms seem to emerge when GAH crosses the BBB due to overdose or other mechanisms. Predicting fatal CNS toxicity solely based on initial plasma ammonia levels measured upon the ED admission, except in cases with exceptionally high levels (at least >100 µg/dL), is challenging [88]. Severe CNS toxicity symptoms and signs likely result from stimulation of NMDA receptors by GAH or related metabolic products that have crossed the BBB. Additionally, exceptionally high plasma ammonia levels upon the ED admission may indicate exposure to a large amount of GAH or suggest specificity in GAH metabolism. While an increase in blood ammonia levels upon the ED admission may suggest exposure to a certain degree of overdose, accurately predicting severe CNS toxicity is challenging. Given the diverse findings and perspectives on the influence of hyperammonemia in the development of neurological toxicity and its role in the progression and prognosis of acute GAH poisoning, the above information should be interpreted with caution. The main toxic symptoms and signs and the clinical progression are summarized in Fig. 4 [85,86,89–94].

Management

All personnel encountering patients exposed to GAH should exercise caution given the potential for secondary poisoning. If the patient seeks medical attention within 1 hour of ingestion, gastric lavage is performed, and activated charcoal should be administered. Administration of activated charcoal may be beneficial for several hours after exposure. There is no specific antidote for acute GAH poisoning. Therefore, treatment typically involves provision of supportive care, including supporting breathing and cardiac function, as well as administering medications to manage symptoms. In cases where hypotension, loss of consciousness, or breathing difficulty occurs, fluid resuscitation including the administration of vasopressors and inotropic agents, and respiratory support, which includes endotracheal intubation, is necessary. At the discretion of the attending physician, IHD or CRRT may be administered in the early stages of acute poisoning to reduce plasma GAH concentrations [95]. However, the effectiveness of these interventions in preventing severe complications, such as seizures and respiratory arrest, remains uncertain [82,95,96]. Considering that the renal clearance of glufosinate ammonium is 1.6 to 1.8 times larger than that of extracorporeal elimination, it is recommended to limit extracorporeal elimination to patients experiencing the early phase of serious toxic symptoms or those with acute kidney injury. To date, there is no evidence supporting the administration of intravenous lipid emulsion as a therapeutic agent in cases of acute GAH poisoning.

Plasma ammonia concentrations should be assessed in acute GAH poisoning at admission and thereafter to monitor patient status, although the clinician should be aware they may not accurately reflect CNS ammonia concentrations or CNS symptoms [79,88,97–100]. Early symptoms or ammonia test results have limitations in predicting severity in cases of acute GAH poisoning [101]. Hence, closely monitoring patients for at least 48 hours after GAH exposure appears essential. Clear treatment guidelines for managing hyperammonemia in patients with acute GAH poisoning have not been reported. However, given that elevated ammonia levels can lead to changes in consciousness, cognitive function, ataxia, seizures, and even coma, treatment is deemed necessary. Nonabsorbable disaccharides (such as lactulose, composed of the monosaccharides fructose and galactose) are considered the primary therapeutic approach for hyperammonemia. Rifaximin has emerged as the most effective antibiotic for hyperammonemia treatment due to its safety, efficacy, and tolerability. Additionally, sodium benzoate contributes to reducing blood ammonium levels by inhibiting glycine metabolism in the liver, kidney, and brain. Recovery from an acute poisoned state to everyday life may be prolonged. While few studies addressing long-term complications or sequelae following recovery from acute GAH poisoning are available, caution is warranted regarding potential complications, including reversible amnesia, prolonged overall cognitive dysfunction, psychotic features, and other neurolopsychological sequelae.

OTHER PESTICIDES

The following substances in Korea have been discontinued due to their high fatality in cases of acute poisoning, but they continue to be used due to their efficient functionality as pesticides. Therefore, proper disposal and handling of existing stocks are crucial to prevent accidental exposure.

Methomyl

Methomyl is a highly toxic carbamate insecticide commonly used to control a wide range of insects on crops, vegetables, and ornamental plants. It is known for its rapid action against pests, making it effective but also potentially dangerous to humans and other nontarget organisms. Regarding acute methomyl poisoning, it is important to note that liquid formulations may contain methanol as a surfactant [102]. The possible rapid onset of severe symptoms, such as altered consciousness, requires close monitoring of exposed patients. In Korea, sales and distribution of methomyl were discontinued in 2012; however, products containing thiocarb, which can be metabolized into methomyl, are still available in the market, often mixed with other insecticidal compounds.

Mechanism of toxicity

Methomyl reversibly inhibits acetylcholinesterase, an enzyme that plays a crucial role in the nervous system by breaking down the neurotransmitter acetylcholine. When acetylcholinesterase is inhibited, acetylcholine accumulates in the synapses of cholinergic neurons, leading to cholinergic overstimulation [103]. This can result in a range of symptoms affecting various bodily functions.

Clinical features

Exposure to methomyl can lead to a variety of symptoms, which can vary depending on the level of exposure and the route of exposure (ingestion, inhalation, or skin contact). The symptoms and signs of acute methomyl poisoning are represented in the mnemonic DUMBELS (diarrhea, urination, meiosis, bronchorrhea/bronchospasm, emesis/nausea, lacrimation, and salivation) [103,104]. Additional toxic symptoms and signs included profound sweating, dyspnea, headache, dizziness, muscle weakness, tremor, and confusion. In moderate to severe poisoning, breathing difficulties, mental change, and hypotension are characteristic features [103–105]. In rare instances, patients with acute methomyl poisoning did not manifest DUMBELS symptoms, emphasizing the need for caution among treating physicians.

