MOBILE VIEW  | 

CARBAMATE INSECTICIDES

Classification   |    Detailed evidence-based information

Therapeutic Toxic Class

    A) Carbamates are insecticides with cholinergic actions similar to organophosphates.

Specific Substances

    A) Extremely toxic
    1) Aldicarb (Temik)
    2) Oxamyl (Vydate-L)
    3) Carbofuran (Furadan)
    4) Benfuracarb (Oncol, Furacon)
    5) Methomyl (Lannate)
    6) Formetanate (Carzol)
    Highly toxic
    1) Aminocarb (Matacil)
    2) Dimetilan (Snip Fly Bands)
    3) Dimetan (Dimetan)
    4) Dioxacarb (Elocron, Famid)
    5) Methiocarb (Mesurol)
    6) Propoxur (Baygon)
    7) Bendiocarb (Ficam)
    Moderately toxic
    1) Pirimicarb (Pirimor)
    2) Bufencarb (Bux)
    3) MTMC (Tsumacide)
    4) MPMC (Meobal)
    5) Isoprocarb (Etrofolan)
    6) Carbaryl (Sevin)
    GENERAL TERMS
    1) INSECTICIDE, CARBAMATE

Available Forms Sources

    A) FORMS
    1) LIQUIDS: These compounds are commonly formulated in petroleum distillates, to be applied as spray droplet emulsions.
    2) GRANULES: There are also granular formulations for agricultural use.
    3) DUSTING POWDERS: Carbaryl is incorporated into some dusting powder formulations, flea collars, and shampoos for pets. B. Listed below are the most widely available carbamate insecticides.
    Ā Common NameProprietary Name
    Extremely toxicAldicarbTemik
    OxamylVydate-L
    CarbofuranFuradan
    BenfuracarbOncol, Furacon
    MethomylLannate
    FormetanateCarzol
    Highly toxicAminocarbMatacil
    DimetilanSnip Fly Bands
    DimetanDimetan
    DioxacarbElocron, Famid
    MethiocarbMesurol
    PropoxurBaygon
    BendiocarbFicam
    Moderately toxicPirimicarbPirimor
    BufencarbBux
    MTMCTsumacide
    MPMCMeobal
    IsoprocarbEtrofolan
    CarbarylSevin

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Used for pest control in industrial agriculture (tends to be more toxic agents) to control ectoparasites on farm and companion animals, and for home and garden pest control. Poisoning occasionally occurs from ingestion of contaminated crops or food.
    B) TOXICOLOGY: Carbamates competitively inhibit pseudocholinesterase and acetylcholinesterase, preventing hydrolysis and inactivation of acetylcholine. Acetylcholine accumulates at nerve junctions, causing malfunction of the sympathetic, parasympathetic, and peripheral nervous systems and some of the CNS. Clinical signs of cholinergic excess develop.
    C) EPIDEMIOLOGY: Exposure is common, but serious toxicity is unusual in the US. Common source of severe poisoning in developing countries. Toxicity generally less severe than with organophosphates.
    D) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE POISONING: MUSCARINIC EFFECTS: Can include bradycardia, salivation, lacrimation, diaphoresis, vomiting, diarrhea, urination, and miosis. NICOTINIC EFFECTS: Tachycardia, hypertension, mydriasis, and muscle cramps.
    2) SEVERE POISONING: MUSCARINIC EFFECTS: Bronchorrhea, bronchospasm, and acute lung injury. NICOTINIC EFFECTS: Muscle fasciculations, weakness, and respiratory failure. CENTRAL EFFECTS: CNS depression, agitation, confusion, delirium, coma, and seizures. Hypotension, ventricular dysrhythmias, metabolic acidosis, pancreatitis, and hyperglycemia can also develop.
    3) CHILDREN: May have different predominant signs and symptoms than adults (more likely CNS depression, stupor, coma, flaccidity, dyspnea, and seizures). Children may also have fewer muscarinic and nicotinic signs of intoxication (ie, secretions, bradycardia, fasciculations, and miosis) as compared with adults.
    4) INHALATION EXPOSURE: Vapors rapidly produce mucous membrane and upper airway irritation and bronchospasm, followed by systemic muscarinic, nicotinic, and central effects if exposed to significant concentrations.
    0.2.3) VITAL SIGNS
    A) WITH POISONING/EXPOSURE
    1) Hypothermia and hyperthermia have occurred.
    0.2.20) REPRODUCTIVE
    A) Structural malformations have been produced in animals only at exposure levels toxic to the pregnant animal.

Laboratory Monitoring

    A) Monitor vital signs frequently. Obtain serial ECGs and Institute continuous cardiac and pulse oximetry monitoring.
    B) Monitor for respiratory distress (i.e. bronchorrhea, bronchospasm) and for clinical evidence of cholinergic excess (i.e. salivation, vomiting, urination, defecation, miosis).
    C) Determine plasma and/or red blood cell cholinesterase activities (plasma is generally more sensitive, but red cell correlates somewhat better with clinical signs and symptoms). Depression in excess of 50% of baseline is generally associated with cholinergic effects; in severe poisoning, cholinesterase activity may be depressed by 90% of baseline. Correlation between cholinesterase levels and clinical effects in milder poisonings may be poor.
    D) Monitor electrolytes and serum lipase in patients with significant poisoning.
    E) Monitor pulmonary function (i.e. forced vital capacity, expiratory volume in 1 second, negative inspiratory force) in symptomatic patients; may help anticipate need for intubation.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TOXICITY
    1) A patient who is either asymptomatic or presents with mild clinical symptoms (i.e. normal vitals, pulse oximetry and an acetylcholinesterase greater than 80% of lower reference range), and remains stable for 12 hours can be discharged. Obtain appropriate psychiatric evaluation if an intentional exposure.
    B) MANAGEMENT OF MODERATE TO SEVERE TOXICITY
    1) Immediate assessment and evaluation. Airway management is likely to be necessary. Simple decontamination (i.e. skin and gastrointestinal, removal of contaminated clothes). Administer antidotes: atropine for muscarinic manifestations (e.g. salivation, diarrhea, bronchorrhea), pralidoxime for severe toxicity with nicotinic manifestations (e.g. weakness, fasciculations). Treat seizures with benzodiazepines. Admit to intensive care with continuous monitoring, titration of antidotes, ventilation, and inotropes as needed. Consult a medical toxicologist and/or poison center.
    C) DECONTAMINATION
    1) PREHOSPITAL: Activated charcoal is contraindicated because of possible respiratory depression and seizures and risk of aspiration. Remove contaminated clothing, wash skin with soap and water. Universal precautions and nitrile gloves to protect personnel.
    2) HOSPITAL: INGESTION: Activated charcoal for large ingestions. Consider nasogastric tube for aspiration of gastric contents, or gastric lavage for recent large ingestions, if patient is intubated or able to protect airway. DERMAL: Remove contaminated clothing. Wash skin thoroughly with soap and water. Universal precautions and nitrile gloves to protect staff from contamination. Systemic toxicity can result from dermal exposure. OCULAR: Copious eye irrigation.
    D) AIRWAY MANAGEMENT
    1) Immediately assess airway and respiratory function. Endotracheal intubation may be necessary because of respiratory muscle weakness or bronchorrhea. Avoid succinylcholine for rapid sequence intubation as prolonged paralysis may result. Monitoring pulmonary function (FVC, FEV1, NIF) may help anticipate need for intubation.
    E) ANTIDOTES
    1) There are two primary classes of antidotes: ATROPINE is used to antagonize muscarinic effects. OXIMES (pralidoxime in the US, or obidoxime in some other countries) are used to reverse neuromuscular blockade. Use of oximes is usually indicated for patients with severe toxicity and are used in conjunction with atropine.
    a) ATROPINE
    1) Atropine is used to treat muscarinic effects (e.g. salivation, lacrimation, defecation, urination, bronchorrhea). ADULT: 1 to 3 mg IV; CHILD: 0.02 mg/kg IV. If inadequate response in 3 to 5 minutes, double the dose. Continue doubling the dose and administer it IV every 3 to 5 minutes as needed to dry pulmonary secretions. Once secretions are dried, maintain with an infusion of 10% to 20% of the loading dose every hour. Monitor frequently for evidence of cholinergic effects or atropine toxicity (e.g. delirium, hyperthermia, ileus) and titrate dose accordingly. Large doses (hundreds of milligrams) are sometimes required. Atropinization may be required for hours to days depending on severity.
    b) PRALIDOXIME
    1) Treat moderate to severe poisoning (fasciculations, muscle weakness, respiratory depression, coma, seizures) with pralidoxime in addition to atropine; most effective if given within 48 hours. Administer for 24 hours after cholinergic manifestations have resolved. May require prolonged administration. ADULT DOSE: A loading dose of 30 mg/kg (maximum: 2 grams) over 30 minutes followed by a maintenance infusion of 8 to 10 mg/kg/hr (up to 650 mg/hr). ALTERNATE ADULT DOSE: 1 to 2 grams diluted in 100 mL of 0.9% sodium chloride infused over 15 to 30 minutes. Repeat initial bolus dose in 1 hour and then every 3 to 8 hours if muscle weakness or fasciculations persist (continuous infusion preferred). In patients with serious cholinergic intoxication, a continuous infusion of 500 mg/hr should be considered. Intravenous dosing is preferred; however, intramuscular administration may be considered. A continuous infusion of pralidoxime is generally preferred to intermittent bolus dosing to maintain a target concentration with less variation. CHILD DOSE: A loading dose of 20 to 40 mg/kg (maximum: 2 grams/dose) infused over 30 to 60 minutes in 0.9% sodium chloride. Repeat initial bolus dose in 1 hour and then every 3 to 8 hours if muscle weakness or fasciculations persist (continuous infusion preferred). ALTERNATE CHILD DOSE: 25 to 50 mg/kg (up to a maximum dose of 2 g), followed via continuous infusion of 10 to 20 mg/kg/hr. In patients with serious cholinergic intoxication, a continuous infusion of 10 to 20 mg/kg/hr up to 500 mg/hr should be considered.
    F) SEIZURES
    1) IV benzodiazepines are indicated for seizures or agitation, diazepam 5 to 10 mg IV, lorazepam 2 to 4 mg IV; repeat as needed.
    G) HYPOTENSIVE EPISODE
    1) IV fluids, dopamine, norepinephrine.
    H) BRONCHOSPASM
    1) Inhaled ipratropium or glycopyrrolate may be useful in addition to intravenous atropine.
    I) PATIENT DISPOSITION
    1) HOME CRITERIA: Patients with unintentional trivial exposures who are asymptomatic can be observed in the home or in the workplace.
    2) OBSERVATION CRITERIA: Patients with deliberate or significant exposure and those who are symptomatic should be sent to a health care facility for evaluation, treatment and observation for 6 to 12 hours. Onset of toxicity is variable; most patients will develop symptoms within 6 hours. Patients that remain asymptomatic 12 hours after an ingestion or a dermal exposure are unlikely to develop severe toxicity. Cholinesterase activity should be determined to confirm the degree of exposure.
    3) ADMISSION CRITERIA: All intentional ingestions should be initially managed as a severe exposure. Determine cholinesterase activity to assess if a significant exposure occurred. Patients who develop signs or symptoms of cholinergic toxicity (e.g. muscarinic, nicotinic OR central) should be admitted to an intensive care setting.
    4) CONSULT CRITERIA: Consult a medical toxicologist and/or poison center for assistance with any patient with moderate to severe cholinergic manifestations.
    J) PITFALLS
    1) Inadequate initial atropinization. Patients with severe toxicity require rapid administration of large doses, titrate to the endpoint or drying pulmonary secretions.
    2) Monitor respiratory function closely, pulmonary function testing may provide early clues to the development of respiratory failure.
    3) Some component of dermal exposure occurs with most significant overdoses, inadequate decontamination may worsen toxicity.
    4) Patients should be monitored closely for 48 hours after discontinuation of atropine and pralidoxime for evidence of recurrent toxicity or intermediate syndrome.
    K) TOXICOKINETICS
    1) Well absorbed across the lung, mucous membranes (including gut), and skin; significant toxicity has been reported after all these routes of exposure.
    2) Most patients who develop severe toxicity have signs and symptoms within 6 hours of exposure, onset of toxicity is rarely more than 12 hours after exposure.
    3) Recurrence of toxicity after apparent improvement has been described.
    L) PREDISPOSING CONDITIONS
    1) Patients with chronic occupational exposure to carbamate insecticides may have chronically depressed cholinesterase activity and may develop severe toxicity after smaller acute exposures.
    2) Dermal absorption is enhanced in young children due to larger surface area to volume ratio and more permeable skin.
    M) DIFFERENTIAL DIAGNOSIS
    1) Gastroenteritis, food poisoning, asthma, myasthenic crisis, cholinergic excess from medications.
    0.4.3) INHALATION EXPOSURE
    A) Remove from exposure and administer oxygen if respiratory distress develops.
    B) Inhaled ipratropium or glycopyrrolate may be useful in addition to intravenous atropine for bronchorrhea and bronchospasm. Inhaled beta agonists may be useful for bronchospasm unresponsive to anticholinergics.
    C) Monitor for the development of cholinergic toxicity and treat as in oral exposure.
    0.4.4) EYE EXPOSURE
    A) Irrigate exposed eyes with water or normal saline. Systemic toxicity is unlikely to develop from ocular exposure alone.
    0.4.5) DERMAL EXPOSURE
    A) OVERVIEW
    1) Systemic effects can occur from dermal exposure to carbamate insecticides. Remove contaminated clothing, wash skin thoroughly with soap and water. Use universal precautions and nitrile gloves to protect staff from contamination.
    2) Monitor for the development of cholinergic toxicity and treat as in oral exposure.
    0.4.6) PARENTERAL EXPOSURE
    A) Monitor for the development of compartment syndrome, tissue necrosis, cellulitis, and thrombophlebitis in addition to systemic cholinergic toxicity (which may be prolonged) after subcutaneous, intramuscular or intravenous injection.

Range Of Toxicity

    A) TOXICITY: Carbamates are absorbed across the lung, mucous membranes (including gut), and skin. Poisoning depends upon inherent toxicity, dosage, rate of absorption, rate of metabolic breakdown, and prior exposure to other cholinesterase inhibitors. Generally carbamates are less toxic than organophosphates. Aldicarb is considered the most toxic carbamate.

