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].

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.

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.

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.

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.

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].

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].

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].

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.

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.

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].

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.

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].

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.

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.

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.