MALATHION

Classification | Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

Specific Substances

1) Lice Care
2) Lice Rid
3) Malathion Lotion USP
4) CAS 121-75-5

1) 1,2-Di(ethoxycarbonyl)ethyl O,O-dimethyl phosphorodithioate
2) American Cyanamid 4,049
3) Carbethoxy malathion
4) Carbetovur
5) Carbetox
6) Carbofos
7) Carbophos
8) Chemathion
9) Cimexan
10) Compound 4049
11) Cythion
12) Detmol MA
13) Detmol MA 96%
14) Dicarboethoxyethyl O,O-dimethyl phosphorodithioate
15) Diethyl (dimethoxyphosphionthioylthio) butanedioate
16) Diethyl (dimethoxyphosphinothioylthio) succinate
17) Diethyl mercaptosuccinate S-ester with O,O dimethylphosphorodithioate
18) Diethyl mercaptosuccinate, O,O-dimethyl phosphorodithioate
19) Diethyl mercaptosuccinic acid O,O-dimethyl phosphorodithioate
20) EL 4049
21) Emmatos
22) Emmatos Extra
23) ENT 17,034
24) Ethiolacar
25) Etiol
26) Experimental insecticide 4049
27) Extermathion
28) Forthion
29) Fosfothion
30) Fosfotion
31) Fosfotion 550
32) Fyfanon
33) Hilthion
34) Hilthion 25 WDP
35) Karbofos
36) Kop-thion
37) Kypfos
38) Latka 4049 (Czech)
39) Malacide
40) Malafor
41) Malagran
42) Malakill
43) Malamar
44) Malamar 50
45) Malaphele
46) Malaphos
47) Malasol
48) Malaspray
49) Malatol
50) Malatox
51) Maldison
52) Malmed
53) Malphos
54) Mercaptosuccinic acid diethyl ester
55) Mercaptothion
56) Moscarda
57) O,O-dimethyl S-(1,2-bis(ethoxycaronyl)ethyl)dithiophoshate
58) O,O-dimethyl S-(1,2-dicarbethoxyethyl) dithiophosphate
59) O,O-dimethyl S-(1,2-dicarbethoxyethyl) thiothionophosphate
60) O,O-dimethyl S-(1,2-dicarbethoxyethyl) phosphorodithioate
61) Oleophosphothion
62) Ortho malathion
63) Phosphothion
64) Prentox malathion 95% spray
65) Prioderm
66) Sadofos
67) Sadophos
68) SF 60
69) Siptox I
70) Sumitox
71) TAK
72) TM-4049
73) Vegfru Malatox
74) Vetiol
75) Zithiol
76) (RTECS, 2006)

1.2.1) MOLECULAR FORMULA
1) C10-H19-O6-P-S2

Available Forms Sources

1) THERAPEUTIC USE - The lotion is supplied in bottles of 2 ounces and contains 0.5% malathion. Each bottle contains 0.005 g of malathion per mL in a vehicle of isopropyl alcohol (78%), terpineol, dipentene, and pine needle oil (Prod Info OVIDE(R) topical lotion, 2005).
2) INSECTICIDE - It is sold as a 99.6% technical grade liquid. Other available formulations include emulsifiable concentrates, wettable powders, dusts, aerosols, and ultralow-volume concentrates (ACGIH, 1991a; Sittig, 1991a).

1) Malathion is produced by adding O,O-dimethyl dithiophosphoric acid to diethyl maleate (Ashford, 1994a; Lewis, 1997a).
2) It is not known to occur as a natural product (Howard, 1991a).

1) Malathion is a nonsystemic acaracide and insecticide and is considered the least toxic of the organophosphates. It is used for the control of mosquitoes, flies, and spiders on fruits, vegetables, and ornamental plants, as well as for animal ectoparasites (Baselt, 2000a; Bingham et al, 2001a; Lewis, 1997a; Sittig, 1991a; Hartley & Kidd, 1990a).
2) Malathion is also used in the treatment of pediculus humanus capitis (head lice and their ova) infections of the scalp hair. It is able to kill nits at all stages of parasitic development and molting (Prod Info OVIDE(R) topical lotion, 2005; Meinking et al, 2004).

Overview

Life Support

Clinical Effects

0.2.1)

A) WITH THERAPEUTIC USE

1) The following are signs and symptoms from organophosphates in general, which are due to the anticholinesterase activity of this class of compounds. All of these effects may not be documented for malathion, but could potentially occur in individual cases.
2) USES: Malathion is a nonsystemic acaracide and insecticide and is considered the least toxic of the organophosphates. Malathion is also used in the treatment of pediculus humanus capitis (head lice and their ova) infections of the scalp hair.
3) TOXICOLOGY: Organophosphates 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 can develop.
4) EPIDEMIOLOGY: Exposure to organophosphates is common, but serious toxicity is unusual in the US.

B) WITH POISONING/EXPOSURE

1) EFFECTS FOLLOWING THERAPEUTIC USE

a) Systemic effects have not been reported with topical use of malathion 0.5% solution used in the treatment of pediculus humanus capitis (head lice). The solution is manufactured in an isopropyl alcohol (78%) vehicle which can produce local irritation to the skin. If inadvertent ingestion of malathion solution occurs, the effects of isopropyl alcohol toxicity should be considered. Refer to ISOPROPYL ALCOHOL document for more information.

2) ORGANOPHOSPHATE POISONING EFFECTS

a) 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.
b) 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.
c) DELAYED EFFECTS: Intermediate syndrome is characterized by paralysis of respiratory, cranial motor, neck flexor, and proximal limb muscles 1 to 4 days after apparent recovery from cholinergic toxicity, and prior to the development of delayed peripheral neuropathy. Manifestations can include the inability to lift the neck or sit up, ophthalmoparesis, slow eye movements, facial weakness, difficulty swallowing, limb weakness (primarily proximal), areflexia, and respiratory paralysis. Recovery begins 5 to 15 days after onset. Distal sensory-motor polyneuropathy may rarely develop 6 to 21 days following exposure to some organophosphate compounds, however, it has not yet been reported in humans after exposure to malathion. Characterized by burning or tingling followed by weakness beginning in the legs which then spreads proximally. In severe cases, it may result in spasticity or flaccidity. Recovery requires months and may not be complete.
d) 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 (i.e., secretions, bradycardia, fasciculations and miosis) as compared to adults.
e) INHALATION EXPOSURE: Organophosphate 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)

A) WITH POISONING/EXPOSURE

1) Fever has been reported following ingestion of malathion. Hypothermia has been reported in one adult following a mixed ingestion with organophosphates.

0.2.4)

A) WITH POISONING/EXPOSURE

1) Miosis, lacrimation and blurred vision are common findings in organophosphate poisoning. Mydriasis may be seen in severe poisonings. Excessive salivation may occur after malathion poisoning.

0.2.5)

A) WITH POISONING/EXPOSURE

1) Bradycardia and tachycardia can occur following ingestion. Hypotension or hypertension may develop with severe toxicity. Conduction disturbances have been reported with malathion exposure.

0.2.6)

A) WITH POISONING/EXPOSURE

1) MUSCARINIC EFFECTS may produce bronchorrhea or bronchospasm, and an increase in bronchial secretions following malathion exposure.

0.2.7)

A) WITH POISONING/EXPOSURE

1) EARLY EFFECTS - Malathion poisoning has produced typical neurologic effects of organophosphate poisoning. Giddiness, anxiety, headache, and restlessness followed by ataxia, drowsiness, and confusion are common with moderate to severe exposures. Fasciculations, profound weakness, coma and seizures may develop in severe cases. CNS depression and seizures may be more common in children than adults.
2) INTERMEDIATE SYNDROME - Characterized by the development of proximal weakness and paralysis 12 hours to 7 days after exposure and following resolution of cholinergic symptoms. It is unresponsive to pralidoxime or atropine; treatment is supportive.
3) DELAYED POLYNEUROPATHY - Distal sensory-motor polyneuropathy may develop 6 to 21 days following exposure; recovery may be slow or incomplete.

0.2.8)

A) WITH POISONING/EXPOSURE

1) Nausea, vomiting, abdominal cramps, and diarrhea are common muscarinic effects. Fecal and urinary incontinence have been reported with malathion poisoning. Several cases of acute pancreatitis have also been associated with ingestion.

0.2.14)

A) WITH THERAPEUTIC USE

1) Skin irritation may occur with therapeutic malathion lotion.

B) WITH POISONING/EXPOSURE

1) Organophosphates including malathion can be absorbed transdermally. Diaphoresis is common with acute exposure.

0.2.15)

A) WITH POISONING/EXPOSURE

1) NICOTINIC EFFECTS may produce generalized muscle fasciculations, muscle cramps, and eventually weakness following malathion exposure.

0.2.19)

A) WITH POISONING/EXPOSURE

1) Dermal sensitization to malathion has been reported following skin exposure. It has not been reported with therapeutic use of malathion lotion.