Summary Of Exposure

    A) USES: Used for pest control in industrial agriculture (tends to be more toxic agents) to control ectoparasites on farm and companion animals, and for home and garden pest control. Poisoning occasionally occurs from ingestion of contaminated crops or food.
    B) TOXICOLOGY: Carbamates competitively inhibit pseudocholinesterase and acetylcholinesterase, preventing hydrolysis and inactivation of acetylcholine. Acetylcholine accumulates at nerve junctions, causing malfunction of the sympathetic, parasympathetic, and peripheral nervous systems and some of the CNS. Clinical signs of cholinergic excess develop.
    C) EPIDEMIOLOGY: Exposure is common, but serious toxicity is unusual in the US. Common source of severe poisoning in developing countries. Toxicity generally less severe than with organophosphates.
    D) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE POISONING: MUSCARINIC EFFECTS: Can include bradycardia, salivation, lacrimation, diaphoresis, vomiting, diarrhea, urination, and miosis. NICOTINIC EFFECTS: Tachycardia, hypertension, mydriasis, and muscle cramps.
    2) SEVERE POISONING: MUSCARINIC EFFECTS: Bronchorrhea, bronchospasm, and acute lung injury. NICOTINIC EFFECTS: Muscle fasciculations, weakness, and respiratory failure. CENTRAL EFFECTS: CNS depression, agitation, confusion, delirium, coma, and seizures. Hypotension, ventricular dysrhythmias, metabolic acidosis, pancreatitis, and hyperglycemia can also develop.
    3) CHILDREN: May have different predominant signs and symptoms than adults (more likely CNS depression, stupor, coma, flaccidity, dyspnea, and seizures). Children may also have fewer muscarinic and nicotinic signs of intoxication (ie, secretions, bradycardia, fasciculations, and miosis) as compared with adults.
    4) INHALATION EXPOSURE: Vapors rapidly produce mucous membrane and upper airway irritation and bronchospasm, followed by systemic muscarinic, nicotinic, and central effects if exposed to significant concentrations.

Vital Signs

    3.3.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Hypothermia and hyperthermia have occurred.
    3.3.3) TEMPERATURE
    A) WITH POISONING/EXPOSURE
    1) HYPOTHERMIA: Slight or moderate hypothermia, not correlated with Glasgow Coma Score, was reported in 6 patients out of a series of 18 patients following acute aldicarb poisoning (Ragoucy-Sengler et al, 2000). In a pediatric case series (n=54) of anticholinesterase (carbamate and organophosphate) poisonings, hypothermia was reported in 7% and hyperthermia was reported in 6% of the children (Verhulst et al, 2002).