Management

All personnel encountering patients exposed to methomyl should exercise caution given the potential for secondary poisoning. Decontamination methods such as gastric lavage or administration of activated charcoal may be used to reduce absorption. The treatment of acute methomyl poisoning involves supportive care and atropine administration to counteract the effects of excess acetylcholine if DUMBELS are identified [103,105]. When toxic symptoms and signs are vague, the atropine challenge test can be useful to identify the class of toxicant and evaluate the severity of poisoning. While the administration of pralidoxime (2-PAM) or obidoxime is not typically recommended for acute methomyl poisoning, in instances of prolonged cholinesterase inhibition 2-PAM is warranted, following a similar approach as in acute organophosphate poisoning [106]. In cases of severe respiratory distress, patients may require oxygen supplementation or mechanical ventilation. Additional medications may be indicated to manage specific symptoms such as seizures or muscle tremors. Furthermore, in the event of a rapid decline in mental status and severe metabolic acidosis, it may be necessary to initiate treatment for concurrent acute methanol poisoning [107].

Endosulfan

Endosulfan, a highly toxic organochlorine insecticide and acaricide, was commonly used to control a variety of pests on crops like fruits, vegetables, and cotton. However, due to its high toxicity, persistence in the environment, and potential to accumulate in organisms, many countries have restricted or banned its use. Therefore, incidents of acute endosulfan poisoning have decreased.

Mechanism of action

Endosulfan acts on the nervous system by affecting the normal function of the neurotransmitter GABA. GABA is the major inhibitory neurotransmitter in the CNS [108,109]. Endosulfan inhibits GABA receptors, leading to overstimulation of nerve cells and various physiological effects [108,109].

Clinical features

Exposure to endosulfan can lead to a range of symptoms, which may vary depending on the level and route of exposure (ingestion, inhalation, or skin contact). Symptoms of acute endosulfan poisoning may include the following [4,109–113]:

(1) Neurological effects: CNS symptoms are common and can include headache, dizziness, confusion, agitation, tremors, and intractable convulsions (seizures).

(2) Gastrointestinal distress: Nausea, vomiting, abdominal pain, and diarrhea are common gastrointestinal symptoms associated with endosulfan poisoning.

(3) Respiratory effects: Breathing difficulties, chest tightness, coughing, and wheezing can occur due to effect on the nervous system and respiratory muscles.

(4) Skin and eye irritation: Skin contact with endosulfan can cause irritation, redness, and itching. Eye exposure can lead to eye irritation and redness.

(5) Cardiovascular effects: Rapid heart rate (tachycardia) and hypotension may occur due to pulmonary embolism.

(6) Miosis: Constricted pupils can be a sign of endosulfan poisoning.

Management

All personnel encountering patients exposed to endosulfan should exercise caution given the potential for secondary poisoning. There is no specific antidote for acute endosulfan poisoning. The treatment of acute endosulfan poisoning involves provision of immediate medical attention and supportive care and may include the following:

(1) Decontamination: If the exposure is recent, decontamination methods such as washing the skin and eyes thoroughly or removing contaminated clothing can help reduce exposure.

(1) Symptomatic treatment: Medications can be prescribed to manage specific symptoms like seizures or respiratory distress.

(2) Respiratory support: In cases of severe respiratory distress, patients may require oxygen supplementation or mechanical ventilation.

(3) Vigilant monitoring: Patients exposed to endosulfan should be closely monitored for the development of symptoms and complications.

While seizures associated with acute endosulfan poisoning can occur for up to approximately 24 hours [114,115], the prognosis is generally more favorable compared to seizures resulting from other neurological diseases [115]. Seizure management, including intravenous administration of lorazepam and antiepileptic agents, and continuous electroencephalogram monitoring is deemed necessary in cases of endosulfan-related status epilepticus [115,116].

CONCLUSION

The continued use of highly toxic pesticides, such as chlorfenapyr, bentazone, G-SH, and GAH, in agricultural practices poses a continuous risk of acute pesticide poisoning. These compounds exhibit multiple mechanisms of toxicity and clinical manifestations, necessitating early recognition, supportive care, and appropriate management. It is highly advantageous for physicians and health providers to possess knowledge about the clinical course of these pesticides, as this understanding can substantially enhance the provision of effective treatment and ultimately lead to improved patient outcomes.

Notes

Author contributions

Conceptualization: SC; Formal analysis: SC, GWK; Investigation: GWK, HL; Methodology: SC; Supervision: SC, HL; Validation: GWK, SC; Visualization: SC; Writing–original draft: SC; Writing–review & editing: all authors. All authors read and approved the final manuscript.

Conflicts of interest

The authors have no conflicts of interest to declare.

Funding

The authors received no financial support for this study.

Data availability

Data sharing is not applicable as no new data were created or analyzed in this study.

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Notes

Capsule Summary

What is already known

Despite global efforts to curtail the use of highly toxic pesticides, certain pesticides still exhibit a level of lethality surpassing their established clinical toxicity profiles.

What is new in the current study

Understanding the clinical progression of potentially lethal pesticides is paramount for physicians and toxicologists in order to enhance patient prognoses in cases of acute poisoning. This review would unveil the persistence of such highly lethal pesticides, which continue to pose a grave threat to victims of acute poisoning.