0.2.20)

A) Malathion 0.5% topical lotion has a Pregnancy Category B rating.
B) Malathion 0.5% topical lotion for head lice therapy is Pregnancy Category B.
C) ANIMAL STUDIES - There was no evidence of teratogenicity in studies in rats and rabbits given malathion. Malathion can inhibit microsomal enzyme systems; it has been suggested that it should be investigated for possible effects on pregnancy.
D) HUMAN STUDIES - Detectable malathion metabolites in maternal urine have been linked to abnormal neonatal reflexes.

0.2.21)

A) Malathion has been classified as probably carcinogenic to humans (Group 2A) by IARC following a systematic review and evaluation. However, a long term study of pesticide applicators found no overall increased risk of cancer related to malathion exposure.
B) Long term oral administration of technical grade malathion to rodents produced an increase in hepatocellular neoplastic lesions.

Laboratory Monitoring

1) Obtain a metabolic panel, serum isopropyl alcohol and acetone concentrations. Ketonemia and ketonuria may present within 1 to 3 hours of ingestion, but acidosis is NOT expected. Isopropanol elevates measured serum osmolality. Refer to ISOPROPYL ALCOHOL document for further information.

Treatment Overview

0.4.2)

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 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: 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.
3) 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.
4) OCULAR: Copious eye irrigation.

D) AIRWAY MANAGEMENT

1) Immediately assess airway and respiratory function. Administer oxygen. Suction secretions. 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) 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 moderate to severe toxicity.

a) AUTOINJECTORS: PREHOSPITAL TREATMENT: DuoDote(R) (Meridian Medical Technologies, Columbia, MD) is a dual chambered device that delivers 2.1 mg atropine and 600 mg pralidoxime in a single needle for intramuscular use. It is intended for use in a civilian/community setting, and is administered by EMS personnel who have been trained to recognize and treat nerve agent or insecticide intoxication. ATNAA (Antidote Treatment Nerve Agent Autoinjector, Meridian Medical Technologies, Columbia, Maryland) is currently used by the US military and provides atropine injection and pralidoxime chloride injection in a single needle. Each self-contained unit dispenses 2.1 mg of atropine in 0.7 mL and 600 mg of pralidoxime chloride in 2 mL via intramuscular injection. The safety and efficacy of ATNAA or DuoDote(R) has not been established in children. These autoinjectors contain benzyl alcohol as a preservative. The AtroPen(R) autoinjector (atropine sulfate; Meridian Medical Technologies, Inc, Columbia, MD) delivers a dose of atropine in a self-contained unit. Since the AtroPen(R) comes in different strengths, certain dose units have been approved for use in children. If pralidoxime is required, pralidoxime prefilled autoinjector delivers 600 mg IM (adult dosing). The safety and efficacy of pralidoxime auto-injector for use in nerve agent poisoning have not been established in pediatric patients.
b) 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.

c) 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. However, highly lipophilic agents (like fenthion) can produce initially subtle effects followed by progressive weakness including respiratory failure. 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. Highly lipophilic organophosphates (e.g. fenthion) may produce subtle early toxicity that can progress to severe weakness/respiratory failure over many hours.
3) Recurrence of toxicity after apparent improvement has been described.
4) Some organophosphates undergo "ageing", a process by which the bond of the organophosphate to acetylcholinesterase becomes stronger, and cannot be reversed readily by oximes. Early oxime administration may prevent aging and shorten clinical manifestations of toxicity.

L) PREDISPOSING CONDITIONS

1) Patients with chronic occupational exposure to organophosphates 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)

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.

0.4.4)

A) Irrigate exposed eyes with water or normal saline. Systemic toxicity is unlikely to develop from ocular exposure alone.

0.4.5)

A) OVERVIEW

1) Systemic effects can occur from dermal exposure to organophosphates. 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)

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

Clinical Effects

Endocrine

3.16.2)

A) HYPERGLYCEMIA

1) WITH POISONING/EXPOSURE

a) GENERAL - Hyperglycemia and glycosuria (with or without ketosis) may develop in severe organophosphate poisoning (Wu et al, 2001; Namba, 1972).

B) DIABETES INSIPIDUS

1) WITH POISONING/EXPOSURE

a) CASE REPORT - A 28-year-old man intentionally ingested a malathion-containing pesticide (57% malathion solution dissolved in kerosene), and approximately 8 days after exposure, transient diabetes insipidus developed with severe polyuria and a urine output of 16.7 L/day. Laboratory studies included: serum sodium of 159 mmol/L, potassium 5.1 mmol/L, chloride 130 mmol/L, blood sugar 7.3 mmol/L, and BUN 11.7 mmol/L. A 6 hour water deprivation test was positive. An organic pituitary lesion was excluded by computed tomography. The symptoms resolved spontaneously (Abdul-Ghaffar, 1997).

Immunologic

3.19.1)

A) WITH POISONING/EXPOSURE

1) Dermal sensitization to malathion has been reported following skin exposure. It has not been reported with therapeutic use of malathion lotion.

3.19.2)

A) DISORDER OF IMMUNE FUNCTION

1) WITH THERAPEUTIC USE

a) At the time of this review, it is not known if 0.5% malathion lotion can produce contact allergic sensitization (Prod Info OVIDE(R) topical lotion, 2005).

2) WITH POISONING/EXPOSURE

a) SENSITIZATION - Dermal sensitization to malathion has been reported following skin exposure (Milby et al, 1964).

1) Some organophosphates cause dermal sensitization, but most have not been adequately evaluated for this effect (Coye, 1984).

B) ACUTE ALLERGIC REACTION

1) Urticaria, angioedema, and nonspecific skin rash have been reported following exposure to malathion (Schanker et al, 1992).

Reproductive

3.20.1)

3.20.3)

A) PREGNANCY CATEGORY

1) Malathion 0.5% topical lotion for head lice therapy is Pregnancy Category B (Prod Info OVIDE(R) topical lotion, 2005).
2) Malathion can inhibit microsomal enzyme systems; it has been suggested that it should be investigated for possible effects on pregnancy (Conney et al, 1973).
3) Neonates of mothers with detectable levels of malathion dicarboxylic acid had an increased rate of abnormal reflexes on the Brazelton Neonatal Behavioral Assessment Scale. Results on the other 5 elements of the Brazelton scale were not affected. Long term follow-up was not reported (Engel et al, 2007).
4) Eskenazi et al (2007) studied the relationship of prenatal and child malathion urinary metabolite levels with children's neurodevelopment using Bayley Scales of Infant Development at 6, 12, and 24 months of age. Malathion was not linked to any adverse offspring outcome (Eskenazi et al, 2007).

B) ANIMAL STUDIES

1) There was no evidence of teratogenicity in studies in rats and rabbits at doses up to 900 mg/kg/day and 100 mg/kg/day of malathion, respectively. No gross fetal abnormalities were attributable to feeding rats malathion up to 2500 ppm (approximately 200 mg/kg/day) during a three generation evaluation period. The dose was estimated to be 40 to 180 times higher than a dose anticipated in a 60 kg adult (Prod Info OVIDE(R) topical lotion, 2005).
2) Malathion did not cause birth defects in rats exposed by the oral route (Kalow & Marton, 1961; Dobbins, 1967; Khera, 1978). Mild fetal malformations (hydronephrosis and hydroureter) were seen with malathion exposure in rats (Dobbins, 1967).
3) At lower doses, both carbaryl and malathion were relatively harmless when given alone, but decreased the number of implantation sites and live fetuses when given together (Lechner & Abdel-Harman, 1984).
4) In a 2-generation feeding study in rats, malathion at a dose of 4,000 mg/kg/day produced a decrease in body weights in the second generation (Dalow & Marton, 1961).

3.20.4)

A) LACK OF INFORMATION

1) It is not known if malathion is excreted in human milk. Caution is advised when malathion lotion is used or handled by a nursing mother (Prod Info OVIDE(R) topical lotion, 2005).

3.20.5)

A) LACK OF EFFECT

1) THERAPEUTIC - Reproductive studies in rats with malathion 0.5% lotion at doses over 180-fold greater than anticipated in a 60 kg adult showed no evidence of impaired fertility (Prod Info OVIDE(R) topical lotion, 2005).

Carcinogenicity

3.21.1)

A) IARC Carcinogenicity Ratings for CAS121-75-5 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):

1) IARC Classification

a) Listed as: Malathion
b) Carcinogen Rating: 2A

1) The agent (mixture) is probably carcinogenic to humans. The exposure circumstance entails exposures that are probably carcinogenic to humans. This category is used when there is limited evidence of carcinogenicity in humans and sufficient evidence of carcinogenicity in experimental animals. In some cases, an agent (mixture) may be classified in this category when there is inadequate evidence of carcinogenicity in humans and sufficient evidence of carcinogenicity in experimental animals and strong evidence that the carcinogenesis is mediated by a mechanism that also operates in humans. Exceptionally, an agent, mixture or exposure circumstance may be classified in this category solely on the basis of limited evidence of carcinogenicity in humans.

3.21.2)

3.21.3)

A) CARCINOMA

1) The International Agency for Research on Cancer (IARC) has determined that malathion is probably carcinogenic to humans (Group 2A) after a systematic review and evaluation of the scientific evidence by leading independent experts (International Agency for Research on Cancer, 2015).

a) The IARC classification is based on limited evidence of carcinogenicity, including development of non-Hodgkins lymphoma and prostate cancer, in humans and sufficient evidence in animals (Guyton et al, 2015).