Heent

    3.4.3) EYES
    A) WITH POISONING/EXPOSURE
    1) MIOSIS and blurred vision may occur. Miosis, a muscarinic effect, is characteristic of severe and moderately severe poisonings, but may appear late (Waseem et al, 2010; Hoffmann et al, 2008; Tsatsakis et al, 2001; Tracqui et al, 2001; Park et al, 2000; Flesch et al, 1999; Covaci et al, 1999) .
    a) INCIDENCE: In a series of 26 children with methomyl or aldicarb poisoning, 21 (80%) developed miosis (Lifshitz et al, 1994). In a series of 18 aldicarb poisonings (all age groups), 17 patients developed miosis (Ragoucy-Sengler et al, 2000). In another case series of 35 pediatric and adult patients, 71% developed miosis following aldicarb poisoning (Nelson et al, 2001). Miosis was the most common symptom seen (57%) in a retrospective observational study of 54 children admitted to a pediatric intensive care unit following anticholinesterase (carbamate and organophosphate) poisoning (Verhulst et al, 2002a).
    b) CASE REPORT: A 52-year-old man presented to the emergency department with pupils 1 mm in diameter after accidentally ingesting a gulp of methomyl (Ekins & Geller, 1994a).
    c) CASE REPORT: A 2-year-old child became comatose with miotic pupils following accidental ingestion of aldicarb (Anon, 1997).
    2) ANISOCORIA: A patient who complained of unequal pupils was found to have inserted her left contact lens after changing her dog's flea collar. The active ingredient of the flea collar was O-isopropoxyphenyl methylcarbamage, a cholinesterase inhibitor. Twenty minutes after the initial examination, both pupils were equal and reactive (Ellenberg et al, 1992).
    3) MYDRIASIS: Pupil dilation may occur as a nicotinic effect and may be present in up to 10% of patients (Aaron & Howland, 1998).
    4) Ptosis and diplopia were reported in a 60-year-old female farmer following 6 hours of exposure to a spray application of carbendazim (Uludag et al, 2001).
    3.4.5) NOSE
    A) WITH POISONING/EXPOSURE
    1) Rhinorrhea has been reported following ingestion of pirimicarb (Hoffmann et al, 2008).
    3.4.6) THROAT
    A) WITH POISONING/EXPOSURE
    1) Excessive salivation and bronchial secretions are common following severe carbamate poisoning (Waseem et al, 2010; Park et al, 2000). Dysphagia was reported in a female farmer following topical and inhalation exposure to carbendazim (Uludag et al, 2001).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) BRADYCARDIA
    1) WITH POISONING/EXPOSURE
    a) Muscarinic effects may commonly include bradycardia (Covaci et al, 1999; Park et al, 2000; Tsatsakis et al, 2001).
    b) INCIDENCE: In a series of 26 children with methomyl or aldicarb poisoning, 6 (23%) developed bradycardia (Lifshitz et al, 1994). In a series of 18 aldicarb poisonings (all age groups), 10 patients (55%) were reported to have bradycardia (Ragoucy-Sengler et al, 2000).
    c) CASE REPORTS: A 43-year-old man with aldicarb poisoning presented with a heart rate of 50 beats/minute (Burgess et al, 1994). In another intentional aldicarb ingestion of 10 grams, heart rate of 40 beats/minute was reported in a 30-year-old woman (Flesch et al, 1999). Bradycardia with second degree AV block that resolved following 1 mg intravenous atropine was reported in a 63-year-old woman after ingesting aldicarb-contaminated coffee (Covaci et al, 1999).
    d) INCIDENCE: In a case series of 35 patients (pediatric and adult), 22% developed bradycardia (hr <60) following aldicarb ingestion (Nelson et al, 2001).
    B) TACHYARRHYTHMIA
    1) WITH POISONING/EXPOSURE
    a) Nicotinic effects may include sinus tachycardia and hypertension (Aaron & Howland, 1998) Traqui et al, 2001).
    b) CASE REPORT: Ekins & Geller (1994) reported the case of a 52-year-old man who accidentally ingested a gulp of methomyl and presented to the emergency department with a pulse of 146 beats per minute and blood pressure of 228/120 mm Hg (Ekins & Geller, 1994).
    c) In another ingestion of aldicarb, an 18-year-old man presented to the emergency department with tachycardia, tachypnea, diffuse muscle fasciculations and profuse bronchorrhea (Anon, 1997).
    d) CASE REPORT: Sinus tachycardia (100 bpm) was reported in a 29-year-old man who intentionally ingested an unknown amount of "Tres Pasitos", a rodenticide containing aldicarb (Waseem et al, 2010).
    e) INCIDENCE: In a case series of 35 patients (pediatric and adult), 63% developed tachycardia following aldicarb ingestion (Nelson et al, 2001).
    C) HYPOTENSIVE EPISODE
    1) WITH POISONING/EXPOSURE
    a) Hypotension has been reported following carbamate insecticide poisoning due to weakened cardiac contractility (Park et al, 2000; Tsatsakis et al, 2001).
    b) INCIDENCE: In a pediatric case series (n=54) of anticholinesterase (carbamate and organophosphate) poisonings, 9% developed hypotension (Verhulst et al, 2002).
    D) ELECTROCARDIOGRAM ABNORMAL
    1) WITH POISONING/EXPOSURE
    a) Sinus tachycardia with ST segment depression may occur early in the course of poisoning. Repolarization abnormalities may occur and are generally transient (Tracqui et al, 2001).
    b) CASE REPORT: Severe ST depression was reported in one pediatric carbamate poisoning (Sethi et al, 1989).
    c) CASE SERIES: Conduction abnormalities were reported in 4 out of 18 aldicarb poisonings in one study (Ragoucy-Sengler et al, 2000). The abnormalities in these 4 patients were reported as heart block in 3 and torsade de pointes in one.
    d) CASE REPORT: Atrial fibrillation with a normal ventricular response was reported in a 26-year-old man following exposure to methomyl dust. The episode resolved within 24 hours (Topacoglu et al, 2007).
    E) HYPERTENSIVE EPISODE
    1) WITH POISONING/EXPOSURE
    a) Hypertension is a reported toxic effect. In a pediatric case series (n=54) of anticholinesterase (carbamate and organophosphate) poisonings, hypertension was reported in 20% of the children (Verhulst et al, 2002).
    b) CASE REPORT: Repeated hypertensive crises and persistent seizures occurred in a 68-year-old man who intentionally ingested an unknown amount of pirimicarb. The patient recovered following benzodiazepine administration over a 2-day period (Hoffmann et al, 2008).
    F) ATRIAL FIBRILLATION
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 26-year-old man presented with nausea and vomiting after exposure to methomyl dust. Cardiac examination showed an irregular heart rate. ECG revealed atrial fibrillation with normal ventricular response. On admission, patient's acetylcholinesterase (ACE) level was 3319 International Units/L (normal 4400 to 13500 IU/L). Therefore, pralidoxime use was considered unnecessary. Following supportive care, his heart rhythm spontaneously returned to sinus rhythm 24 hours post-admission. He was discharged home without further sequela (Topacoglu et al, 2007).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) APNEA
    1) WITH POISONING/EXPOSURE
    a) RESPIRATORY FAILURE: Usual cause of death is respiratory failure as a result of respiratory muscle weakness and central depression of the respiratory drive (Aaron & Howland, 1998; Park et al, 2000). Incidences are shown as follows:
    1) CASE SERIES: Respiratory failure was reported in 2 of 13 (15%) patients with carbamate poisoning in one series (Tsao et al, 1990).
    2) CASE SERIES: Respiratory insufficiency developed in 3 of 26 (11%) children with methomyl or aldicarb poisoning in one series (Lifshitz et al, 1994).
    3) CASE REPORT: Death due to respiratory failure was reported after ingestion of an unknown amount of carbaryl in an adult (Sargin et al, 1992).
    B) DYSPNEA
    1) WITH POISONING/EXPOSURE
    a) Dyspnea is a common manifestation of carbamate insecticide exposure (Uludag et al, 2001; Ragoucy-Sengler et al, 2000). Chest tightness, bronchospasm, increased pulmonary secretions, and rales may develop secondary to muscarinic effects (Markowitz, 1992). Incidences are shown as follows:
    1) PEDIATRIC CASE SERIES: Dyspnea was reported in 7 of 8 children with carbamate poisoning (Sethi et al, 1989; Morgan, 1989).
    2) ADULT CASE SERIES: Six men exposed to aldicarb in a sprayed field and working with sheep grazing in the contaminated field all experienced dyspnea and sore throats within 24 hours (Grendon et al, 1994).
    3) CASE REPORT: An adult was admitted 2 hours following development of pulmonary secretions and was found 13 hours later to have a blood aldicarb level of 0.1 mg/mL. Plasma cholinesterase was 6% of normal 3.5 hours after admission, and remained depressed for 56 hours (Burgess et al, 1994).
    4) CASE REPORT: A 29-year-old man developed respiratory distress with harsh breath sounds and rhonchi in both lung fields after intentionally ingesting an unknown amount of "Tres Pasitos", a rodenticide containing aldicarb (Waseem et al, 2010).
    C) REACTIVE AIRWAYS DYSFUNCTION SYNDROME
    1) WITH POISONING/EXPOSURE
    a) CASE SERIES: Cone et al (1994) reported a retrospective study concerning a toxic spill of metam sodium. 20 cases of irritant-induced asthma and 10 cases of persistent exacerbation of asthma were reported following a toxic spill of the airborne irritant, methyl isothiocyanate, a breakdown product of sodium methyl dithiocarbamate (Cone et al, 1994).
    b) CASE SERIES: An investigation into the association between self-reported asthma and carbamate pesticide use found a significant association in 1939 male farm workers independent of age, smoking pack-years, and nasal allergic reactions (Senthilselvan et al, 1992).
    D) SPUTUM ABNORMAL - AMOUNT
    1) WITH POISONING/EXPOSURE
    a) INCREASED BRONCHIAL SECRETIONS may occur secondary to muscarinic effects (Waseem et al, 2010; Tracqui et al, 2001; Covaci et al, 1999) and be significant requiring frequent suctioning.
    b) CASE REPORT - Ekins & Geller (1994) reported a case of accidental ingestion of a gulp of methomyl by a 52-year-old man. He presented to the emergency department with pink, frothy secretions in the oropharynx and wet-sounding inspiratory and expiratory rales and rhonchi on auscultation (Ekins & Geller, 1994a).
    c) INCIDENCE: In a case series of 35 patients (pediatric and adult), 34% developed bronchorrhea following aldicarb ingestion (Nelson et al, 2001).
    E) PULMONARY ASPIRATION
    1) WITH POISONING/EXPOSURE
    a) Aspiration pneumonitis may occur after ingestion of carbamates in hydrocarbon vehicles. A complication of prolonged intubation and mechanical ventilation following pulmonary effects of poisoning is aspiration pneumonia (Aaron & Howland, 1998).
    F) ACUTE LUNG INJURY
    1) WITH POISONING/EXPOSURE
    a) Acute lung injury (pulmonary edema) is a potential clinical manifestation of severe carbamate poisoning and is attributed to the muscarinic action of the insecticide. Contributing factors to the development of pulmonary edema include bradycardia and weakened cardiac contraction from an accumulation of acetylcholine on the cardiovascular system. Hypoxia may develop due to increasing capillary permeability (Park et al, 2000; Tsatsakis et al, 2001).
    b) CASE REPORT: A 2-year-old child was admitted to the hospital in a comatose state with miosis, muscle fasciculations and pulmonary edema following accidental ingestion of aldicarb. Intubation was required for respiratory insufficiency. The child recovered following supportive therapy and atropine and pralidoxime injections (Anon, 1997).
    c) CASE REPORT: - Following a suicidal ingestion of approximately 40 mL of an 80% carbaryl (1-naphthyl-N-methylcarbamate; (Sevin)), a 41-year-old woman was shown to have alveolar pulmonary edema and pneumomediastinum on initial chest x-ray. Following resolution of pulmonary edema, high resolution CT scan and pathologic findings revealed interstitial pneumonitis. The patient recovered following symptomatic care (Park et al, 2000).
    G) PNEUMONITIS
    1) WITH POISONING/EXPOSURE
    a) Interstitial pneumonitis may occur following carbamate insecticide poisonings. Park et al (2000) reported a case of ingestion in a 41-year-old woman which resulted in pulmonary edema, which resolved, and was followed by interstitial pneumonitis as shown on high resolution CT and pathological examinations. The patient recovered following symptomatic care (Park et al, 2000).
    b) A cross-sectional study of occupational risk factors for farmer's lung (n=50,000 farmers and spouses, controlled for age, state and smoking status) or hypersensitivity pneumonitis concluded that carbamate insecticides were associated with hypersensitivity pneumonitis (OR=1.32, 95% CI=1.03-1.68) (Hoppin et al, 2007).
    H) INJURY OF UPPER RESPIRATORY TRACT
    1) WITH POISONING/EXPOSURE
    a) DUSTING POWDERS: Laryngeal irritation, violent coughing, diaphoresis, and tachypnea occur frequently following inhalation of carbamate dusting powders and may not necessarily be associated with systemic signs and symptoms of carbamate poisoning (Alcorn & Hughes, 1980).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) DIZZINESS
    1) WITH POISONING/EXPOSURE
    a) INCIDENCE: In an outbreak of gastrointestinal tract illness reported in patrons of a Thai restaurant (n=107), it was discovered that the food had been seasoned with methomyl-contaminated salt. Patients reported dizziness (72%), headache (52%) and chills (48%). Dizziness, lightheadedness or a feeling of disequilibrium were reported as the initial symptom in 51 cases (48%) (Buchholz et al, 2002).
    B) COMA
    1) WITH POISONING/EXPOSURE
    a) CNS depression leading to coma may occur after severe poisonings, with decreased or absent tendon and brainstem reflexes (Ratner et al, 1983; Umehara et al, 1991; Flesch et al, 1999; Park et al, 2000; Tsatsakis et al, 2001; Tracqui et al, 2001). Incidences are shown as follows:
    1) CASE SERIES (PEDIATRIC): In one series, 8 of 8 children with carbamate poisoning developed severe CNS depression with stupor and coma (Sethi et al, 1989).
    2) CASE SERIES (PEDIATRIC): In another series of 26 children with aldicarb or methomyl poisoning all developed stupor or coma (Lifshitz et al, 1994). In a later expanded case series, all 36 children developed stupor or coma, while 0 out of 24 adults with aldicarb or methomyl poisoning developed stupor or coma (Lifshitz et al, 1997).
    3) CASE SERIES (PEDIATRIC): In a series of 36 children intoxicated with methomyl and aldicarb, predominant symptoms were related to CNS depression and severe hypotonia. Absence of classic muscarinic effects was noted (Lifshitz et al, 1999).
    4) CASE SERIES: In a series of 18 aldicarb poisonings (all age groups), 8 patients (44%) developed coma (Ragoucy-Sengler et al, 2000).
    5) CASE SERIES: In a case series of 35 patients (pediatric and adult), 51% developed lethargy or coma following aldicarb ingestion (Nelson et al, 2001).
    6) CASE REPORT (ADULT): A 55-year-old woman (suicide attempt) was comatose for 3 days after ingestion of m-tolyl methyl carbamate (Umehara et al, 1991).
    C) SEIZURE
    1) WITH POISONING/EXPOSURE
    a) Seizures may occur in severe poisonings. Children may be more susceptible than adults. Incidences are shown as follows:
    1) CASE SERIES (PEDIATRIC): In a series of 26 children with aldicarb or methomyl poisoning, 3 (11%) developed seizures (Lifshitz et al, 1994). In a later expanded case series of 36 children, 3 (8%) developed seizures (Lifshitz et al, 1997).
    2) CASE SERIES (PEDIATRIC): In one series, 2 children poisoned by carbamates had seizures (Zwiener & Ginsburg, 1988).
    3) CASE SERIES - In a series of 18 aldicarb poisonings (all age groups), 4 patients (22%) developed seizures (Ragoucy-Sengler et al, 2000).
    4) CASE SERIES: In a pediatric series of 54 anticholinesterase (carbamate and organophosphate) poisonings, 30% developed seizures (Verhulst et al, 2002).
    b) CASE REPORT: A 68-year-old man intentionally ingested an unknown amount of pirimicarb and subsequently developed persistent seizures and fasciculations as well as miosis, rhinorrhea, somnolence, and repeated hypertensive crises. The patient recovered with supportive treatment, including benzodiazepines administered over a 2-day period (Hoffmann et al, 2008).
    D) NEUROPATHY
    1) WITH POISONING/EXPOSURE
    a) Various peripheral neuropathies have been reported after carbamate use. The symptoms are similar to those seen with organophosphates.
    b) CARBARYL: Delayed axonal peripheral neuropathy, similar to that seen with organophosphates, was seen in a patient who ingested 500 mg/kg of carbaryl (Dickoff et al, 1987).
    c) m-TOLYL METHYL CARBAMATEL: Sensorimotor polyneuropathy with axonal degeneration was described 6 days postingestion in a 55-year-old woman following a suicide attempt. The patient was comatose for 3 days prior to development of paresthesias. Symptoms improved 3 months later, but deep tendon reflexes remained absent (Umehara et al, 1991).
    d) CASE REPORT - SUBACUTE NEUROTOXICITY: A patient with chronic, excessive exposure to carbaryl developed a progressive debilitating syndrome, including headaches, memory loss, proximal muscle weakness, muscle fasciculation, muscle cramps, and anorexia with marked weight loss (Branch & Jacqz, 1986).
    E) ALTERED MENTAL STATUS
    1) WITH POISONING/EXPOSURE
    a) ALDICARB/CASE SERIES: Seven farm workers presented to an emergency department with nausea, vomiting, diarrhea, abdominal cramping, and altered mental status. Interviews conducted with the patients revealed that they had each consumed a portion of a freshly picked watermelon from the farm prior to symptom-onset. Analysis of the uningested portion of the watermelon, as well as another watermelon from the same farm, detected the presence of aldicarb, aldicarb sulfone, and aldicarb sulfoxide. Six of the seven patients were discharged without sequelae following symptomatic and supportive therapy and 24 hours of observation. The seventh patient, a 53-year-old man with diabetes, hypertension, and hypokalemia, was admitted for electrolyte abnormalities and recovered uneventfully (D'Haenens et al, 2013).
    F) MUSCLE WEAKNESS
    1) WITH POISONING/EXPOSURE
    a) Acute muscle weakness may occur as a nicotinic effect.
    b) CASE REPORT (ADULT): An adult man was admitted 2 hours after development of weakness. Thirteen hours later the blood aldicarb level was 0.1 mg/mL. Plasma cholinesterase was 6% of normal 3.5 hours after admission, and remained depressed for 56 hours.
    1) The weakness improved after administration of pralidoxime 4 grams IV over 10 hours. Recovery was uneventful (Burgess et al, 1994).
    c) Protracted malaise and weakness may occur after apparent recovery from carbamate poisoning (Garber, 1987).
    G) DYSTONIA
    1) WITH POISONING/EXPOSURE
    a) Acute dystonic torticollis relieved by diphenhydramine was described in one patient following parenteral injection of a household combination of dichlorovos and propoxur (Moody & Terp, 1988).
    H) DECREASED MUSCLE TONE
    1) WITH POISONING/EXPOSURE
    a) SUMMARY: Hypotonia is a common nicotinic effect of carbamate insecticide poisoning (Ragoucy-Sengler et al, 2000; Tsatsakis et al, 2001).
    b) METHOMYL/CASE SERIES: In a case series of 36 children and 24 adults with aldicarb or methomyl poisoning, all the children developed hypotonia, while none of the adults developed hypotonia (Lifshitz et al, 1997; Lifshitz et al, 1999).
    c) ALDICARB/CASE SERIES: In a series of 18 aldicarb poisonings (all age groups), 7 patients developed hypotonia (Ragoucy-Sengler et al, 2000).
    I) INTRACRANIAL HEMORRHAGE
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT/ METHOMYL: An adult ingested methomyl powder. The woman died 19 hours after ingestion in spite of intensive care. At autopsy a large number of miliary hemorrhages were found in both thalami of the brain (Miyazaki et al, 1989).
    J) SPASMODIC MOVEMENT
    1) WITH POISONING/EXPOSURE
    a) Muscle fasciculations may develop as a nicotinic effect (Waseem et al, 2010; Hoffmann et al, 2008; Ragoucy-Sengler et al, 2000; Flesch et al, 1999; Burgess et al, 1994; Ekins & Geller, 1994a) . Incidence is shown as follows:
    1) CASE SERIES (PEDIATRIC): Fasciculations developed in 1 of 26 (4%) children poisoned with methomyl or aldicarb (Lifshitz et al, 1994). In a case series, muscle fasciculations were a main sign in adults (83.3%) with carbamate poisoning, and were less frequent in children (5.5%) (Lifshitz et al, 1997).
    2) CASE SERIES: In a series of 18 aldicarb poisonings (all age groups), 14 patients (78%) developed fasciculations (Ragoucy-Sengler et al, 2000).
    3) CASE SERIES: In a case series of 35 patients (pediatric and adult), 42% developed fasciculations following aldicarb ingestion (Nelson et al, 2001).
    b) Transient motor end plate or neuromuscular junction dysfunction was shown by voluntary single fiber EMG (SPEMG) in a patient following carbendazim exposure. SPEMG was used to assess the orbicularis oculi muscle, with 2 out of 5 muscle fibers demonstrating increased jitter values (66 and 116 mcs) with a mean value of 54 mcs (Uludag et al, 2001).
    K) CENTRAL PONTINE MYELINOLYSIS
    1) WITH POISONING/EXPOSURE
    a) CARBARYL: A 4-year-old boy developed severe hypotonia, generalized weakness and ataxia following exposure to diluted carbaryl insecticide that was inadvertently used on the family dog and sprayed around the home. Despite supportive care the patient continued to have CNS symptoms on day 11, and a brain MRI was performed which revealed central pontine myelinolysis. Dexamethasone was started and the patient recovered completely within 3 weeks. Demyelination completely disappeared 2 years after exposure, but the child had persistent neuropsychological decline as noted by minor deficits in attention, concentration and learning ability. Anxiety, emotional lability and irritability were also present (Santinelli et al, 2006).
    L) DEMENTIA
    1) WITH POISONING/EXPOSURE
    a) A nationwide population-based cohort study, evaluating the risk of dementia in patients with acute organophosphate and carbamate poisoning, identified 9616 exposed patients and compared them with 38,510 control patients. The incidence of dementia was 29.4 per 10,000 person-years in the exposed group as compared with 14.2 per 10,000 person-years in the control group, indicating a 1.98-fold increased risk of dementia compared with the control cohort. The risk of dementia was the highest during the first year of exposure, peaked among patients 50 to 64 years of age, and was independent of underlying diseases(Lin et al, 2015).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH POISONING/EXPOSURE
    a) Nausea and vomiting are common muscarinic signs (Topacoglu et al, 2007; Ratner et al, 1983; Burgess et al, 1994; Lifshitz et al, 1994). Following an incident of aldicarb food poisoning, gastrointestinal effects were most common, with abdominal cramps in 13 (93%), diarrhea in 12 (86%), and nausea in 13 (93%) (Anon, 1999).
    b) INCIDENCE: In a series of 18 aldicarb poisonings (all age groups), 13 patients developed vomiting (Ragoucy-Sengler et al, 2000).
    c) INCIDENCE: In an outbreak of gastrointestinal tract illness reported in patrons of a Thai restaurant (n=107), it was discovered that the food had been seasoned with methomyl-contaminated salt. Symptoms reported included nausea (95%), abdominal cramps (58%), vomiting (51%) and diarrhea (46%) (Buchholz et al, 2002).
    d) ALDICARB/CASE SERIES: Seven farm workers presented to an emergency department with nausea, vomiting, diarrhea, abdominal cramping, and altered mental status. Interviews conducted with the patients revealed that they had each consumed a portion of a freshly picked watermelon from the farm prior to symptom-onset. Analysis of the uningested portion of the watermelon, as well as another watermelon from the same farm, detected the presence of aldicarb, aldicarb sulfone, and aldicarb sulfoxide. Six of the seven patients were discharged without sequelae following symptomatic and supportive therapy and 24 hours of observation. The seventh patient, a 53-year-old man with diabetes, hypertension, and hypokalemia, was admitted for electrolyte abnormalities and recovered uneventfully (D'Haenens et al, 2013).
    B) DIARRHEA
    1) WITH POISONING/EXPOSURE
    a) Diarrhea is common (Ratner et al, 1983; Burgess et al, 1994; Lifshitz et al, 1994; Lifshitz et al, 1999). Incidence is shown as follows:
    1) CASE SERIES: Diarrhea developed in 12 of 36 (33%) children compared with 0 of 26 adults poisoned with methomyl or aldicarb (Lifshitz et al, 1997; Lifshitz et al, 1999). In another series of 18 aldicarb poisonings (all age groups), 7 patients developed diarrhea (Ragoucy-Sengler et al, 2000).
    C) ABDOMINAL PAIN
    1) WITH POISONING/EXPOSURE
    a) Abdominal pain and cramping may develop (Sargin et al, 1992).
    D) EXCESSIVE SALIVATION
    1) WITH POISONING/EXPOSURE
    a) Salivation may occur as a cholinergic crisis effect following intentional ingestions (Waseem et al, 2010; Park et al, 2000; Flesch et al, 1999) . A typical garlic odor may be noted, particularly in cases of methomyl poisoning (Tsatsakis et al, 2001).
    b) INCIDENCE: In a series of 18 aldicarb poisonings (all age groups), 15 patients developed hypersalivation (Ragoucy-Sengler et al, 2000).
    c) INCIDENCE: In a case series of 35 patients (pediatric and adult), 54% developed salivation following aldicarb ingestion (Nelson et al, 2001).
    E) ACUTE PANCREATITIS
    1) WITH POISONING/EXPOSURE
    a) CASE SERIES
    1) In a prospective case study of 17 children with documented organophosphate or carbamate insecticide poisoning, 5 were diagnosed with acute pancreatitis. All of the 5 had significantly elevated serum levels of immunoreactive trypsin and 4 had a significant increase in serum amylase levels. Clinical manifestations were mild. One case was a documented carbamate poisoning (Weizman & Sofer, 1992).
    2) In a series of 18 aldicarb poisonings (all age groups), 4 patients developed pancreatitis, with elevated lipase and amylase levels (Ragoucy-Sengler et al, 2000).
    b) CASE REPORTS
    1) CARBOFURAN: A 36-year-old woman intentionally ingested approximately 10 mL of carbamate insecticide (carbofuran 35%) and had characteristic cholinergic symptoms, along with acute abdominal pain and an amylase level of 1,149 IU/L upon admission. An abdominal CT scan the following day indicated a lack of pancreatic enhancement of the body and tail of the pancreas and intrapancreatic fluid collection, which confirmed the diagnosis of acute pancreatitis. The patient improved with treatment. A repeat CT scan 4 weeks later showed pseudocyst formation in the body and tail of the pancreas, where fluid collection was initially observed (Rizos et al, 2004).
    2) METHOMYL: Although infrequently reported, methomyl has produced acute pancreatitis in several cases of intentional ingestion. Symptoms developed between 24 to 72 hours after exposure and included abdominal pain, paralytic ileus and vomiting. Clinical findings and laboratory studies improved within 5 days with supportive care. One patient required surgical drainage persistent pancreatic pseudocyst and abdominal pain (Brahmi et al, 2005).
    3) METHOMYL: An 18-year-old man ingested an unknown amount of methomyl and was admitted in cholinergic crisis. Two days after admission a CT scan revealed inflammation of the pancreas and pancreatic ascites as confirmed by paracentesis. Approximately 11 days after exposure, intrapancreatic fluid was observed on a follow-up CT scan. A noticeable reduction in fluid was found one month later (Makrides et al, 2005).
    4) PROPOXYFUR: Pancreatitis was reported in a 35-year-old man who intentionally ingested 200-300 mL of Baygon (Propoxyfur). On initial presentation to the emergency department, the patient displayed typical cholinergic symptoms and had a mildly elevated serum amylase (320 U/L). On his third day of admission he developed upper abdominal pain of moderate severity, with a markedly elevated serum amylase (800 U/L). Pancreatitis was confirmed by computerized tomography (CT). The patient was treated conservatively and recovered (Singh et al, 2003).
    5) PROPOXYFUR: Pancreatitis was reported in an 80-year-old man following aerosol inhalation of 150 mL of Baygon (propoxyfur). On presentation 4 days after the exposure, the patient complained of severe abdominal pain, but did not display any cholinergic symptoms. His labs were significant for a white blood cell count of 15.9 and a mildly elevated amylase (116 Units/L). Computed tomography revealed acute pancreatitis with decreased contrast enhancement. The patient improved with conservative treatment and was discharged home on day 3 (Votanopoulos et al, 2007).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) ACUTE INTERMITTENT PORPHYRIA
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A syndrome similar to acute intermittent porphyria was described in one case 2 to 23 days after ingestion of an unknown amount of carbaryl (Sargin et al, 1992).
    1) Twenty-three days postingestion, urine porphobilinogen, uroporphyrin, and coproporphyrin were 3 to 7 times higher than normal.
    2) The patient experienced abdominal pain, quadriparesis, and behavior changes (signs consistent with AIP). Despite symptomatic treatment death resulted from respiratory and circulatory failure.
    B) HYPERBILIRUBINEMIA
    1) WITH POISONING/EXPOSURE
    a) In a case series of 49 carbamate insecticide poisonings, 9 patients (11%) developed elevated serum bilirubin concentrations. Mean total serum bilirubin was reported to be 69.05 micromols/liter, while the mean indirect serum bilirubin concentration was 45.2 micromols/liter (Saadeh, 2001).
    3.9.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) HEPATOCELLULAR DAMAGE
    a) Rats exposed orally to 25 to 50 mg/kg carbaryl for 2 weeks had significant decreases in liver weights ranging from 11 to 13% (Ladics et al, 1994).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) INCONTINENCE
    1) WITH POISONING/EXPOSURE
    a) Urinary incontinence was seen in 7 percent of children (n= 54) admitted to a pediatric intensive care unit following severe anticholinesterase (carbamate and organophosphate) insecticide poisoning (Verhulst et al, 2002a).
    B) RENAL FUNCTION TESTS ABNORMAL
    1) WITH POISONING/EXPOSURE
    a) Renal biochemical abnormalities in a study of patients (n=84) following acute poisoning with carbamate insecticides or organophosphates included azotemia (BUN >6.7 mmol/L) (21%), hematuria (17%), glycosuria (15%) and proteinuria (5%) (Saadeh, 2001).

Acid-Base

    3.11.2) CLINICAL EFFECTS
    A) ACIDOSIS
    1) WITH POISONING/EXPOSURE
    a) A combined acidosis with very low oxygen saturation (arterial blood gases pH 7.22, O2 saturation 80.2%) was reported in a 63-year-old woman after consuming aldicarb-contaminated coffee (Covaci et al, 1999).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) DISSEMINATED INTRAVASCULAR COAGULATION
    1) WITH POISONING/EXPOSURE
    a) PROPOXUR: Disseminated intravascular coagulation caused by propoxur has been reported (Misra et al, 1987).
    B) HEMORRHAGE
    1) WITH POISONING/EXPOSURE
    a) METHOMYL: An adult ingested methomyl powder. The woman died 19 hours after ingestion in spite of intensive care. At autopsy a large number of miliary hemorrhages were found in both thalami of the brain (Miyazaki et al, 1989).
    3.13.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) ANEMIA
    a) FURDAN: Multiple intraperitoneal doses of furdan in mice caused a significant decrease in hemoglobin content, total red blood cell count, platelets, erythrocyte sedimentation rate, and hematocrit. Total white blood cells were increased and clotting time was prolonged; there was an increase in neutrophils and basophils and a decrease in the lymphocyte count (HSDB , 1992).
    b) Rats exposed orally to 25 to 50 mg/kg carbaryl daily for 2 weeks exhibited a significant decrease in WBC's (34%) and a 13% increase in RBC's at the 50 mg/kg dose level (Ladics et al, 1994).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) EXCESSIVE SWEATING
    1) WITH POISONING/EXPOSURE
    a) Diaphoresis may commonly develop as a muscarinic effect (Waseem et al, 2010; Park et al, 2000; Burgess et al, 1994).
    b) INCIDENCE: In a series of 18 aldicarb poisonings (all age groups), 9 patients developed sweating (Ragoucy-Sengler et al, 2000).
    c) INCIDENCE: In a case series of 35 patients (pediatric and adult), 58% developed diaphoresis following aldicarb ingestion (Nelson et al, 2001).
    B) CONTACT DERMATITIS
    1) WITH POISONING/EXPOSURE
    a) METHOMYL: Occupational allergic contact dermatitis was described in two nursery workers; patch testing was positive to an insecticidal spray containing methomyl. Pure methomyl was not available for testing, so it is possible that one of the inert ingredients was responsible (Bruynzeel, 1991).
    C) CELLULITIS
    1) WITH POISONING/EXPOSURE
    a) Two cases of cellulitis developed after injection of household sprays.
    1) CASE REPORT: Goldberg et al (1982) reported 2 patients who injected (subcutaneously and intravenously) commercially available household spray insecticides and presented with cellulitis around the injection site. These progressed to abscess which showed negative bacterial growth (Goldberg et al, 1982).
    2) Commercially available household insecticides may contain some combination of chlorinated hydrocarbons, piperonyl butoxide, pyrethrins, organophosphates, and carbamates, in a hydrocarbon vehicle.
    b) CASE REPORT: Following the self-injection (subcutaneous) and topical application of propoxur, a carbamate insecticide, of both lower extremities, a 17-year-old girl was admitted to the hospital with pain, swelling and diffuse erythema. The next day, fever, blisters and pustules developed on both lower limbs. Incision and drainage of the sites revealed extensive muscle and fat necrosis. Following surgical and antibiotic treatment, the patient recovered (Sethi et al, 2001).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) RHABDOMYOLYSIS
    1) WITH POISONING/EXPOSURE
    a) Rhabdomyolysis with transient renal dysfunction has been reported in 2 adults following consumption of aldicarb-contaminated coffee. Both patients were treated with atropine injections over a 4-day period and recovered (Covaci et al, 1999).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) DISORDER OF IMMUNE FUNCTION
    1) WITH POISONING/EXPOSURE
    a) ALDICARB: Drinking water contamination with aldicarb was associated with an increase in CD8+ T-lymphocytes in a cohort of 23 women; exposures ranged from 1 to 61 ppb. When examined two years later, 2 women with continued exposure to water containing 1.2 to 5 ppb (mean average daily ingestion 0.022 mcg/kilogram/day) had no significant change in the CD8+ count, while 14 women who had discontinued exposure experienced decreased CD8+ counts. No clinical immune dysfunction was noted (Mirkin et al, 1990).
    b) CARBARYL: A lifetime exposure to carbaryl has not resulted in increased infectious disease or cancer or produced other significant effects on the immune system. A number of xenobiotics, including carbaryl, have been shown, in tissue culture experiments, to be capable of enhancing viral growth.
    1) Epidemiologic studies have not linked carbaryl exposures with Reye's syndrome or any other viral disease. Carbaryl does not appear to represent a risk factor to the human immune system (Cranmer, 1986).
    3.19.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) IMMUNE SYSTEM DISORDER
    a) IMMUNOGLOBULINS: Results of a study in pregnant mice who received CARBOFURAN throughout gestation suggest that prenatal exposure may result in moderate disturbances of serum concentrations of immunoglobulins in apparently normal mice (HSDB , 1992).
    b) HUMORAL IMMUNE RESPONSE: Results of a study in rats who had 2 week exposures to carbaryl by the oral, dermal or inhalational routes demonstrated humoral immune suppression following inhalation, but not following oral or dermal exposures (Ladics et al, 1994).

Reproductive

    3.20.1) SUMMARY
    A) Structural malformations have been produced in animals only at exposure levels toxic to the pregnant animal.
    3.20.2) TERATOGENICITY
    A) SKELETAL MALFORMATION
    1) CARBARYL (ANIMAL DATA) - The potential of carbaryl to produce developmental toxicity has been studied in numerous mammalian species utilizing a wide variety of study designs and routes of administration.
    a) TERATOGENIC DOSES - Structural malformations have been produced in animals only at exposure levels obviously toxic to the pregnant animal. Doses tested often approach the LD50 (Cranmer, 1986).
    3.20.3) EFFECTS IN PREGNANCY
    A) ABORTION
    1) CARBOFURAN (CASE REPORT) - A 17-year-old pregnant woman (18 weeks gestation) ingested carbofuran to commit suicide. She arrived at a health care facility 2 hours after ingestion. She was treated with carbon gastric lavage and intensive symptomatic care.
    a) Fetal pulse was not audible on the second day of admission. Neither heart tones nor fetal movement could be detected by ultrasonography. Induction of delivery because of still pregnancy occurred on the seventh day of hospital admission.
    b) Postmortem examination of the fetus revealed a macerated, intrauterine-dead female, of age 4 to 5 lunar months, with no congenital defects. Concentration of carbofuran in the kidney, liver, and brain of the fetus was comparable with the concentration in the mother's blood (Klys et al, 1989).
    B) PLACENTAL BARRIER
    1) ANIMAL - A transplacental effect on activity of acetylcholinesterase has been observed in the day 18 rat fetus with CARBOFURAN administration (HSDB , 1992).

Carcinogenicity

    3.21.3) HUMAN STUDIES
    A) LACK OF EFFECT
    1) CARBARYL - No oncogenicity has been attributed to carbaryl in long term oncogenicity-carcinogenicity studies. Carbaryl when coadministered with background nitrite has not been shown to induce or promote cancer.
    a) N-nitrosocarbaryl, although carcinogenic when administered at high doses, does not represent a significant risk factor (Cranmer, 1986).