2) In case-control studies from the USA, Canada, and Sweden, occupational malathion exposure was associated with an increased risk of non-Hodgkins lymphoma. However, in a large Agricultural Health Study cohort (AHS), the risk of non-Hodgkin lymphoma was not increased. In addition, an increased risk of prostate cancer has been reported with occupational malathion exposure (Guyton et al, 2015).

B) LACK OF EFFECT

1) A long term study of pesticide applicators found no overall increased risk of cancer related to malathion exposure (Bonner et al, 2007).

Summary Of Exposure

1) EFFECTS FOLLOWING THERAPEUTIC USE

2) ORGANOPHOSPHATE POISONING EFFECTS

Vital Signs

3.3.1)

A) WITH POISONING/EXPOSURE

1) Fever has been reported following ingestion of malathion. Hypothermia has been reported in one adult following a mixed ingestion with organophosphates.

3.3.3)

A) WITH POISONING/EXPOSURE

1) CASE SERIES - In a retrospective review of 23 adults with organophosphate poisoning due to malathion ingestion, fever (38 degrees C or higher) was reported in 18 (78%) patients within 24 hours of admission (Lee & Tai, 2001).
2) CASE REPORT - Severe hypothermia (27.5 degrees C) was reported in a woman after the ingestion of 100 mL of an insecticide containing 35% fenitrothion and 15% malathion (Kamijo et al, 1999).

Heent

3.4.1)

A) WITH POISONING/EXPOSURE

1) Miosis, lacrimation and blurred vision are common findings in organophosphate poisoning. Mydriasis may be seen in severe poisonings. Excessive salivation may occur after malathion poisoning.

3.4.3)

A) WITH THERAPEUTIC USE

1) Conjunctivitis may occur following inadvertent exposure of 0.5% malathion lotion (Prod Info OVIDE(R) topical lotion, 2005).

B) WITH POISONING/EXPOSURE

1) MUSCARINIC EFFECTS may produce miosis following malathion exposure, while nicotinic effects may result in mydriasis (HSDB, 2006).
2) RARE EFFECTS - One case of opsoclonus (rapid, involuntary saccades) developed 3 days after hospital admission in a patient who ingested malathion. It gradually resolved over the following 2 weeks (Pullicino & Aquilina, 1989).
3) GENERAL - Miosis, lacrimation, and blurred vision are common findings in organophosphate poisoning. Mydriasis may be seen in severe poisonings. Decreased visual acuity and photophobia are less often reported.
4) MIOSIS - Intense miosis (pinpoint pupils), a muscarinic sign, is typical and is useful diagnostically, but is not invariably present (pupils may be normal or dilated) following organophosphate poisoning (Guven et al, 2004a; Nair et al, 2001; Futagami et al, 2001).

3.4.6)

A) WITH POISONING/EXPOSURE

1) Excessive salivation is a common muscarinic sign and can occur following malathion poisoning (HSDB, 2006) .
2) It has also been reported following the cutaneous absorption of organophosphates (Bjornsdottir & Smith, 1999).

Cardiovascular

3.5.1)

A) WITH POISONING/EXPOSURE

1) Bradycardia and tachycardia can occur following ingestion. Hypotension or hypertension may develop with severe toxicity. Conduction disturbances have been reported with malathion exposure.

3.5.2)

A) CARDIOVASCULAR FINDING

1) WITH POISONING/EXPOSURE

a) NICOTINIC EFFECTS that are associated with the cardiovascular system following malathion exposure can include: tachycardia and hypertension, while muscarinic effects can produce bradycardia (HSDB, 2006).

B) BRADYCARDIA

1) WITH POISONING/EXPOSURE

a) GENERAL - Bradycardia and hypotension occur following moderate to severe organophosphate poisoning (Karki et al, 2004; Kamijo et al, 1999; Ganendran, 1974) . Total peripheral vascular resistance may be low and cardiac output increased in patients with pre-existing vascular disease (Buckley et al, 1994).

C) CONDUCTION DISORDER OF THE HEART

1) WITH POISONING/EXPOSURE

a) ORGANOPHOSPHATE POISONING - Cardiac dysrhythmias and conduction defects have been reported in severely poisoned patients (Wren et al, 1981; Kiss & Fazekas, 1982; Chhabra & Sepaha, 1970; Agarwal, 1993).
b) Dysrhythmias and ECG abnormalities may include: sinus bradycardia or tachycardia, atrioventricular and/or intraventricular conduction delays, idioventricular rhythm, multiform premature ventricular extrasystoles, ventricular tachycardia or fibrillations, torsades de pointes, prolongation of the PR, QRS, and/or QT intervals, ST-T wave changes, and atrial fibrillation (Karki et al, 2004; Kamijo et al, 1999; Ludomirsky et al, 1982; Brill et al, 1984) .
c) CASE REPORT - Premature ventricular complexes, ventricular tachycardia and a prolonged Q-T interval (0.55 seconds) developed in a 65-year-old woman 5 days after a suicide attempt with malathion, despite complete recovery from severe acute toxicity and the absence of measurable cholinesterase inhibitor in the plasma (Dive et al, 1994).

1) The woman had ingested approximately 100 ml of an insecticide which contained 15% malathion in isopropyl alcohol. Large amounts of isopropylmalathion and traces of O,O,S-tri-methylphosphorothioate were also identified in the insecticide.

Respiratory

3.6.1)

A) WITH POISONING/EXPOSURE

1) MUSCARINIC EFFECTS may produce bronchorrhea or bronchospasm, and an increase in bronchial secretions following malathion exposure.

3.6.2)

A) RESPIRATORY FINDING

1) WITH POISONING/EXPOSURE

a) MUSCARINIC EFFECTS may produce bronchorrhea or bronchospasm, and an increase in bronchial secretions following malathion exposure (HSDB, 2006).
b) CASE SERIES - In a retrospective review of 23 adults with organophosphate poisoning due to malathion ingestion, mechanical ventilation was needed by 74% of patients due to one or more toxic effects including excessive bronchial secretions and pneumonia. Other events were attributable to CNS effects including impaired consciousness level and flaccid paralysis (Lee & Tai, 2001).

B) DYSPNEA

1) Increased bronchial secretions, bronchospasm, chest tightness, heartburn, and dyspnea have occurred in severe and moderately severe organophosphate poisonings including malathion (Hayes, 1965; Dive et al, 1994).

C) BRONCHOSPASM

1) Bronchospasm may occur as result of the muscarinic activity of organophosphates (HSDB, 2006; Lund & Monteagudo, 1986).
2) Wheezing had a weak statistical association with previous malathion exposure (OR 1.13, 95% CI 1 to 1.27) in farmers enrolled in the Agricultural Health Study (Hoppin et al, 2006).

D) HYPERVENTILATION

1) WITH POISONING/EXPOSURE

a) Hyperventilation has been reported following the cutaneous absorption of organophosphates (Bjornsdottir & Smith, 1999).

E) INTERSTITIAL FIBROSIS

1) WITH POISONING/EXPOSURE

a) A 65-year-old woman intentionally ingested approximately 100 mL of a 15% malathion-containing pesticide in isopropyl alcohol and developed progressive hypoxia approximately 2 weeks after exposure. Physical signs were not consistent with an infection, and an open lung biopsy revealed mild diffuse interstitial fibrosis. Treatment included corticosteroids, and the patient was successfully weaned from mechanical ventilation 32 days after exposure (Dive et al, 1994a).

F) RESPIRATORY FAILURE

1) WITH POISONING/EXPOSURE

a) ORGANOPHOSPHATE POISONING: Acute respiratory insufficiency, due to any combination of CNS depression, respiratory paralysis, bronchospasm, acute lung injury, or increased bronchial secretions, is the main cause of death in acute organophosphate poisonings (Lin et al, 2004; Nair et al, 2001; Uzyurt et al, 1992; Tsao et al, 1990) .
b) CASE REPORT: Delayed respiratory failure developed in a 53-year-old man 30 hours after ingesting about 300 mL of 50% malathion. Following supportive care, including atropine and pralidoxime treatment, his condition gradually improved and he was extubated on day 13 and transferred to the psychiatric service 5 days later (Berman et al, 2015).

G) PNEUMONIA

1) ORGANOPHOSPHATE POISONING - Aspiration of preparations containing hydrocarbon solvents may cause potentially fatal lipoid pneumonitis (Lund & Monteagudo, 1986).

Neurologic

3.7.1)

A) WITH POISONING/EXPOSURE

3.7.2)

A) NEUROLOGICAL FINDING

1) WITH POISONING/EXPOSURE

a) MUSCARINIC EFFECTS producing CNS symptoms following malathion exposure can include anxiety, restlessness, and headache. In more severe toxicity, tremors, confusion, drowsiness, slurred speech, coma, loss of reflexes and seizures may develop (HSDB, 2006).
b) CASE SERIES - In a retrospective review of 23 adults with organophosphate poisoning due to malathion ingestion, impaired consciousness was reported in 18 (78%) patients. Three patients developed seizures (Lee & Tai, 2001).