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs frequently. Obtain serial ECGs and Institute continuous cardiac and pulse oximetry monitoring.
    B) Monitor for respiratory distress (i.e. bronchorrhea, bronchospasm) and for clinical evidence of cholinergic excess (i.e. salivation, vomiting, urination, defecation, miosis).
    C) Determine plasma and/or red blood cell cholinesterase activities (plasma is generally more sensitive, but red cell correlates somewhat better with clinical signs and symptoms). Depression in excess of 50% of baseline is generally associated with cholinergic effects; in severe poisoning, cholinesterase activity may be depressed by 90% of baseline. Correlation between cholinesterase levels and clinical effects in milder poisonings may be poor.
    D) Monitor electrolytes and serum lipase in patients with significant poisoning.
    E) Monitor pulmonary function (i.e. forced vital capacity, expiratory volume in 1 second, negative inspiratory force) in symptomatic patients; may help anticipate need for intubation.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) CHOLINESTERASE LEVELS: Unless the patient has had extraordinary exposure to an N-methyl carbamate compound, it is unlikely that blood cholinesterase activities will be depressed.
    2) Nonetheless, there is some merit in ordering cholinesterase levels to assess the approximate magnitude of toxicant absorption. In symptomatic patients, the red blood cell and serum cholinesterase activity correlated in 20 of 24 patients (Zweiner & Ginsburg, 1988).
    3) Since pre-exposure cholinesterase levels are usually not available, serial measurements may be used to estimate the pre-exposure cholinesterase levels in patients. Serial measurements may be taken every 5 to 6 weeks for 3 readings (Markowitz, 1992).
    a) The clinical significance of a level of erythrocyte or plasma cholinesterase is measured by its percent decrease from a baseline pre-exposure level or by the degree to which the values are below the established reference range.
    4) Measurement of cholinesterase activity in blood may be misleading due to in vitro reactivation of carbamylated enzyme. In vitro decarbamylation has been found to be promoted by dilution of the sample. The carbamylated sample should be stored undiluted and refrigerated or frozen (Rotenberg & Almog, 1995).
    5) Rotenberg et al (1995) propose an assay technique to distinguish between carbamate and organophosphate poisoning. Carbamylated cholinesterase activity follows a non-linear kinetic pattern over time, whereas phosphorylated enzyme activity is linear. At inhibition of greater than 40%, the non-linear pattern characteristic of carbamates is easily mapped.
    6) ANIMAL DATA: Blood cholinesterase was inhibited one day after oral administration of 1.4 milligrams/kilogram of carbofuran in experimental animals (HSDB , 1992).
    7) PEDIATRIC DATA: A study measuring plasma cholinesterase (ChE) activity in healthy Thai children found that average ChE activity is higher than adult ChE activity. Female children were found to have lower ChE activity than males, but the results were not statistically significant. Decreases below 10 percent of normal levels may be a lethal anti-ChE poisoning (Ruangyuttikarn et al, 2001).
    B) SPECIFIC AGENT
    1) ALDICARB: The limit of sensitivities for aldicarb for different laboratories ranged from 0.01 to 0.2 parts per million (Witt & Wagner, 1986).
    4.1.3) URINE
    A) URINARY LEVELS
    1) METABOLITES: One technique for assessing absorption of the principal N-methyl carbamate compounds is measurement of specific phenolic metabolites in urine. Compound/metabolites are:
    1) CARBARYL/Alpha-naphthol
    2) CARBOFURAN/carbofuranphenol
    3) PROPOXUR/Isopropoxyphenol
    4.1.4) OTHER
    A) OTHER
    1) OTHER
    a) A case of carbaryl poisoning was studied using repetitive stimulation and edrophonium administration to measure the effect of the toxin on the myoneural junction. The study supported the use of edrophonium in cases where anticholinesterase poisoning is suspected, but initial electrophysiologic studies are normal (Robinson, 1990).

Radiographic Studies

    A) CHEST RADIOGRAPH
    1) Chest x-ray should be obtained in all symptomatic patients. The major cause of morbidity and mortality in carbamate insecticide poisonings is respiratory failure and associated pulmonary edema.
    B) CT RADIOGRAPH
    1) High resolution CT (HRCT) has been used in the follow-up of carbamate poisoning with pulmonary edema. HRCT demonstrated diffuse bilateral reticular opacities with parenchymal distortion and multifocal areas of ground glass attenuation and consolidation associated with traction bronchiectasis on both lungs. HRCT and pathologic findings revealed interstitial pneumonitis after resolution of pulmonary edema in one case (Park et al, 2000).

Methods

    A) OTHER
    1) CHOLINESTERASE LEVELS can be done by specialized toxicology laboratories.
    B) CHROMATOGRAPHY
    1) GAS CHROMATOGRAPHY has been used to detect carbofuran and its metabolites in the urine of occupationally exposed workers (Drevenkar et al, 1983).
    2) Lee et al (1999) described a thin layer chromatography (TLC) and gas chromatography/mass spectrophotometry (GC/MS) method for the quantification in blood of furathiocarb using a gas chromatograph equipped with a nitrogen-phosphorus detector (NPD) (Lee et al, 1999).
    3) Benfuracarb and its major metabolite, carbofuran, were measured in body fluids with a thin layer chromatograph (TLC) and gas chromatography/mass spectrophotometry (GC/MS) method following extraction with ethyl acetate and quantified using gas chromatography (GC) equipped with NPD (Lee et al, 1999a).
    4) Ragoucy-Sengler et al (2000) and Tracqui et al (2001) described the identification and quantification of aldicarb in human blood and urine by UV spectra and retention time after HPLC separation. The authors used a HPLC system with diode array detection. Limit of detection (assay on 1 mL blood) was 0.05 mcg/mL; limit of quantification was 0.10 mcg/mL (Tracqui et al, 2001; Ragoucy-Sengler et al, 2000).
    5) A GC/MS ionization method was used for identification and quantification of carbaryl in human serum and tissue following a fatal ingestion (Yamazaki et al, 2001).
    6) GC/MS was used to detect and quantitate gastric fluid, blood, and urine samples from a 68-year-old man who intentionally ingested an unknown amount of pirimicarb. In plasma, the limits of detection and quantification were 10 ng/mL and 20 ng/mL, respectively (Hoffmann et al, 2008).
    C) SPECTROSCOPY/SPECTROMETRY
    1) MASS SPECTROMETRY: Positive-ion electron impact (PIEI), positive-ion chemical ionization (PICI), and negative-ion chemical ionization (NICI) mass spectra were used after isolation with Sep-Pak C cartridges to identify nine carbamate pesticides in human urine, plasma, whole blood, and liver, kidney, and brain tissues (Suzuki et al, 1990).
    2) Spectrophotometric enzyme assay along with cholinesterase (ChE) enzyme inhibition has been used as a screening test for anti-ChE intoxication. Results were verified with thin layer chromatography (Ruangyuttikarn et al, 2001).

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) All intentional ingestions should be initially managed as a severe exposure. Determine cholinesterase activity to assess if a significant exposure occurred. Patients who develop signs or symptoms of cholinergic toxicity (e.g. muscarinic, nicotinic OR central) should be admitted to an intensive care setting.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Patients with unintentional trivial exposures who are asymptomatic can be observed in the home or in the workplace.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a medical toxicologist and/or poison center for assistance with any patient with moderate to severe cholinergic manifestations.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with deliberate or significant exposure and those who are symptomatic should be sent to a health care facility for evaluation, treatment and observation for 6 to 12 hours. Onset of toxicity is variable; most patients will develop symptoms within 6 hours. Patients that remain asymptomatic 12 hours after an ingestion or a dermal exposure are unlikely to develop severe toxicity. Cholinesterase activity should be determined to confirm the degree of exposure.

Monitoring

    A) Monitor vital signs frequently. Obtain serial ECGs and Institute continuous cardiac and pulse oximetry monitoring.
    B) Monitor for respiratory distress (i.e. bronchorrhea, bronchospasm) and for clinical evidence of cholinergic excess (i.e. salivation, vomiting, urination, defecation, miosis).
    C) Determine plasma and/or red blood cell cholinesterase activities (plasma is generally more sensitive, but red cell correlates somewhat better with clinical signs and symptoms). Depression in excess of 50% of baseline is generally associated with cholinergic effects; in severe poisoning, cholinesterase activity may be depressed by 90% of baseline. Correlation between cholinesterase levels and clinical effects in milder poisonings may be poor.
    D) Monitor electrolytes and serum lipase in patients with significant poisoning.
    E) Monitor pulmonary function (i.e. forced vital capacity, expiratory volume in 1 second, negative inspiratory force) in symptomatic patients; may help anticipate need for intubation.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) PREHOSPITAL: Activated charcoal is contraindicated because of possible respiratory depression, seizures, and risk of aspiration. Remove contaminated clothing and wash skin with soap and water. Universal precautions and nitrile gloves to protect personnel. Vomiting should be contained and treated as hazardous material. Rescue personnel should avoid dermal exposure to vomiting because of the risk of intoxication.
    B) There are two primary classes of antidotes: ATROPINE (muscarinic antagonist); OXIMES (pralidoxime in the US, or obidoxime in some other countries) to reverse neuromuscular blockade. Use of oximes is generally indicated for patients with severe toxicity and are used in conjunction with atropine.
    6.5.2) PREVENTION OF ABSORPTION
    A) SUMMARY
    1) Gastric lavage or activated charcoal should be administered if ingestion has been recent. Seizures may occur; protect the airway.
    B) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    C) GASTRIC LAVAGE
    1) INDICATIONS: Consider gastric lavage with a large-bore orogastric tube (ADULT: 36 to 40 French or 30 English gauge tube {external diameter 12 to 13.3 mm}; CHILD: 24 to 28 French {diameter 7.8 to 9.3 mm}) after a potentially life threatening ingestion if it can be performed soon after ingestion (generally within 60 minutes).
    a) Consider lavage more than 60 minutes after ingestion of sustained-release formulations and substances known to form bezoars or concretions.
    2) PRECAUTIONS:
    a) SEIZURE CONTROL: Is mandatory prior to gastric lavage.
    b) AIRWAY PROTECTION: Place patients in the head down left lateral decubitus position, with suction available. Patients with depressed mental status should be intubated with a cuffed endotracheal tube prior to lavage.
    3) LAVAGE FLUID:
    a) Use small aliquots of liquid. Lavage with 200 to 300 milliliters warm tap water (preferably 38 degrees Celsius) or saline per wash (in older children or adults) and 10 milliliters/kilogram body weight of normal saline in young children(Vale et al, 2004) and repeat until lavage return is clear.
    b) The volume of lavage return should approximate amount of fluid given to avoid fluid-electrolyte imbalance.
    c) CAUTION: Water should be avoided in young children because of the risk of electrolyte imbalance and water intoxication. Warm fluids avoid the risk of hypothermia in very young children and the elderly.
    4) COMPLICATIONS:
    a) Complications of gastric lavage have included: aspiration pneumonia, hypoxia, hypercapnia, mechanical injury to the throat, esophagus, or stomach, fluid and electrolyte imbalance (Vale, 1997). Combative patients may be at greater risk for complications (Caravati et al, 2001).
    b) Gastric lavage can cause significant morbidity; it should NOT be performed routinely in all poisoned patients (Vale, 1997).
    5) CONTRAINDICATIONS:
    a) Loss of airway protective reflexes or decreased level of consciousness if patient is not intubated, following ingestion of corrosive substances, hydrocarbons (high aspiration potential), patients at risk of hemorrhage or gastrointestinal perforation, or trivial or non-toxic ingestion.
    6.5.3) TREATMENT
    A) MONITORING OF PATIENT
    1) Monitor vital signs frequently. Obtain serial ECGs and institute continuous cardiac and pulse oximetry monitoring.
    2) Monitor for respiratory distress (ie, bronchorrhea, bronchospasm) and for clinical evidence of cholinergic excess (ie, salivation, vomiting, urination, defecation, miosis).
    3) Determine plasma and/or red blood cell cholinesterase activities (plasma is generally more sensitive, but red cell correlates somewhat better with clinical signs and symptoms). Depression in excess of 50% of baseline is generally associated with cholinergic effects; in severe poisoning, cholinesterase activity may be depressed by 90% of baseline. Correlation between cholinesterase levels and clinical effects in milder poisonings may be poor.
    4) Monitor electrolytes and serum lipase in patients with significant poisoning.
    5) Monitor pulmonary function (ie, forced vital capacity, expiratory volume in 1 second, negative inspiratory force) in symptomatic patients; may help anticipate need for intubation.
    B) ATROPINE
    1) SUMMARY
    a) Atropine is used to treat muscarinic effects (e.g. salivation, lacrimation, defecation, urination, bronchorrhea).
    2) DOSE
    a) ADULT: 1 to 3 mg IV; CHILD: 0.02 mg/kg IV. If inadequate response in 3 to 5 minutes, double the dose. Continue doubling the dose and administering it IV every 3 to 5 minutes as needed to dry pulmonary secretions. Once secretions are dried, maintain with an infusion of 10% to 20% of the loading dose every hour. Monitor frequently for evidence of cholinergic effects or atropine toxicity (e.g., delirium, hyperthermia, ileus) and titrate dose accordingly. Large doses (hundreds of milligrams) are sometimes required. Atropinization may be required for hours to days depending on severity (Roberts & Aaron, 2007).
    3) MAINTAIN ATROPINIZATION: For hours or days, depending on estimated toxicity and dose of toxicant. Following a massive exposure, hundreds of milligrams of atropine may be needed. In one adult case, a total atropine dose of 970 milligrams was required (Nelson et al, 2001).
    4) ATROPINE INFUSION: An atropine drip may be compounded using the powdered form of the drug or using the 20 mL multidose vial. Use preservative-free atropine. In one adult case, an atropine drip was started at 6 mg/hr, then titrated up to 9 mg/hr in order to prevent recurrent bronchorrhea. This was continued for 5 days until a total dose of 970 mg had been administered (Nelson et al, 2001).
    5) ATROPINE WITHDRAWAL: Done gradually by lengthening interval between doses. Check lung bases for rales, and observe patient for return of cholinergic signs. Increase atropine dosage promptly if there are indications of relapse.
    6) PRESERVATIVE TOXICITY: Many parenteral atropine preparations are preserved with benzyl alcohol or chlorobutanol. High dose atropine therapy may result in excipient toxicity if these formulations are used. Preservative-free atropine injection is available.
    7) SUCTIONING: Careful suctioning of oral and tracheal secretions may be necessary until atropinization is achieved.
    C) PRALIDOXIME
    1) INDICATIONS
    a) USE IS CONTROVERSIAL: Critical reviews of the use of oximes in carbamate poisoning have been published (Pelfrene, 1986; Kurtz, 1990). Clinical experience in humans has not consistently confirmed the value of pralidoxime in carbamate poisoning.
    1) A consensus of experts concluded that 6 of 10 had or would use pralidoxime in conjunction with atropine for specific indications listed below. Four of 10 would not use pralidoxime. One expert presented anecdotal experience in two patients who appeared to worsen after receiving pralidoxime(Consensus, 1986).
    b) INDICATIONS: After adequate atropinization, pralidoxime may be indicated in the following situations (Consensus, 1986).
    1) Life-threatening symptoms such as severe muscle weakness, fasciculations, paralysis, or decreased respiratory effort.
    2) Continued excessive requirements of atropine.
    3) Concomitant organophosphate and carbamate exposure.
    2) INCREASED TOXICITY WITH USE
    a) In one human case report of carbaryl poisoning, pralidoxime was implicated in contributing to toxicity, but the patient appeared to be inadequately atropinized (Farago, 1969).
    b) ANIMAL STUDIES: In laboratory animals, when pralidoxime was given alone or an alternate oxime (obidoxime) was given with atropine, an increase in carbaryl toxicity (but not other carbamates) was seen (Natoff & Reiff, 1973). A total of 5 animals were studied.
    3) NO INCREASED TOXICITY WITH USE
    a) Pralidoxime was used in 5 of 13 patients with carbamate poisoning in one series, with no adverse outcome (Tsao et al, 1990).
    4) EFFICACIOUS USE
    a) CASE REPORT: Progressive weakness due to severe aldicarb poisoning, with a plasma cholinesterase 6% of normal, responded to administration of pralidoxime 4 grams over 10 hours (Burgess et al, 1992).
    b) CASE REPORT: Pralidoxime stopped muscle fasciculations in a severe carbamate poisoning caused by methomyl in a 52-year-old man. A total of 16 grams pralidoxime (2 grams in the emergency department and 0.5 gm/hr for 28 hours) and 18 mg atropine were given. Rapid and pronounced clinical improvement occurred (Ekins & Geller, 1994a).
    c) ANIMAL STUDY: In laboratory animals, pralidoxime in combination with atropine decreased toxicity of various carbamates, including carbaryl. A total of 5 animals were studied (Natoff & Reiff, 1973).
    d) ANIMAL STUDY: In another study involving 6 animals, pralidoxime alone was effective in isolan and dimetilan, but not with carbaryl (Sanderson, 1961).
    e) ANIMAL STUDY: A study of effectiveness of atropine, pralidoxime, and HI-6 against carbaryl intoxication in rats demonstrated a decrease LD50 (intraperitoneally) when pralidoxime was used alone compared to control (39.4 milligrams/kilogram pralidoxime vs 69.9 milligrams/kilogram control).
    1) Pralidoxime used with atropine decreased the LD50 compared to atropine alone, but was still above control (244 milligrams/kilogram atropine + pralidoxime vs 460 milligrams/kilogram atropine vs 69.9 milligrams/kilogram control) (Harris et al, 1989).
    2) LD50 data for pralidoxime alone (no carbaryl) in rats was not done in this study.
    5) CASE SERIES
    a) OBIDOXIME: 26 children were administered IV atropine and obidoxime during the first 5 hours of suspected organophosphate poisoning. Obidoxime was given in 2 doses of 6 mg/kg each, the first on admission and the second 3 to 4 hours later.
    b) Marked clinical improvement occurred within 2 to 4 hours and all children had recovered completely by 24 hours. Subsequently, all 26 children were confirmed to have carbamate poisoning. As rapid improvement within 24 hours is described in most reported cases of carbamate poisoning, there was no clear effect from obidoxime therapy. Secondary complications of oxime-related adverse effects were not observed (Lifshitz et al, 1994).
    6) DOSE
    a) PRALIDOXIME DOSE
    1) ADULT: A loading dose of 30 mg/kg (maximum: 2 grams) over 30 minutes followed by a maintenance infusion of 8 to 10 mg/kg/hr (up to 650 mg/hr) (Howland, 2011). In vitro studies have recommended a target plasma concentration of close to 17 mcg/mL necessary for pralidoxime to be effective, which is higher than the previously suggested concentration of at least 4 mcg/mL (Howland, 2011; Eddleston et al, 2002). ALTERNATE ADULT: An alternate initial dose for adults is 1 to 2 grams diluted in 100 mL of 0.9% sodium chloride infused over 15 to 30 minutes. Repeat initial bolus dose in 1 hour and then every 3 to 8 hours if muscle weakness or fasciculations persist (continuous infusion preferred). In patients with serious cholinergic intoxication, a continuous infusion of 500 mg/hr should be considered. In patients with acute lung injury, a 5% solution may be administered by a slow IV injection over at least 5 minutes (Howland, 2006). Intravenous dosing is preferred; however, intramuscular administration may be considered using a 1-g vial of pralidoxime reconstituted with 3 mL of sterile water for injection or 0.9% sodium chloride for injection, producing a solution containing 300 mg/mL (Howland, 2011). An initial intramuscular pralidoxime dose of 1 gram or up to 2 grams in cases of very severe poisoning has also been recommended (Haddad, 1990; S Sweetman , 2002).
    2) CHILD: A loading dose of 20 to 40 mg/kg (maximum: 2 grams/dose) infused over 30 to 60 minutes in 0.9% sodium chloride (Howland, 2006; Schexnayder et al, 1998). Repeat initial bolus dose in 1 hour and then every 3 to 8 hours if muscle weakness or fasciculations persist (continuous infusion preferred). ALTERNATE CHILD: An alternate loading dose of 25 to 50 mg/kg (up to a maximum dose of 2 g), followed via continuous infusion of 10 to 20 mg/kg/hr. In patients with serious cholinergic intoxication, a continuous infusion of 10 to 20 mg/kg/hr up to 500 mg/hr should be considered (Howland, 2006).
    3) Presently, the ideal dose has NOT been established and dosing is likely based on several factors: type of OP agent (ie, diethyl OPs appear to respond more favorably to oximes, while dimethyl OPs seem to respond poorly) which may relate to a variation in the speed of ageing, time since exposure, body load, and pharmacogenetics (Eddleston et al, 2008)
    4) CONTINUOUS INFUSION
    a) A continuous infusion of pralidoxime is generally preferred to intermittent bolus dosing to maintain a target concentration with less variation (Howland, 2011; Eddleston et al, 2008; Roberts & Aaron, 2007; Gallagher et al, 1989; Thompson, 1987). In an open label, randomized study of moderately severe organophosphate poisoned patients treated with high dose continuous infusions required less atropine, were less likely to be intubated and had shorter duration of ventilatory support than patients treated with intermittent bolus doses. HIGH DOSE CONTINUOUS INFUSION: In this study, an initial 2 g bolus (pralidoxime chloride or iodide) was given, followed by 1 g over an hour every hour for 48 hours. Followed by 1 g every 4 hours until the patient could be weaned from mechanical ventilation. The response to therapy was beneficial in patients exposed to either a dimethyl or diethyl organophosphate pesticide (Pawar et al, 2006).
    b) Infusion over a period of several days may be necessary and is generally well tolerated (Namba et al, 1971).
    5) MAXIMUM DOSE
    a) The maximum recommended dose for pralidoxime is 12 grams in 24 hours for adults (S Sweetman , 2002); based on WHO, this dose may be exceeded in severely poisoned adults (Tang et al, 2013).
    6) DURATION OF INTRAVENOUS DOSING
    a) Dosing should be continued for at least 24 hours after cholinergic manifestations have resolved (Howland, 2006). Prolonged administration may be necessary in severe cases, especially in the case of poisoning by lipophilic organophosphates (Wadia & Amin, 1988). Observe patients carefully for recurrent cholinergic manifestations after pralidoxime is discontinued.
    7) ADVERSE EFFECTS
    a) SUMMARY
    1) Minimal toxicity when administered as directed; adverse effects may include: pain at injection site; transient elevations of CPK, SGOT, SGPT; dizziness, blurred vision, diplopia, drowsiness, nausea, tachycardia, hyperventilation, and muscular weakness (Prod Info PROTOPAM(R) CHLORIDE injection, 2006). Rapid injection may produce laryngospasm, muscle rigidity and tachycardia (Prod Info PROTOPAM(R) CHLORIDE injection, 2006).
    b) MINIMAL TOXICITY
    1) When administered as directed, pralidoxime has minimal toxicity (Prod Info PROTOPAM(R) CHLORIDE injection, 2006). Up to 40.5 grams have been administered over seven days (26 grams in the first 54 hours) without ill effects (Namba et al, 1971).
    2) One child developed delirium, visual hallucinations, tachycardia, mydriasis, and dry mucous membranes (Farrar et al, 1990). The authors were uncertain if these effects were related to 2-PAM or organophosphate poisoning per se.
    c) NEUROMUSCULAR BLOCKADE
    1) High doses have been reported to cause neuromuscular blockade, but this would not be expected to occur with recommended doses (Grob & Johns, 1958).
    d) VISUAL DISTURBANCES
    1) Oximes have produced visual disturbances (eg, blurred vision, diplopia) (Prod Info PROTOPAM(R) CHLORIDE injection, 2006).
    2) Transient increases in intraocular pressure may occur (Ballantyne B, 1987).
    e) ASYSTOLE
    1) Pralidoxime administered intravenously at an infusion rate of 2 grams over 10 minutes was associated with asystole in a single reported case, which occurred about 2 minutes after initiation of the infusion (Scott, 1986). A cause and effect relationship was not established.
    f) WEAKNESS
    1) Mild weakness, blurred vision, dizziness, headache, nausea, and tachycardia may occur if the rate of pralidoxime infusion exceeds 500 milligrams/minute (Jager & Stagg, 1958).
    g) ATROPINE SIDE EFFECTS
    1) Concomitant administration of pralidoxime may enhance the side effects of atropine administration (Hiraki et al, 1958). The signs of atropinization may occur earlier than anticipated when the agents are used together (Prod Info PROTOPAM(R) CHLORIDE injection, 2006).
    h) CARDIOVASCULAR
    1) Transient dose-dependent increases in blood pressure have occurred in adults receiving 15 to 30 milligrams/kilogram of 2-PAM (Calesnick et al, 1967). Increases in systolic and diastolic blood pressure have been observed in healthy volunteers given parenteral doses of pralidoxime (Prod Info PROTOPAM(R) CHLORIDE injection, 2006).
    2) Electrocardiographic changes and marked hypertension were observed at doses of 45 milligrams/kilogram (Calesnick et al, 1967).
    8) PHARMACOKINETICS
    a) HALF-LIFE: Pralidoxime is relatively short-acting with an estimated half-life of 75 minutes (Prod Info PROTOPAM(R) CHLORIDE injection, 2006). One report found that the effective half-life of pralidoxime chloride was longer in poisoned individuals than in healthy volunteers. This was attributed to a reduced renal blood flow in the poisoned patients (Jovanovic, 1989).
    9) AVAILABLE FORMS
    a) VIALS
    1) Each 20-mL vial contains 1 gram of pralidoxime chloride (Prod Info PROTOPAM(R) Chloride injection, 2010)
    b) SELF-INJECTOR
    1) Each auto-injector contains 600-mg of pralidoxime chloride in 2 mL of a sterile solution containing 20 mg/mL benzyl alcohol, 11.26 mg/mL glycine in water for injection (Prod Info PRALIDOXIME CHLORIDE intramuscular injection, 2003).
    c) CONVERSION FROM AUTOINJECTOR TO IV SOLUTION
    1) In one study, the conversion of intramuscular pralidoxime (from a MARK I Injector) to an IV solution resulted in a stable and sterile solution for up to 28 days. It is suggested that this conversion may be used in a mass casualty situation when additional IV doses of pralidoxime are needed. The following method may be used to transfer the syringe content: (Corvino et al, 2006).
    a) Avoid a shattered glass incident by using a biological safety cabinet.
    b) Double-glove and use a 30 mL empty sterile glass vial.
    c) Sterilize the vial diaphragm with alcohol.
    d) To vent the vial, insert a 1 1/2 inch 21 gauge IV needle bent to 90 degrees.
    e) Obtain the pralidoxime syringe from the kit and place it over the top of the vial diaphragm.
    f) Keep the syringe perpendicular to the vial and grasp the barrel of the syringe and press down firmly until the needle is deployed, and allow the syringe contents to enter into the vial.
    g) Use 5 pralidoxime injectors for one vial, which will be 10 mL in each vial.
    h) A 19 gauge 1.5 inch 5 micro filter needle is used with the 5 or 10 mL syringe to withdraw the pralidoxime solution from the 30 mL vial.
    i) Each vial (10 mL) is used to prepare either 250 mL, 0.9% sodium chloride injection IV bag at 8 mg/mL OR 100 mL, 0.9% sodium chloride injection IV bag to yield a final pralidoxime concentration of 10 mg/mL; 3.33 mL should be added into a 100 mL bag and 6.66 mL should be added into a 250 mL bag.
    d) OTHER SALTS
    1) Pralidoxime mesylate (P2S) in the United Kingdom (UK License holder, Department of Health).
    2) Pralidoxime methisulfate (Contrathion(R)) available in Greece (from IFET), Turkey (from Keymen), Brazil (from Sanofi-Aventis), Italy (from Sanofi-Aventis) and France (from SERB).
    D) SEIZURE
    1) SUMMARY
    a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
    b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
    c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).
    2) DIAZEPAM
    a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .
    3) NO INTRAVENOUS ACCESS
    a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
    b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).
    4) LORAZEPAM
    a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
    b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
    c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2010; Chin et al, 2008).
    5) PHENOBARBITAL
    a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
    b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
    c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
    d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
    e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
    f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).
    6) OTHER AGENTS
    a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):
    1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
    2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
    3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
    4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).
    E) CARBOFURAN
    1) Specific carbamate recommendations include:
    2) CARBOFURAN: In a case of voluntary acute carbofuran poisoning, pancuronium bromide with assisted ventilation and diazepam were used to treat a persistent nicotinic myoclonic state (Poirier et al, 1987).
    F) EXPERIMENTAL THERAPY
    1) CIMETIDINE has been investigated in isolated perfused rat liver and in one human volunteer for its ability to alter the metabolism of carbaryl. Cimetidine prolonged the half-life of carbaryl in this model (Ward et al, 1988).
    a) The investigators did not measure serial cholinesterase levels in the human volunteer, which would have increased validity. The exact mechanism of carbaryl metabolism is unknown. Additional studies are needed to determine the clinical significance of these findings.
    2) DIPHENHYDRAMINE: Al-Baggou and Mohammad (1999) reported antagonism of methomyl- induced toxicosis by diphenhydramine the rat model. When diphenhydramine was administered to rats (20 mg/kg SubQ.) immediately following methomyl (6 mg/kg i.p.), cholinergic toxicity was decreased, with prevention of seizures, gasping and death by 100% in comparison to controls (methomyl- saline group). The actions of diphenhydramine may be attributed to antimuscarinic and possibly antinicotinic effects. Further studies are needed to test the antidotal efficacy of diphenhydramine in poisonings with other carbamate insecticides. No reports on efficacy in humans were available. (Al-Baggou & Mohammad, 1999).
    3) MEMANTINE: In a rat study, memantine, a NMDA receptor antagonist and atropine pretreatment, produced attenuation of carbofuran induced changes in acetylcholinesterase and radical oxygen species formation. The authors concluded that memantine protected against neuronal oxidative injury and dendritic changes (Gupta et al, 2007).
    4) N-ACETYLCYSTEINE: In a rat study, n-acetylcysteine had a protective effect on carbofuran induced alterations in calcium homestasis and neurobehavioral function (Kamboj & Sandhir, 2007).