B) POLYNEUROPATHY

1) WITH POISONING/EXPOSURE

a) DELAYED POLYNEUROPATHY - Improvement may be observed followed by the delayed development of a motor or sensory-motor peripheral neuropathy in organophosphate poisoning. The motor component is usually more pronounced than the sensory component (Moretto & Lotti, 1998).

1) INCIDENCE - Delayed neurotoxicity appears to be a rare complication (Aygun et al, 2003; Wadia et al, 1987), but its incidence may be underestimated (Cherniack, 1988).
2) ONSET - Typically, delayed neurotoxicity appears 4 to 21 days after acute exposure by any route and involves progressive distal weakness and ataxia in the lower limbs. Flaccid paralysis, spasticity, ataxia or quadriplegia may ensue (Nisse et al, 1998; Cherniack, 1988).
3) CASE REPORT - Generalized muscle weakness, paresis, absent tendon reflexes, delayed motor nerve conduction velocities and electromyographic evidence of muscle denervation developed in a 65-year-old woman who intentionally ingested 100 mL of a 15% malathion-containing pesticide in isopropyl alcohol 10 days after exposure. The neurological effects slowly resolved over 3 months (Dive et al, 1994).

C) INTERMEDIATE SYNDROME

1) WITH POISONING/EXPOSURE

a) SUMMARY - Type II neurological effects involve paralysis appearing from 12 hours to 7 days after organophosphate exposure including several reports following malathion toxicity; this paralysis is unresponsive to atropine and may be due to a persistent excess of acetylcholine at nicotinic receptors (Aygun, 2004 ; Karki et al, 2004; Villamangca et al, 2000; Sudakin et al, 2000).

1) Several investigators have proposed that intermediate syndrome (IMS) may develop as a result of several factors: inadequate oxime therapy, the dose and route of exposure, the chemical structure of the organophosphates, the time to initiation of therapy, and possibly efforts to decrease absorption or enhance elimination of the organophosphates (Sudakin et al, 2000; Villamangca et al, 2000).
2) PATHOPHYSIOLOGY - IMS can occur due to an organophosphate-induced alteration in postjunctional acetylcholine receptors. Based on this alteration, it has been suggested by some that a delay in oxime therapy may contribute to the development of IMS. Clinical presentation is described as the delayed development of proximal and diaphragmatic muscle paralysis after the resolution of initial organophosphate (OP) poisoning. Unlike delayed polyneuropathy that may occur after OP poisoning, symptoms of IMS usually occur within 24 to 96 hours. Unlike delayed polyneuropathy, IMS does not begin distally and progress and it often involves cranial nerves or proximal weakness. This syndrome can increase the risk of death due to respiratory depression. Agents that may produce this syndrome include: malathion, fenthion, dimethoate, monocrotophos, and methamidophos (Lee & Tai, 2001; Sudakin et al, 2000a).
3) ONSET - Intermediate syndrome develops after the resolution of cholinergic signs and before the onset of delayed neuropathy (Sudakin et al, 2000a; Nisse et al, 1998; De Bleecker, 1995).

b) CLINICAL SIGNS - Paralytic signs include inability to lift the neck or sit up, ophthalmoparesis, slow eye movements, facial weakness, difficulty swallowing, limb weakness (primarily proximal), areflexia, respiratory paralysis, and death (Villamangca et al, 2000; Nisse et al, 1998; Good et al, 1993).
c) THERAPY - Intermediate syndrome occurs unexpectedly, does not respond to atropine and pralidoxime (Mattingly et al, 2001; Sudakin et al, 2000; Nisse et al, 1998).

1) Some believe that early aggressive gastric decontamination, followed by atropinization and high-dose pralidoxime therapy (1 gram every 4 to 6 hours or 500 milligrams/hour as a continuous infusion in severe cases) may reduce the incidence of the intermediate syndrome (Haddad, 1992; Benson et al, 1992). Clinical trials will be necessary to confirm this hypothesis.

d) CASE REPORTS

1) CASE SERIES - In a retrospective review of 23 adults with organophosphate poisoning due to malathion ingestion, muscarinic features were predominant. Despite prompt oxime therapy, 5 patients developed intermediate syndrome as evidenced by proximal limb muscle weakness and neck palsies which occurred within 3 to 5 days after exposure. All patients made a complete recovery within 10 to 18 days of onset (Lee & Tai, 2001).
2) CASE REPORT - A 33-year-old woman intentionally ingested an unknown quantity of a 50% malathion solution and developed evidence of intermediate syndrome approximately 3 days after exposure. Oxime therapy was initially started about 11 hours after exposure and was continuously maintained when symptoms developed. Pralidoxime was continued for a total of 5 days, and then changed to an intermittent dosing schedule. The patient was successfully weaned from mechanical ventilation by hospital day 12 with no evidence neurologic sequelae (Sudakin et al, 2000a).
3) CASE REPORT - Paralysis of the diaphragm occurred in a patient who ingested malathion. Full recovery required 9 months (Rivett & Potgieter, 1987).

D) MOVEMENT DISORDER

1) WITH POISONING/EXPOSURE

a) LACK OF EFFECT - A case control study found no statistically significant link between organophosphate exposures and Parkinson disease (Firestone et al, 2005).

Gastrointestinal

3.8.1)

A) WITH POISONING/EXPOSURE

3.8.2)

A) GASTROINTESTINAL TRACT FINDING

1) WITH POISONING/EXPOSURE

a) MUSCARINIC EFFECTS can produce nausea, vomiting, salivation and diarrhea following malathion exposure (HSDB, 2006).
b) Nausea and vomiting have been reported following the cutaneous absorption of organophosphates (Bjornsdottir & Smith, 1999).

B) ACUTE NECROTIZING PANCREATITIS

1) WITH POISONING/EXPOSURE

a) GENERAL - Acute pancreatitis has been reported in the literature following oral ingestion of organophosphates, including malathion, parathion, difonate, coumaphos, diazinon, mevinphos and dermal exposure to dimethoate (Hsiao et al, 1996).
b) CASE REPORT - A 16-year-old girl intentionally ingested approximately 100 mL of a 10% malathion solution and developed severe abdominal pain on the second day of hospitalization. Laboratory studies included an elevated WBC count (16,900), serum amylase 1,500 (normal up to 55 Units/L), and increased lactate dehydrogenase and aminotransferase. Hemorrhagic necrotizing pancreatitis was confirmed by laparotomy and a partial pancreatectomy was performed. The patient recovered and was discharged to home 2 weeks after admission (Zamir & Novis, 1994).

C) INCONTINENCE OF FECES

1) WITH POISONING/EXPOSURE

a) Fecal incontinence may occur in severe organophosphate poisoning (Koga et al, 1999; Kecik et al, 1993), and has been reported following oral malathion exposure (Sudakin et al, 2000a).

Genitourinary

3.10.2)

A) URINARY INCONTINENCE

1) WITH POISONING/EXPOSURE

a) Involuntary urination occurs in severe cases of organophosphate poisoning (Wu et al, 2001; Koga et al, 1999), and has been reported following malathion exposure (Lee & Tai, 2001; Sudakin et al, 2000a).
b) Urinary frequency with incontinence has been reported following the cutaneous absorption of organophosphate (Bjornsdottir & Smith, 1999).

Dermatologic

3.14.1)

A) WITH THERAPEUTIC USE

1) Skin irritation may occur with therapeutic malathion lotion.

B) WITH POISONING/EXPOSURE

1) Organophosphates including malathion can be absorbed transdermally. Diaphoresis is common with acute exposure.

3.14.2)

A) DISORDER OF SKIN

1) WITH POISONING/EXPOSURE

a) SENSITIZATION - Dermal sensitization to malathion has been reported following skin exposure (Milby et al, 1964).

1) INCIDENCE - 23 percent of patients in one study (Bardin et al, 1987).

B) HYPERSENSITIVITY REACTION

1) WITH POISONING/EXPOSURE

a) Urticaria, angioedema, and nonspecific skin rash have been reported following exposure to malathion (Schanker et al, 1992).

C) SKIN IRRITATION

1) WITH THERAPEUTIC USE

a) Irritation of the scalp and skin may develop with therapeutic use of 0.5% malathion lotion (Prod Info OVIDE(R) topical lotion, 2005).

2) WITH POISONING/EXPOSURE

a) A burning sensation of the skin has been reported following overspray exposure to malathion (Dahlgren et al, 2004).

D) EXCESSIVE SWEATING

1) WITH POISONING/EXPOSURE

a) Profuse sweating may occur as one of the muscarinic signs of malathion poisoning (HSDB, 2006).