Inhalation Exposure

    6.7.1) DECONTAMINATION
    A) Move patient from the toxic environment to fresh air. Monitor for respiratory distress. If cough or difficulty in breathing develops, evaluate for hypoxia, respiratory tract irritation, bronchitis, or pneumonitis.
    B) OBSERVATION: Carefully observe patients with inhalation exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.
    C) INITIAL TREATMENT: Administer 100% humidified supplemental oxygen, perform endotracheal intubation and provide assisted ventilation as required. Administer inhaled beta-2 adrenergic agonists, if bronchospasm develops. Consider systemic corticosteroids in patients with significant bronchospasm (National Heart,Lung,and Blood Institute, 2007). Exposed skin and eyes should be flushed with copious amounts of water.

Eye Exposure

    6.8.1) DECONTAMINATION
    A) EYE IRRIGATION, ROUTINE: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, an ophthalmologic examination should be performed (Peate, 2007; Naradzay & Barish, 2006).

Dermal Exposure

    6.9.1) DECONTAMINATION
    A) CLOTHING
    1) DECONTAMINATION: Remove contaminated clothing and jewelry and place them in plastic bags. Wash exposed areas with soap and water for 10 to 15 minutes with gentle sponging to avoid skin breakdown. Rescue personnel and bystanders should avoid direct contact with contaminated skin, clothing, or other objects (Burgess et al, 1999). Since contaminated leather items cannot be decontaminated, they should be discarded (Simpson & Schuman, 2002).

Enhanced Elimination

    A) EXTRACORPOREAL ELIMINATION
    1) ENHANCED ELIMINATION is NOT RECOMMENDED.
    2) Enhanced elimination, especially hemoperfusion, is not indicated or useful (Personal Communication, 1995).

Case Reports

    A) CHRONIC EFFECTS
    1) There have been several cases (Ratner et al, 1983) of chronic dietary poisoning due to anticholinesterase pesticides. Most of these individuals were dieters or vegetarians who consumed large amounts of fruits and vegetables.
    a) Symptoms included whole blood CHE reductions of 50% and initial gastrointestinal abnormalities (diarrhea, vomiting, colic) and then CNS symptoms (restlessness, fatigue, insomnia and dizziness).
    b) Treatments consisted of changes in diet which increased the blood CHE and alleviated symptoms in 1 to 6 months.
    B) SPECIFIC AGENT
    1) ALDICARB: he largest recorded outbreak of aldicarb food poisoning originated from contaminated watermelon. There were 692 probable cases reported by California and an additional 483 probable or possible cases were reported in other states of the United States and Canada (Anon, 1986; Green et al, 1987).
    2) ALDICARB: 15-year-old boy developed blurred vision fasciculations, dysarthria, excessive perspiration, and abdominal pain. The patient was admitted for diarrhea and bilateral miosis. The patient was observed and released, asymptomatic, the next morning.
    a) Serum pseudoacetylcholinesterase levels were normal, but the erythrocyte acetylcholinesterase level was 70% of normal (this level returned to normal four weeks later).
    b) This was one of a series of cases with unusual central-nervous-system symptoms due to aldicarb poisoning in Dublin, traced to a single cucumber producer (Stinson et al, 1993).
    3) METHOMYL: 52-year-old man presented after accidentally ingesting a liquid from a soft drink bottle initially thought to contain an organophosphate herbicide. Clinical signs on hospital admission included stupor, coarse leg muscle fasciculations, severe respiratory distress, incontinence, and miotic pupils. Projectile pink frothy secretions were noted with endotracheal intubation. Blood pressure was 228/120 and respiratory rate was 44. The skin smelled of camphor.
    a) Treatment consisted of atropine 6 mg IV, pralidoxime 1 gram IV, lavage and activated charcoal. When fasciculations resumed, another dose of pralidoxime was given. Plasma cholinesterase levels were 3 mmol/mL/min (normal was 7 to 19). When the toxin was analyzed it was discovered to be concentrated methomyl. Methomyl caused a severe organophosphate-like intoxication with decreased cholinesterase levels with improvement following treatment with pralidoxime (Ekins et al, 1993).

Summary

    A) TOXICITY: Carbamates are absorbed across the lung, mucous membranes (including gut), and skin. Poisoning depends upon inherent toxicity, dosage, rate of absorption, rate of metabolic breakdown, and prior exposure to other cholinesterase inhibitors. Generally carbamates are less toxic than organophosphates. Aldicarb is considered the most toxic carbamate.

Minimum Lethal Exposure

    A) GENERAL/SUMMARY
    1) There is great variation in toxic/lethal doses between the various carbamates. When available, toxicity should be considered per substance.
    B) SPECIFIC SUBSTANCE
    1) METHOMYL - Ingestion of contaminated food resulted in three fatalities; the estimated lethal dose from this incident was 12 to 15 milligrams/kilogram (Liddle et al, 1979).
    2) METHOMYL - A fatality resulted following inhalation and transdermal absorption of methomyl in a farmer who used this product with no self-protection. Blood concentration of methomyl on admission (prior to death) was 1.6 milligrams/deciliter (Tsatsakis et al, 2001).
    C) PEDIATRIC
    1) CASE SERIES - In a case series of 54 children with anticholinesterase insecticide poisoning from various routes of exposure, no significant differences in incidence of clinical effects were detected according to route of exposure, or state of decontamination. Four of the children died (7%). The presence of a cardiac dysrhythmia (likelihood ratio 8.3) and respiratory failure (likelihood ratio 3.3) were associated with increased likelihood of a fatal outcome (Verhulst et al, 2002).
    2) CASE STUDY - Plasma cholinesterase (ChE) activity was measured in 105 healthy Thai children. The mean was 7,417 +/- 1,620 units/L. This was compared to the ChE activities (470 and 680 units/L) of two children intentionally poisoned with methomyl. The authors concluded that as little as a 10 percent decrease in plasma ChE levels in children may be a lethal anti-ChE poisoning (Ruangyuttikarn et al, 2001).
    D) ANIMAL DATA
    1) CARBOFURAN - The 30-day empirical minimum lethal dosage was 0.2 milligram/kilogram/day for mallards and 4.2 milligrams/kilogram/day for pheasants (HSDB , 2001).

Maximum Tolerated Exposure

    A) GENERAL/SUMMARY
    1) There is great variation in toxic/lethal doses between the various carbamates. When available, toxicity should be considered per substance.
    B) SPECIFIC SUBSTANCE
    1) CARBAMATE HERBICIDES - There are a number of carbamate herbicides and fungicides used in agriculture which are not cholinesterase inhibitors. The pesticides listed below are cholinesterase inhibitors.
    2) ALDICARB - Aldicarb is a systemic insecticide. It is taken up from soil and translocated into the fruit of some crops in sufficient quantity to cause symptoms of poisoning. Below are some examples of poisoning via contaminated food.
    a) FOOD CONTAMINATION/CALIFORNIA - Illnesses were detected in patients receiving a dose of 0.0011 to 0.06 milligram/kilogram. This amounted to 1/4 to 1 cucumber and 1/2 slice to 5 slices of melon (Goldman et al, 1990).
    b) FOOD CONTAMINATION/NEBRASKA - Illnesses at doses of 0.025 to 0.041 milligram/kilogram of body weight (Jackson & Goldman, 1986; Goes et al, 1980). Severe poisoning requiring hospital treatment only occurred with exposures to more than 0.01 milligram/kilogram (Goldman et al, 1990).
    c) FOOD CONTAMINATION/LOUISIANA - Of 16 persons who ate an aldicarb- contaminated salad, 14 became ill, with predominantly gastrointestinal and neurological symptoms. It was estimated that a 6 gram portion of the salad contained 272.6 parts per million, or approximately 17 milligrams of aldicarb. Thus, a 70-kg adult would have consumed 0.2 milligrams of aldicarb per kilogram of body weight. All the victims recovered following symptomatic therapy (Anon, 1999).
    d) FOOD CONTAMINATION/GREENHOUSES - Two epidemics of poisoning from eating contaminated cucumbers grown in a hydroponic greenhouse have been recorded (Hayes, 1982) with victims becoming ill between 1/2 and 12 hours after ingestion. All recovered without treatment.
    e) FOOD CONTAMINATION/MINT - Eating mint sprigs 24 days after aldicarb soil application caused illness which resolved with atropine (Hayes, 1982).
    C) CASE REPORTS
    1) CARBARYL -
    a) ADULT - A 23-year-old man ingested 500 milligrams/kilogram of carbaryl, the approximate LD50 in rats. The patient survived, but developed a severe delayed peripheral neuropathy (Dickoff et al, 1987).
    2) METHOMYL -
    a) SUMMARY OF CASES - Ingestion of 2 to 16 grams of methomyl products (% not specified) was associated with complete recovery in 8 patients, aged 10 to 60 years.
    1) Treatment included gastric lavage, multiple-dose activated charcoal, and small doses of atropine (0.8 to 6 milligrams).
    2) Plasma cholinesterase normalized within 24 hours in 5 of 7 patients with decreased initial levels (Martinez-Chuecos et al, 1990).

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) SPECIFIC SUBSTANCE
    a) PESTICIDE LEVEL
    1) ALDICARB
    a) An adult was admitted 2 hours following development of nausea, vomiting, diarrhea, weakness, and pulmonary secretions was found 13 hours later to have a blood aldicarb level of 0.1 mg/mL (Burgess et al, 1992).
    b) Following an intentional ingestion of 10 grams of aldicarb, serum levels reached a peak value of 3.22 milligrams/liter at the third hour following hospital admission in a 30-year-old female (Flesch et al, 1999).
    c) On the day of hospital admission following intoxication from aldicarb- contaminated coffee, serum concentration of aldicarb was reported to be 0.90 micrograms/milliliter in a 65-year-old man (Covaci et al, 1999).
    d) In a case series of 18 patients who survived after aldicarb poisoning, biological and clinical signs of poisoning were observed with blood concentrations as low as 0.12 microgram/milliliter. The mean aldicarb serum concentration in deceased patients was 6.7 micrograms/milliliter (Ragoucy-Sengler et al, 2000).
    e) In a case of a suicidal ingestion of an unknown quantity of aldicarb, serial blood aldicarb and pseudocholinesterase levels, as well as urinary aldicarb levels were reported as follows (Tracqui et al, 2001):
    TIME (Hr)SERUM ALDICARB LEVELS (mcg/ml)URINE ALDICARB LEVELS (mcg/mL)PSEUDO- CHOLIN- ESTERASELEVELS (IU/L)
    03.115.54247
    2.53.08Ā Ā 
    3.53.22Ā Ā 
    4.52.744.80Ā 
    5.51.97Ā Ā 
    6.52.29Ā Ā 
    7.51.68Ā Ā 
    8.51.71Ā Ā 
    9.51.47Ā Ā 
    10.50.88Ā Ā 
    13.50.53Ā Ā 
    16.50.32Ā Ā 
    19.50.29Ā Ā 
    22.50.33Ā Ā 
    25.50.355.57Ā 
    31.50.076.95Ā 
    37.50.245.79Ā 
    44.00.12Ā Ā 
    49.5Ā 2.13Ā 
    61.50.103.294329
    73.50Ā Ā 
    79.500.633600

    2) METHOMYL
    a) ADULT LETHAL LEVELS - Blood methomyl concentrations associated with lethality were 700 and 1,400 nanograms/milliliter in two cases.
    b) ADULT LETHAL LEVEL - Loss of control of an airplane caused death in a pilot found to have a blood level of 570 nanograms/milliliter (Driskell et al, 1991).
    c) ADULT LETHAL LEVEL - A woman died 19 hours after ingestion in spite of intensive care. Methomyl concentration was 44 mcg/g in her serum sample collected 1 hour after ingestion, and 0.2 mcg/g in the blood sample collected at autopsy (Miyazaki et al, 1989).
    d) ADULT LEVELS PRIOR TO DEATH - Inhibition of cholinesterase activity and blood methomyl concentrations were reported as follows in a 60-year-old farmer who eventually died due to the unprotected exposure (Tsatsakis et al, 2001):
    .InitialDay 1Day 2Day 3
    Cholinesterase activity (U/L)38086024003200
    Percentage of Inhibition89%75%31%9%
    Blood methomyl conc. (mg/L)1.60.80.60.1

    e) ADULT NON-LETHAL LEVEL - A man recovered after 10 days of treatment. The methomyl concentration his blood sample collected 28 hours after ingestion was from 0.01 to 0.1 mcg/g (Miyazaki et al, 1989).
    3) BENDIOCARB
    a) ADULT LETHAL LEVELS - In a case of oral, self-induced, fatal acute poisoning, bendiocarb blood levels were 40 mg/L, urine levels were 13.5 mg/L; alcohol blood levels were 2.3 g/L, urine levels were 3.15 g/L. Bendiocarb blood concentrations above 1 mg/L are associated with serious toxicity (LD50 greater than 50 mg/kg) (Patel, 1993).
    4) CARBOFURAN
    a) ADULT POSTMORTEM LEVELS - Fatal blood concentrations of carbofuran in 4 postmortem case reports are as follows (Ameno et al, 2001):
    CASE #CONCENTRATION (mcg/mL)
    111.6
    210.0
    34.0
    40.32