E) SKIN ABSORPTION

1) WITH THERAPEUTIC USE

a) Based on experience with malathion insecticides, transdermal absorption may occur. The manufacturer recommends adherence to dosing regimens for malathion lotion in the treatment of head lice (Prod Info OVIDE(R) topical lotion, 2005). It has been suggested that significant skin absorption can occur with malathion lotion (Elgart, 1999).
b) In an in vitro study, malathion penetration was examined transdermally in human abdominal skin and haired rat skin to assess whether reducing malathion (0.5 mg malathion lotion) application time decreased skin absorption. Thirty minutes after topical application, malathion penetration in human skin was 0.36 +/- 0.14%, as compared to a 3-fold increase (1.02 +/- 0.41) after 8 hours of topical application. Similar results were found for haired rat skin. The authors suggested that a shorter application period is recommended to avoid absorption while still maintaining the drug's effectiveness (Brand et al, 2005).

2) WITH POISONING/EXPOSURE

a) Organophosphates can be systemically absorbed through intact skin (Guloglu et al, 2004; Bjornsdottir & Smith, 1999; Wester et al, 1993).

Musculoskeletal

3.15.1)

A) WITH POISONING/EXPOSURE

1) NICOTINIC EFFECTS may produce generalized muscle fasciculations, muscle cramps, and eventually weakness following malathion exposure.

3.15.2)

A) MUSCULOSKELETAL FINDING

1) WITH POISONING/EXPOSURE

a) NICOTINIC EFFECTS may produce generalized muscle fasciculations, muscle cramps, and eventually weakness following malathion exposure (HSDB, 2006).

B) MUSCLE WEAKNESS

1) WITH POISONING/EXPOSURE

a) Organophosphate compounds cause skeletal muscle weakness by 3 different mechanisms (Karalliedde & Henry, 1993):

1) CHOLINERGIC PHASE OF POISONING - Muscle fasciculations and repetitive muscle fiber firing leads to depolarization and desensitization block at the myoneural junction;
2) INTERMEDIATE SYNDROME - Prolonged transmitter-receptor interaction causes intracellular excessive calcium influx and cellular necrosis;
3) DELAYED PERIPHERAL NEUROPATHY - Muscle weakness can be due to nerve demyelination which usually begins 2 to 3 weeks following acute poisoning.

Genotoxicity

Laboratory Monitoring

Monitoring Parameters Levels

4.1.1)

A) LOTION - At the time of this review, systemic effects have not been reported with normal therapeutic use of 0.5% malathion lotion. Laboratory evaluation is generally not necessary, unless patients manifest signs and symptoms of cholinergic excess.
B) Monitor vital signs frequently. Institute continuous cardiac and pulse oximetry monitoring. 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) Obtain serial ECGs. Patients who develop a prolonged QTc interval or PVCs are more likely to develop respiratory insufficiency and have a worse prognosis.
E) Monitor electrolytes and serum lipase in patients with significant poisoning. Patients who have increased pancreatic enzyme concentrations are more likely to develop respiratory insufficiency and have a worse prognosis.
F) 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.
G) Isopropyl alcohol is contained in high concentrations in malathion lotions used in the treatment of head lice.

4.1.2)

A) SUMMARY - Cholinesterase monitoring may be indicated following a significant oral ingestion of malathion or as indicated. See ORGANOPHOSPHATE management if severe toxicity suspected.
B) CHOLINESTERASE MONITORING - Considerations for monitoring plasma pseudocholinesterase and erythrocyte acetylcholinesterase levels involve their relationship with adverse clinical effects, kinetics of recovery, and other factors affecting their activity:

1) Plasma ChE appears to be a more sensitive index of exposure, and erythrocyte AChE activity may be better correlated with clinical effects (Muller & Hundt, 1980). Usually this biochemical manifestation of toxicity appears at lower dosage levels than amounts producing symptoms or signs.
2) Symptomatic patients usually have depression of blood cholinesterase activities in excess of 50% of the pre-exposure value (Milby, 1971). Depressions in excess of 90% may occur in severe poisonings (Klemmer et al, 1978).
3) Moderate to severe organophosphate poisoning has been diagnosed in patients with "normal" red blood AChE activity (Hodgson & Parkinson, 1985; Midtling et al, 1985; Coye et al, 1986; Coye et al, 1987). In these patients, AChE decreased by as much as 50%, but was still within the normal range.
4) The correlation between plasma cholinesterase levels and onset or extent of clinical effects may be poor (Nouira et al, 1994), especially if assays are done in different laboratories. Comparison with pre-exposure values may be helpful.

C) ACID/BASE

1) Monitor arterial blood gases in patients with significant respiratory symptomatology.

4.1.3)

A) DIAGNOSIS - Urine assay for alkyl phosphate and phenolic organophosphate metabolites may be a sensitive indicator of exposure (Davies & Peterson, 1997). Malathion mono- and dicarboxylic acid metabolites have also been studied as a more specific marker of exposure.

1) One study found that urine alkyl phosphate levels were more sensitive markers of exposure than whole-blood ChE activity. Levels of diethyl phosphate (DEP) and dimethyl phosphate (DMP) ranging from 0.1 to 1.0 mg/L were associated with trivial depressions in ChE (Richter et al, 1992a).

B) CHRONIC - Levels of malathion metabolites seen in the urine of dermally exposed workers were 1.27 milligrams in urine for 7.62 milligrams total dose in applicators and 0.98 milligrams in urine for 4.25 milligrams total dose in mixers, giving ratios of 0.167 and 0.23 total dose respectively (Fenske, 1988).
C) Malathion dicarboxylic acid was detected in 52% of 1997 urine samples taken in the 1999-2000 National Health and Nutrition Examination Survey (NHANES). Subjects were aged 6 to 59 years. The 95th percentile value was 1.6 mcg/L, or 1.8 mcg/g creatinine. The 95th percentile value in children 6 to 11 years was higher at 2.8 mcg/L (3.7 mcg/g creatinine) (Barr et al, 2005).

4.1.4)

A) OTHER

1) ECG

a) Obtain a baseline ECG following a significant exposure and repeat as indicated.

2) ELECTROPHYSIOLOGICAL TESTING

a) ELECTROPHYSIOLOGIC FEATURES - Electrophysiologic features of organophosphate poisoning in humans include early (4 hours or more postingestion) occurrence of spontaneous repetitive firing of single evoked compound muscle action potentials (CMAP), followed by a decrement-increment phenomenon at mild stages, and an absence of CMAP in severe stages.

1) Persistent decrement responses at frequencies of 10 to 20 Hz predicted the need for mechanical ventilation (Besser et al, 1989).

b) Although not specific for peripheral neuropathy, one study of persons previously acutely poisoned with organophosphates found increased normalized vibrotactile thresholds as compared to an unexposed control group (McConnell et al, 1994). Abnormal vibrotactile thresholds have been found in chronically exposed pesticide applicators (Stokes et al, 1995).
c) Electrodiagnostic studies may be useful in assisting diagnosis of organophosphate poisoning, monitoring the effect of pralidoxime on neuromuscular transmission, and assessing phrenic nerve involvement in patients with diaphragmatic paralysis (Singh et al, 1998).

3) RESPIRATORY MUSCLE PERFORMANCE

a) RESPIRATORY MUSCLE PERFORMANCE (RMP) - Measurements of RMP such as negative inspiratory force may be more valuable than erythrocyte acetylcholinesterase activity in determining readiness for extubation (Routier et al, 1989).

Methods

1) Nearly all organophosphates depress the activities of either plasma pseudocholinesterase (ChE) or red cell acetylcholinesterase (AChE), or both.

2) PLASMA PSEUDOCHOLINESTERASE - Plasma ChE may be measured by the electrometric Michel Method, the titrimetric method (Coye et al, 1986b), Merck-I cholinesterase kinetic test (Perold & Bezuidenhout, 1980), or the colorimetric Ellman method (Ellman et al, 1961).

a) Approximate Lower Limits of Plasma and Erythrocyte (RBC) Cholinesterase Activities in Humans (Morgan, 1989)

Method	Plasma	RBC	Units
pH (Michel)	0.45	0.55	pH change/mL/hr
pH Stat (Nabb-Whitfield)	2.3	8.0	mcM/mL/min
BMC Reagent (Ellmann-Boehringer)	1,875		mU/mL
Dupont ACA	<8		Units/mL
Technicon	2.0	8.0	mcM/mL/min

3) RED BLOOD CELL ACETYLCHOLINESTERASE - Can be determined by the Ellman, Delta pH, Michel, or micro-Michel methods (Hayes, 1982).

a) The enzyme is bound to the red blood cell membrane; total activity is related to the individual's total number and average age of erythrocytes (Brown SS, 1989).

4) HPLC - A high performance thin layer chromatography technique can be used to identify 25 organophosphate compounds in human serum (Gotoh et al, 2001; Sudakin et al, 2000; Kamijo et al, 1999; Futagami et al, 1997).

5) Liquid chromatography - Atmospheric pressure chemical ionization mass spectrometry has been used to screen for up to 21 different organophosphate compounds in human blood (Kawasaki & Ueda, 1992).

6) Gas chromatography-mass spectrometry has been used to identify and quantify malathion in body fluids following intentional exposure of a malathion-containing pesticide (Thompson et al, 1998; Cruz et al, 2001).

1) Whole body dosimetry has been used as a method to measure dermal exposure of agricultural workers using malathion pesticide, and is considered to be compatible with biological monitoring (Cruz et al, 2001).

Treatment

Life Support

Patient Disposition

6.3.1)

6.3.1.1) ADMISSION CRITERIA/ORAL

A) All intentional ingestions should be initially managed as a severe exposure. Patients that are asymptomatic, have only mild symptoms, or were unintentionally exposed do not usually require hospital admission. Determine cholinesterase activity to assess if a significant exposure occurred (Roberts & Aaron, 2007). Patients who develop signs or symptoms of cholinergic toxicity (muscarinic, nicotinic OR central) should be admitted to an intensive care setting.
B) Patients with a moderate to severe exposure that remain stable for 12 hours after receiving oxime can be transferred to a medical floor. If the patient remains stable 48 hours after discharge from intensive care they may be discharged to home with appropriate follow-up care (Roberts & Aaron, 2007).

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 (Roberts & Aaron, 2007).

6.3.1.3) CONSULT CRITERIA/ORAL

A) Consult a medical toxicologist and/or poison control center for assistance with patients who have moderate to severe toxicity.

6.3.1.4) PATIENT TRANSFER/ORAL

A) If intensive care capabilities are not available or there are inadequate supplies of antidote (atropine, pralidoxime) at the initial treating facility, the patient should be transferred to a facility with intensive care capabilities and adequate antidote supplies (Roberts & Aaron, 2007).

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 ingestion or a dermal exposure are unlikely to develop severe toxicity. However, highly lipophilic agents (like fenthion) can produce initially subtle effects followed by progressive weakness including respiratory failure. Cholinesterase activity should be determined to confirm the degree of exposure (Roberts & Aaron, 2007).
B) Following acute poisoning, patients should be precluded from further organophosphate exposure until sequential red cell acetylcholinesterase (AChE) levels have been obtained and confirm that AChE activity has reached a plateau. Plateau has been obtained when sequential determinations differ by no more than 10% (Midtling et al, 1985). This may take 3 to 4 months following severe poisoning.

Monitoring

Oral Exposure

6.5.1)

A) ORAL EXPOSURE

1) Prehospital gastrointestinal decontamination is NOT recommended because of the potential for early coma or seizures and aspiration.

B) DERMAL EXPOSURE

1) Remove contaminated clothing. Wash skin thoroughly with soap and water.

C) EYE EXPOSURE

1) Copious eye irrigation.

D) INHALATION EXPOSURE

1) Immediately assess airway and respiratory function. Administer oxygen.

E) PERSONNEL PROTECTION

1) Universal precautions should be followed by all individuals (i.e., first responders, emergency medical, and emergency department personnel) caring for the patient to avoid contamination. Nitrile gloves are suggested. Avoid direct contact with contaminated clothing, objects or body fluids.
2) Vomiting containing organophosphates should be placed in a closed impervious container for proper disposal.

F) DECONTAMINATION OF SPILLS/SUMMARY

1) A variety of methods have been described for organophosphate spill decontamination, most of which depend on changing the pH to promote hydrolysis to inactive phosphate diester compounds (EPA, 1978). The rate of hydrolysis depends on both the specific organophosphate compound involved and the increase in pH caused by the detoxicant used (EPA, 1978; EPA, 1975).

a) NOTE: Do NOT use a MIXTURE of BLEACH and ALKALI for DECONTAMINATING ACEPHATE or ACETYL ORGANOPHOSPHATE COMPOUNDS such as ORTHENE(R). This can cause release of toxic acetyl chloride, acetylene, and phosgene gas. Spills of acephate organophosphates should be decontaminated by absorption and scrubbing with concentrated detergent (Ford JE, 1989).

2) Treatment of the spilled material with alkaline substances such as sodium carbonate (soda ash), sodium bicarbonate (baking soda), calcium hydroxide (slaked or hydrated lime), calcium hydroxide (lime or lime water, when in dilute solutions), and calcium carbonate (limestone) may be used for detoxification (EPA, 1975a).
3) Chlorine-active compounds such as sodium hypochlorite (household bleach) or calcium hypochlorite (bleaching powder, chlorinated lime) may also be used to detoxify organophosphate spills (EPA, 1975a).

a) In some instances, a combination of an alkaline substance with a chlorine-active compound may be used (Pesticide User's Guide, 1976).

4) While ammonia compounds have also been suggested as alternate detoxicants for organophosphate spills, UNDER NO CIRCUMSTANCES SHOULD AMMONIA EVER BE COMBINED WITH A CHLORINE-ACTIVE COMPOUND (BLEACH) AS HIGHLY IRRITATING CHLORAMINE GAS MAY BE EVOLVED.

G) SMALL SPILL DECONTAMINATION

1) Three cups of Arm & Hammer washing soda (sodium carbonate) or Arm & Hammer baking soda (sodium bicarbonate) may be combined with one-half cup of household bleach and added to a plastic bucket of water. The washing soda is more alkaline and may be more efficacious, if available. Wear rubber gloves, and use a respirator certified effective against toxic vapors. Several washes may be required for decontamination (EPA, 1978).

a) Spilled liquid may first be adsorbed with soil, sweeping compound, sawdust, or dry sand and then both the adsorbed material and the floor decontaminated with one of the above solutions (EPA, 1975a).
b) NOTE: Do NOT use a COMBINATION of BLEACH and ALKALI to DECONTAMINATE ACEPHATE or ACETYL ORGANOPHOSPHATE COMPOUNDS such as ORTHENE(R). Spills involving acephate organophosphates should be decontaminated by the following procedure - Isolate and ventilate the area; keep sources of fire away; wear rubber or neoprene gloves and overshoes; get fire-fighting equipment ready; contain any liquid spill around the edge and absorb with Zorb-All(R) or similar material; dispose of absorbed or dry material in disposable containers; scrub the spilled area with concentrated detergent such as TIDE(R), ALL(R) or similar product; re-absorb scrubbing liquid and dispose as above; dispose of cleaning materials and contaminated clothing; wash gloves, overshoes and shovel with concentrated detergent. Call the National Pesticide Telecommunications Network for further assistance at 1-800-858-7378 or on the web at http://nptn.orst.edu.

H) LARGE SPILL DECONTAMINATION

1) Sprinkle or spray the area with a mixture of one gallon of sodium hypochlorite (bleach) mixed with one gallon of water. Then spread calcium hydroxide (hydrated or slaked lime) liberally over the area and allow to stand for at least one hour (Pesticide User's Guide, 1976). Wear rubber gloves, and use a respirator certified effective against toxic vapors. Several washes may be required for decontamination (EPA, 1978).
2) Other decontamination methods may be recommended by manufacturers of specific agents. Check containers, labels, or product literature for possible instructions regarding spill decontamination.

a) NOTE: Do NOT USE a COMBINATION of BLEACH and ALKALI to DECONTAMINATE ACEPHATE or ACETYL ORGANOPHOSPHATE COMPOUNDS such as ORTHENE(R). Spills involving acephate organophosphates should be decontaminated by the following procedure - Isolate and ventilate the area; keep sources of fire away; wear rubber or neoprene gloves and overshoes; get fire-fighting equipment ready; contain any liquid spill around the edge and absorb with Zorb-All(R) or similar material; dispose of absorbed or dry material in disposable containers; scrub the spilled area with concentrated detergent such as TIDE(R), ALL(R) or similar product; re-absorb scrubbing liquid and dispose as above; dispose of cleaning materials and contaminated clothing; wash gloves, overshoes and shovel with concentrated detergent.

3) FURTHER CONTACT INFORMATION

a) For further information contact the National Pesticide Telecommunications Network at 1-800-858-7378 or contact on the web at http://nptn.orst.edu.
b) Disposal of large quantities or contamination of large areas may be regulated by various governmental agencies and reporting may be required. For small pesticide spills or for further information call the pesticide manufacturer or the National Pesticide Information Center (NPIC) at 1-800-858-7378.
c) The National Response Center (NRC) is the federal point of contact for reporting of spills and can be reached at 1-800-424-8802. For those without 800 access, contact 202-267-2675.
d) CHEMTREC can provide technical and hazardous materials information and can be reached at 1-800-424-9300 in the US; or 703-527-3887 outside the US.