    5) FURATHIOCARB
    a) POST-MORTEM LEVELS - Lee et al (1999) reported post-mortem blood levels of furathiocarb in 7 fatalities due to furathiocarb ingestions. Fatal blood concentrations ranged from 0.1 to 21.6 micrograms/milliliter, with differences thought to be related to the dose ingested and time that elapsed between ingestion and death.
    6) PIRIMICARB
    a) CASE REPORT - A 68-year-old man intentionally ingested an unknown amount of pirimicarb and subsequently developed miosis, rhinorrhea, somnolence, hypertensive crisis, seizures, and fasciculations. Toxicological screening detected the following pirimicarb concentrations (Hoffmann et al, 2008):
    1) Gastric fluid - 960 mcg/mL
    2) Plasma - 75 mcg/mL
    3) Urine - 41 mcg/mL
    2) OTHER
    a) CHOLINESTERASE LEVEL
    1) ALDICARB
    a) An adult was admitted 2 hours following development of nausea, vomiting, diarrhea, weakness, and pulmonary secretions. Plasma cholinesterase was 6% of normal 3.5 hours after admission, and remained depressed for 56 hours (Burgess et al, 1992).
    b) Following an intentional ingestion of 10 grams aldicarb, serum cholinesterase activity was significantly decreased to 247 units/liter (normal, 3500-8000 units/liter) three hours after hospital admission in a 30-year-old female. Serum cholinesterase level returned to normal by 60 hours post hospital admission (Flesch et al, 1999).
    2) METHOMYL
    a) PEDIATRIC - Two boys fatally poisoned by their parents with an unknown amount of methomyl were found to have serum cholinesterase (ChE) activity levels of 470 and 680 units/liter (Ruangyuttikarn et al, 2001).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) ALDICARB
    1) LD50- (ORAL)MOUSE:
    a) 0.3 mg/kg (RTECS, 2001)
    2) LD50- (ORAL)RAT:
    a) 0.6-0.8 mg/kg (Hayes, 1982)
    b) 0.5 mg/kg (RTECS, 2001)
    3) LD50- (SKIN)RAT:
    a) 2.5-3 mg/kg (Hayes, 1982; RTECS, 2001)
    B) CARBENDAZIM
    1) LD50- (ORAL)MOUSE:
    a) 7700 mg/kg (RTECS, 2001)
    2) LD50- (ORAL)RAT:
    a) 6400 mg/kg (RTECS, 2001)
    3) LD50- (SKIN)RAT:
    a) 2 gm/kg (RTECS, 2001)
    C) CARBOFURAN
    1) LD50- (ORAL)MOUSE:
    a) 2 mg/kg (RTECS, 2001)
    2) LD50- (ORAL)RAT:
    a) 5 mg/kg (RTECS, 2001)
    3) LD50- (SKIN)RAT:
    a) 120 mg/kg (RTECS, 2001)
    D) METHOMYL
    1) LD50- (ORAL)MOUSE:
    a) 10 mg/kg (RTECS, 2001)
    2) LD50- (ORAL)RAT:
    a) 14.7 mg/kg (RTECS, 2001)
    3) LD50- (SKIN)RAT:
    a) >1600 mg/kg (RTECS, 2001)
    E) PROPOXUR
    1) LD50- (ORAL)MOUSE:
    a) 23.5 mg/kg (RTECS, 2001)
    2) LD50- (SKIN)MOUSE:
    a) >1360 mg/kg (RTECS, 2001)
    3) LD50- (ORAL)RAT:
    a) 41 mg/kg (RTECS, 2001)

Toxicologic Mechanism

    A) These esters of methyl carbamic acid cause poisoning by inhibition of acetylcholinesterase enzyme, which is essential for normal transmission of nerve impulses in the central nervous system and autonomic ganglia and at cholinergic neuroeffector junctions.
    B) The inhibitory effect of these carbamates on cholinesterase enzymes is due to carbamylation of the esteratic sites on the enzyme molecule. The chemical bond is much more labile than that characterizing the phosphorylation by organophosphate insecticides.
    1) In general, this feature tends to make poisonings by the carbamates less prolonged than poisonings by organophosphates, but they may be as acutely severe.

Physical Characteristics

    A) ALDICARB: Crystals from isopropyl ether (Budavari, 1989)
    B) AMINOCARB: Crystals (Budavari, 1989)
    C) BENDIOCARB: White solid (Budavari, 1989)
    D) BUFENCARB: Yellow-amber solid (Budavari, 1989)
    E) CARBARYL: Crystals (Budavari, 1989)
    F) CARBOFURAN: White crystalline solid (Budavari, 1989)
    G) DIMETAN: Crystals from cyclohexane (Budavari, 1989)
    H) DIMETILAN: Colorless solid or yellow to reddish-brown solid (Budavari, 1989)
    I) METHIOCARB: White crystalline powder (Budavari, 1989)
    J) METHOMYL: Crystals (Budavari, 1989)
    K) OXAMYL: Crystalline solid, slight sulfurous odor (Budavari, 1989)
    L) PIRIMICARB: Crystalline solid (Budavari, 1989)
    M) PROPOXUR: Crystals (Budavari, 1989)

Molecular Weight

    A) ALDICARB: 190.25
    B) AMINOCARB: 208.26
    C) BENDIOCARB: 223.23
    D) BUFENCARB: 221.30
    E) CARBARYL: 201.22
    F) CARBOFURAN: 221.26
    G) DIMETAN: 211.25
    H) DIMETILAN: 240.27
    I) METHIOCARB: 225.31
    J) METHOMYL: 162.20
    K) OXAMYL: 219.25
    L) PIRIMICARB: 238.29
    M) PROPOXUR: 209.24

Clinical Effects

    11.1.2) BOVINE/CATTLE
    A) SUMMARY - Hypersalivation, abdominal bloating, lacrimation, fine muscular tremors, bradycardia, respiratory distress, and transient diarrhea may occur.
    B) DELIBERATE POISONING - Dairy cattle maliciously poisoned with aldicarb developed hypersalivation, abdominal bloating, lacrimation, fine muscle tremors, bradycardia, respiratory distress, and diarrhea.
    1) TREATMENT - Cows treated with atropine 0.5 mg/kg were clinically normal 4 hours later. Many died suddenly with no antecedent signs of toxicity.
    2) ALDICARB - Aldicarb was found sporadically in contaminated feed in amounts of 0.037 to 0.05% (Kerr et al, 1991).
    11.1.9) OVINE/SHEEP
    A) ALDICARB POISONING - Acute aldicarb poisoning killed all 318 grazing sheep (288 within a very short time and the remaining 30 within 3 weeks). Chronic toxicity was reported in other poisoned sheep, and included low fertility, poor health in general and malformations in lambs born after the incident (Grendon et al, 1994).
    11.1.13) OTHER
    A) OTHER
    1) SUMMARY - Signs include muscle fasciculations, shallow respiration, constricted pupils, abdominal pain, hyperactivity of GI tract with diarrhea and salivation.
    2) MANEB AND ZINEB - 200 g/100 L doses of maneb and 300 g/100 L doses of zineb were fed to albino mice 3 times/week for 13 weeks. The test mice had larger and more heavily colored livers than the control mice; the test animals had also accumulated fat around the liver, kidney, and pancreas.
    a) Histological examination of the liver and kidney revealed mononuclear cell infiltration, tissue necrosis, and congestion (Mocan et al, 1992).

Treatment

    11.2.1) SUMMARY
    A) GENERAL TREATMENT
    1) Begin treatment immediately.
    2) Keep animal warm.
    3) Sample vomitus, blood, urine, and feces for analysis.
    4) If skin exposure has occurred, wash animal thoroughly with a mild detergent and flush with copious amounts of water.
    11.2.2) LIFE SUPPORT
    A) GENERAL
    1) MAINTAIN VITAL FUNCTIONS: Secure airway, supply oxygen, and begin supportive fluid therapy if necessary.
    11.2.4) DECONTAMINATION
    A) GASTRIC DECONTAMINATION
    1) DOGS/CATS
    a) If within 2 hours of exposure: induce emesis with 1 to 2 milliliters/kilogram syrup of ipecac per os. Dogs may vomit more readily with 1 tablet (6 milligrams) apomorphine diluted in 3 to 5 milliliters water and instilled into the conjunctival sac or per os.
    1) Do not use an emetic if the animal is hypoxic. In the absence of a gag reflex or if vomiting cannot be induced, place a cuffed endotracheal tube and begin gastric lavage.
    2) Pass large bore stomach tube and instill 5 to 10 milliliters/kilogram water or lavage solution, then aspirate. Repeat 10 times (Kirk, 1986).
    b) Administer activated charcoal 2 grams/kilogram per os or via stomach tube.
    c) In case of dermatologic exposure, bathe in mild detergent (animal shampoo or Ivory liquid). Wear gloves to avoid human exposure.
    2) HORSES/CATTLE
    a) Do not attempt to induce emesis in ruminants (cattle) or equids (horses).
    b) Give 250 to 500 grams activated charcoal in a water slurry per os or via stomach tube.
    c) Administer an oral cathartic:
    1) Mineral oil (small ruminants and swine, 60 to 200 milliliters; equids and cattle, 0.5 to 1 gallon) or
    2) Magnesium sulfate (ruminants and swine, 1 to 2 grams/kilogram; equine, 0.2 to 0.9 grams/kilogram) or
    3) Milk of Magnesia (small ruminants, up to 0.25 gram/kilogram in 1 to 3 gallons warm water; adult cattle up to 1 gram/kilogram in 1 to 3 gallons warm water or 2 to 4 boluses MgOH per os).
    4) Give these solutions via stomach tube and monitor for aspiration.
    11.2.5) TREATMENT
    A) DOGS/CATS
    1) Maintain vital functions as necessary.
    2) Atropine sulfate 0.2 milligram/kilogram intravenously, intramuscularly or subcutaneously. Subsequent doses may be given based on clinical impression of degree of respiratory distress and heart rate.
    3) Seizures may be controlled with diazepam or barbiturate anticonvulsants.
    a) Dose of diazepam: 0.5 milligram/kilogram intravenous bolus; may repeat dose every ten minutes for four total doses. Give slowly over 1 to 2 minutes.
    b) Phenobarbital may be used as adjunct treatment at 5 to 30 milligrams/kilogram over 5 to 10 minutes intravenously.
    4) 2-PAM has not been shown to be beneficial in treatment of carbamate toxicosis.
    5) Treated animals should be monitored for 48 hours to assess secondary stress effects, such as active Hemobartinella infection in cats.
    B) RUMINANT
    1) Atropine sulfate 0.2 to 0.5 milligram/kilogram may be given to ruminants. Give one-third of dose intravenously and remainder intramuscularly or subcutaneously. Avoid atropine use in equids; low doses may be given slowly diluted in intravenous fluids while ausculting gut sounds. Administration must stop when gut sounds decrease below normal.
    2) 2-PAM has not been shown to be beneficial in treatment of carbamate toxicosis.

Range Of Toxicity

    11.3.2) MINIMAL TOXIC DOSE
    A) RODENT
    1) RATS - Oral LD50 is 0.8 milligram/kilogram
    B) CATTLE
    1) Acute deaths have occurred after ingestion of feed containing 0.05% aldicarb (Kerr et al, 1991).

Continuing Care

    11.4.1) SUMMARY
    11.4.1.2) DECONTAMINATION/TREATMENT
    A) GENERAL TREATMENT
    1) Begin treatment immediately.
    2) Keep animal warm.
    3) Sample vomitus, blood, urine, and feces for analysis.
    4) If skin exposure has occurred, wash animal thoroughly with a mild detergent and flush with copious amounts of water.
    11.4.2) DECONTAMINATION
    11.4.2.2) GASTRIC DECONTAMINATION
    A) GASTRIC DECONTAMINATION
    1) DOGS/CATS
    a) If within 2 hours of exposure: induce emesis with 1 to 2 milliliters/kilogram syrup of ipecac per os. Dogs may vomit more readily with 1 tablet (6 milligrams) apomorphine diluted in 3 to 5 milliliters water and instilled into the conjunctival sac or per os.
    1) Do not use an emetic if the animal is hypoxic. In the absence of a gag reflex or if vomiting cannot be induced, place a cuffed endotracheal tube and begin gastric lavage.
    2) Pass large bore stomach tube and instill 5 to 10 milliliters/kilogram water or lavage solution, then aspirate. Repeat 10 times (Kirk, 1986).
    b) Administer activated charcoal 2 grams/kilogram per os or via stomach tube.
    c) In case of dermatologic exposure, bathe in mild detergent (animal shampoo or Ivory liquid). Wear gloves to avoid human exposure.
    2) HORSES/CATTLE
    a) Do not attempt to induce emesis in ruminants (cattle) or equids (horses).
    b) Give 250 to 500 grams activated charcoal in a water slurry per os or via stomach tube.
    c) Administer an oral cathartic:
    1) Mineral oil (small ruminants and swine, 60 to 200 milliliters; equids and cattle, 0.5 to 1 gallon) or
    2) Magnesium sulfate (ruminants and swine, 1 to 2 grams/kilogram; equine, 0.2 to 0.9 grams/kilogram) or
    3) Milk of Magnesia (small ruminants, up to 0.25 gram/kilogram in 1 to 3 gallons warm water; adult cattle up to 1 gram/kilogram in 1 to 3 gallons warm water or 2 to 4 boluses MgOH per os).
    4) Give these solutions via stomach tube and monitor for aspiration.
    11.4.3) TREATMENT
    11.4.3.5) SUPPORTIVE CARE
    A) GENERAL
    1) Ongoing treatment is symptomatic and supportive.
    11.4.3.6) OTHER
    A) OTHER
    1) GENERAL
    a) LABORATORY -
    1) If carbamate toxicosis is expected, submit the following samples as soon as possible (within hours) for analysis: blood acetylcholinesterase activity and postmortem brain for caudate nucleus acetylcholinesterase activity. Carbamates bind weakly and reversibly to acetylcholinesterase, so immediate analysis is necessary.

Sources

    A) SPECIFIC TOXIN
    1) Aldicarb is available in 10 and 15% granules.

Other

    A) OTHER
    1) GENERAL
    a) CASE REPORT - One report of malicious poisoning in adult lactating dairy cattle found 23 deaths attributed to ingestion of feed containing 0.05% aldicarb (Kerr et al, 1991).
    b) Carbamate compounds are active for only a few hours in the body, inducing transient biochemical changes that make it difficult to confirm carbamate toxicosis. Laboratory tests must be completed within a few hours of exposure.

General Bibliography

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