I) ANTIDOTES

1) SUMMARY: 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 moderate to severe toxicity.
2) AUTOINJECTORS

a) INDICATION: Atropine-containing autoinjectors are used for the initial treatment of poisoning by organophosphate nerve agents and organophosphate or carbamate insecticides (Prod Info DuoDote(R) intramuscular injection solution, 2011; Prod Info ATROPEN(R) IM injection, 2005). Pralidoxime use following carbamate exposure may not be indicated.
b) NOTE: The safety and efficacy of MARK I kit (Note: the MARK I autoinjector kit was last produced by Meridian Medical Technologies, Columbia, MD in 2008. This product may still be available in some locations.), ATNAA, or DuoDote(R) has not been established in children. All of these autoinjectors contain benzyl alcohol as a preservative (Prod Info DuoDote(R) intramuscular injection solution, 2011; Prod Info ATNAA ANTIDOTE TREATMENT – NERVE AGENT, AUTO-INJECTOR intramuscular injection solution, 2002). Since the AtroPen(R) comes in different strengths, certain dose units have been approved for use in children (Prod Info ATROPEN(R) IM injection, 2005).
c) The AtroPen(R) autoinjector (atropine sulfate; Meridian Medical Technologies, Inc, Columbia, MD) delivers a dose of atropine in a self-contained unit. There are 4 AtroPen(R) strengths: AtroPen(R) 0.25 mg in 0.3 mL of solution (dispenses 0.21 mg of atropine base; equivalent to 0.25 mg of atropine sulfate), AtroPen(R) 0.5 mg in 0.7 mL of solution (dispenses 0.42 mg of atropine base; equivalent to 0.5 mg of atropine sulfate), Atropen(R) 1 mg in 0.7 mL of solution (dispenses 0.84 mg of atropine base; equivalent to 1 mg of atropine sulfate), and AtroPen(R) 2 mg in 0.7 mL of solution (dispenses 1.67 mg of atropine base; equivalent to 2 mg of atropine sulfate) (Prod Info ATROPEN(R) IM injection, 2005).

1) AtroPen(R): DOSE: ADULT AND CHILDREN OVER 10 YEARS OF AGE: Mild symptoms, in cases where exposure is known or suspected: Inject one 2 mg AtroPen(R) (green pen) into the outer thigh as soon as symptoms appear; pralidoxime chloride may also be required. Severe symptoms: Inject one 2 mg AtroPen(R) (green pen) into the outer thigh as soon as symptoms appear, administer 2 additional 2 mg AtroPen(R) doses in rapid succession 10 min after receiving the first dose; pralidoxime chloride and/or an anticonvulsant may also be required, patients should be closely monitored for at least 48 to 72 hr. PEDIATRIC: Mild symptoms, in cases where exposure is known or suspected: dose for infants less than 7 kg (generally less than 6 months of age) = 0.25 mg (yellow pen), dose for children 7 to 18 kg (generally 6 months to 4 years of age) = 0.5 mg (blue pen), dose for children 18 to 41 kg (generally 4 to 10 years of age) = 1 mg (dark red pen), dose for children over 41 kg = 2 mg (green pen): inject one AtroPen(R) into the outer thigh as soon as symptoms appear; pralidoxime chloride may also be required. Severe symptoms: Administer 2 additional AtroPen(R) doses (see above) in rapid succession 10 min after receiving the first dose; pralidoxime chloride and/or an anticonvulsant may also be required, patients should be closely monitored for at least 48 to 72 hr (Prod Info ATROPEN(R) IM injection, 2005).
2) If pralidoxime is required, pralidoxime prefilled autoinjector delivers 600 mg IM (adult dosing); may repeat every 15 minutes up to 3 injections if symptoms persist. The safety and efficacy of pralidoxime auto-injector for use in nerve agent poisoning have not been established in pediatric patients (Prod Info pralidoxime chloride intramuscular auto-imjector solution, 2003)

d) ATNAA (Antidote Treatment Nerve Agent Autoinjector, Meridian Medical Technologies, Columbia, Maryland) is currently used by the US military and provides atropine injection and pralidoxime chloride injection in a single needle. Each self-contained unit dispenses 2.1 mg of atropine in 0.7 mL and 600 mg of pralidoxime chloride in 2 mL via intramuscular injection (Prod Info ATNAA ANTIDOTE TREATMENT – NERVE AGENT, AUTO-INJECTOR intramuscular injection solution, 2002).

1) ATNAA: DOSE: ADULT: One ATNAA into the lateral thigh muscle or buttocks. Wait 10 to 15 minutes for effect (Prod Info ATNAA ANTIDOTE TREATMENT – NERVE AGENT, AUTO-INJECTOR intramuscular injection solution, 2002).

e) MARK I: This device (Meridian Medical Technologies, Columbia, Maryland) was used by the US military. (Note: the MARK I autoinjector kit was last produced by Meridian Medical Technologies, Columbia, MD in 2008. This product may still be available in some locations.) Each kit contains two autoinjectors: an atropine and a pralidoxime autoinjector. The atropine autoinjector delivers 2.1 mg of atropine in 0.7 mL via intramuscular injection. The pralidoxime autoinjector delivers 600 mg pralidoxime chloride in 2 mL via intramuscular injection (Prod Info DUODOTE(TM) IM injection, 2006).
f) DuoDote(R) is a dual chambered device (Meridian Medical Technologies, Columbia, Maryland) that delivers 2.1 mg of atropine in 0.7 mL and 600 mg of pralidoxime chloride in 2 mL sequentially using a single needle for use in a civilian or community setting. It should be administered by Emergency Medical Services personnel who have been trained to recognize and treat nerve agent or insecticide intoxication (Prod Info DuoDote(R) intramuscular injection solution, 2011).
g) DuoDote(R): DOSE: ADULT: Two or more mild symptoms, initial dose, 1 injector (atropine 2.1 mg/pralidoxime chloride 600 mg) IM into the mid-lateral thigh, wait 10 to 15 minutes for effect; subsequent doses, if at any time severe symptoms develop, administer 2 additional injectors in rapid succession IM into the mid-lateral thigh and immediately seek definitive medical care; MAX 3 doses unless definitive medical care is available (Prod Info DuoDote(R) intramuscular injection solution, 2011).
h) Therapeutic plasma concentrations of pralidoxime exceeding 4 mcg/mL were achieved within 4 to 8 minutes after injection (Sidell & Groff, 1974).
i) DIAZEPAM Autoinjector (Meridian Medical Technologies): Contains 10 mg of diazepam in 2 mL for intramuscular injection for seizure control (Prod Info diazepam autoinjector IM injection solution, 2005).
j) These devices are designed for initial field treatment. Although autoinjector doses may be adequate for nerve agent exposures, ORGANOPHOSPHATE exposures may require additional atropine or pralidoxime doses in the hospital setting that exceed those in the available autoinjectors.
k) For medical questions concerning Meridian products, you can call 1-800-438-1985. For general product information, call 1-800-638-8093.

6.5.2)

A) ACTIVATED CHARCOAL

1) Activated charcoal may be considered for a large recent ingestion, if patient is intubated or able to protect airway.
2) 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.

3) 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).

B) GASTRIC LAVAGE

1) Consider nasogastric tube for aspiration of gastric contents, or gastric lavage for recent large ingestions, if patient is intubated or able to protect airway.
2) 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.

3) 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.

4) 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.

5) 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).

6) 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)

A) AIRWAY MANAGEMENT

B) MONITORING OF PATIENT

1) Cardiac monitoring, pulse oximetry, obtain plasma and red cell cholinesterase levels. Monitor clinical exam for evidence of muscarinic (e.g., bronchospasm, bronchorrhea, salivation, lacrimation, defecation, urination, miosis), nicotinic (e.g., muscle weakness or fasciculations, respiratory insufficiency) or CNS (e.g., seizures, coma) manifestations of cholinergic toxicity. Monitor serial ECGs, serum electrolytes and lipase in symptomatic patients.

a) Prolonged QTc interval or presence of PVCs on ECG are associated with a higher risk of respiratory failure and a worse prognosis, as is an initial serum pancreatic isoamylase level greater than the normal range (Grmec et al, 2004; Chuang et al, 1996; Jang et al, 1995; Matsumiya et al, 1996).

2) OBSERVATION: Onset of clinical toxicity is variable, but most patients with a severe exposure become symptomatic within 6 hours. If a patient remains asymptomatic 12 hours after ingestion, severe toxicity is not anticipated. Exceptions can include highly lipophilic compounds (ie, fenthion) which initially produce only subtle cholinergic effects that can progress to muscle weakness and respiratory failure (Roberts & Aaron, 2007).
3) POOR PROGNOSTIC INDICATORS: Systolic blood pressure of less than 100 mmHg and fraction of inspired oxygen (FiO2) greater than 40%, to maintain a SpO2 of greater than 92% within the first 24 hours, are poor prognostic indicators among mechanically ventilated patients (Munidasa et al, 2004).
4) CHOLINESTERASES: Measure plasma pseudocholinesterase (ChE) or red cell acetylcholinesterase (AChE) activities. Specimens should be obtained prior to administration of pralidoxime when possible.
5) Cholinesterase levels are useful for confirmation of diagnosis; they should NOT be used to determine dosage of atropine or when to wean from atropine therapy (LeBlanc et al, 1986). There is generally poor correlation between cholinesterase levels and severity of clinical effects (Brown SS, 1989). However, severe clinical toxicity is likely when the erythrocyte acetylcholinesterase activity is less than 20% of normal (Roberts & Aaron, 2007).

a) Plasma cholinesterase appears to be a more sensitive index of exposure, while erythrocyte acetylcholinesterase activity appears to better correlate with clinical effects (Muller & Hunt, 1980).

C) ANTIDOTE

1) GENERAL

a) There are three 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 usually indicated for patients with moderate to severe toxicity. BENZODIAZEPINES are indicated for agitation and seizures.

2) PREHOSPITAL TREATMENT

a) AUTOINJECTORS

1) INDICATION: Atropine-containing autoinjectors are used for the initial treatment of poisoning by organophosphate nerve agents and organophosphate or carbamate insecticides (Prod Info DuoDote(R) intramuscular injection solution, 2011; Prod Info ATROPEN(R) IM injection, 2005). Pralidoxime use following carbamate exposure may not be indicated.
2) NOTE: The safety and efficacy of MARK I kit (Note: the MARK I autoinjector kit was last produced by Meridian Medical Technologies, Columbia, MD in 2008. This product may still be available in some locations.), ATNAA, or DuoDote(R) has not been established in children. All of these autoinjectors contain benzyl alcohol as a preservative (Prod Info DuoDote(R) intramuscular injection solution, 2011; Prod Info ATNAA ANTIDOTE TREATMENT – NERVE AGENT, AUTO-INJECTOR intramuscular injection solution, 2002). Since the AtroPen(R) comes in different strengths, certain dose units have been approved for use in children (Prod Info ATROPEN(R) IM injection, 2005).
3) The AtroPen(R) autoinjector (atropine sulfate; Meridian Medical Technologies, Inc, Columbia, MD) delivers a dose of atropine in a self-contained unit. There are 4 AtroPen(R) strengths: AtroPen(R) 0.25 mg in 0.3 mL of solution (dispenses 0.21 mg of atropine base; equivalent to 0.25 mg of atropine sulfate), AtroPen(R) 0.5 mg in 0.7 mL of solution (dispenses 0.42 mg of atropine base; equivalent to 0.5 mg of atropine sulfate), Atropen(R) 1 mg in 0.7 mL of solution (dispenses 0.84 mg of atropine base; equivalent to 1 mg of atropine sulfate), and AtroPen(R) 2 mg in 0.7 mL of solution (dispenses 1.67 mg of atropine base; equivalent to 2 mg of atropine sulfate) (Prod Info ATROPEN(R) IM injection, 2005).

a) AtroPen(R): DOSE: ADULT AND CHILDREN OVER 10 YEARS OF AGE: Mild symptoms, in cases where exposure is known or suspected: Inject one 2 mg AtroPen(R) (green pen) into the outer thigh as soon as symptoms appear; pralidoxime chloride may also be required. Severe symptoms: Inject one 2 mg AtroPen(R) (green pen) into the outer thigh as soon as symptoms appear, administer 2 additional 2 mg AtroPen(R) doses in rapid succession 10 min after receiving the first dose; pralidoxime chloride and/or an anticonvulsant may also be required, patients should be closely monitored for at least 48 to 72 hr. PEDIATRIC: Mild symptoms, in cases where exposure is known or suspected: dose for infants less than 7 kg (generally less than 6 months of age) = 0.25 mg (yellow pen), dose for children 7 to 18 kg (generally 6 months to 4 years of age) = 0.5 mg (blue pen), dose for children 18 to 41 kg (generally 4 to 10 years of age) = 1 mg (dark red pen), dose for children over 41 kg = 2 mg (green pen): inject one AtroPen(R) into the outer thigh as soon as symptoms appear; pralidoxime chloride may also be required. Severe symptoms: Administer 2 additional AtroPen(R) doses (see above) in rapid succession 10 min after receiving the first dose; pralidoxime chloride and/or an anticonvulsant may also be required, patients should be closely monitored for at least 48 to 72 hr (Prod Info ATROPEN(R) IM injection, 2005).
b) If pralidoxime is required, pralidoxime prefilled autoinjector delivers 600 mg IM (adult dosing); may repeat every 15 minutes up to 3 injections if symptoms persist. The safety and efficacy of pralidoxime auto-injector for use in nerve agent poisoning have not been established in pediatric patients (Prod Info pralidoxime chloride intramuscular auto-imjector solution, 2003)

4) ATNAA (Antidote Treatment Nerve Agent Autoinjector, Meridian Medical Technologies, Columbia, Maryland) is currently used by the US military and provides atropine injection and pralidoxime chloride injection in a single needle. Each self-contained unit dispenses 2.1 mg of atropine in 0.7 mL and 600 mg of pralidoxime chloride in 2 mL via intramuscular injection (Prod Info ATNAA ANTIDOTE TREATMENT – NERVE AGENT, AUTO-INJECTOR intramuscular injection solution, 2002).

a) ATNAA: DOSE: ADULT: One ATNAA into the lateral thigh muscle or buttocks. Wait 10 to 15 minutes for effect (Prod Info ATNAA ANTIDOTE TREATMENT – NERVE AGENT, AUTO-INJECTOR intramuscular injection solution, 2002).

5) MARK I: This device (Meridian Medical Technologies, Columbia, Maryland) was used by the US military. (Note: the MARK I autoinjector kit was last produced by Meridian Medical Technologies, Columbia, MD in 2008. This product may still be available in some locations.) Each kit contains two autoinjectors: an atropine and a pralidoxime autoinjector. The atropine autoinjector delivers 2.1 mg of atropine in 0.7 mL via intramuscular injection. The pralidoxime autoinjector delivers 600 mg pralidoxime chloride in 2 mL via intramuscular injection (Prod Info DUODOTE(TM) IM injection, 2006).
6) DuoDote(R) is a dual chambered device (Meridian Medical Technologies, Columbia, Maryland) that delivers 2.1 mg of atropine in 0.7 mL and 600 mg of pralidoxime chloride in 2 mL sequentially using a single needle for use in a civilian or community setting. It should be administered by Emergency Medical Services personnel who have been trained to recognize and treat nerve agent or insecticide intoxication (Prod Info DuoDote(R) intramuscular injection solution, 2011).
7) DuoDote(R): DOSE: ADULT: Two or more mild symptoms, initial dose, 1 injector (atropine 2.1 mg/pralidoxime chloride 600 mg) IM into the mid-lateral thigh, wait 10 to 15 minutes for effect; subsequent doses, if at any time severe symptoms develop, administer 2 additional injectors in rapid succession IM into the mid-lateral thigh and immediately seek definitive medical care; MAX 3 doses unless definitive medical care is available (Prod Info DuoDote(R) intramuscular injection solution, 2011).
8) Therapeutic plasma concentrations of pralidoxime exceeding 4 mcg/mL were achieved within 4 to 8 minutes after injection (Sidell & Groff, 1974).
9) DIAZEPAM Autoinjector (Meridian Medical Technologies): Contains 10 mg of diazepam in 2 mL for intramuscular injection for seizure control (Prod Info diazepam autoinjector IM injection solution, 2005).
10) These devices are designed for initial field treatment. Although autoinjector doses may be adequate for nerve agent exposures, ORGANOPHOSPHATE exposures may require additional atropine or pralidoxime doses in the hospital setting that exceed those in the available autoinjectors.
11) For medical questions concerning Meridian products, you can call 1-800-438-1985. For general product information, call 1-800-638-8093.

D) ATROPINE

1) SUMMARY

a) Atropine is primarily effective for the treatment of muscarinic effects (e.g., bronchospasm, bronchorrhea, salivation, lacrimation, defecation, urination, miosis) of organophosphate poisoning, and will not reverse nicotinic effects (muscular weakness, diaphragmatic weakness, etc).

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) DURATION

a) Atropinization must be maintained until all of the absorbed organophosphate has been metabolized. This may require administration of 2 to 2000 mg of atropine over several hours to weeks. One case of parathion overdose required 19,590 mg of atropine over 24 days. In one 24 hour period, 2950 mg were administered (Golsousidis & Kokkas, 1985).
b) Atropine therapy may need to be prolonged in severe cases, because AChE activity may regenerate slowly.
c) Atropine therapy must be withdrawn slowly to prevent recurrence or rebounding of symptoms, often in the form of pulmonary edema. This is especially true of poisonings from lipophilic organophosphates such as fenthion. If atropine has been given for several days, it should be maintained for at least 24 hours after resolution of acute symptoms (Bardin et al, 1987).

4) ATROPINIZATION REGIMENS

a) COMPARISON STUDY: A prospective cohort study of patients with acute cholinesterase inhibitor pesticide poisoning (n=226) was conducted in Sri Lanka to determine the safety and efficacy of titrated atropine therapy (i.e., an initial bolus followed by an infusion until atropinization occurred) vs. ad hoc atropine therapy (i.e., intermittent boluses, an infusion or a combination of bolus and infusion as determined by the treating physician). At baseline, patients in the titrated group had signs of greater toxicity, which included higher doses of insecticide ingested, more clinical symptoms of anticholinesterase poisoning at presentation, and higher rates of dimethoate ingestions as compared to the ad hoc group with a higher proportion of chlorpyrifos ingestions. The total atropine dose in the titrated cohort (n=126) was 37.3 mg as compared to 65.4 mg in the ad hoc cohort (n=100). Likewise, the amount of atropine boluses (3.9 mg {1.2-19.2} vs. 15 mg {10-20}) and infusion rates (1.39 mg/hour {0.46-2.32} vs. 2.1 mg/hour {1.18-3.39}) were also significantly lower in the titrated dose regimen. Atropine toxicity was more likely to occur in the ad hoc regimen with more frequent episodes of agitated delirium (17% vs. 1%) and hallucinations (35% vs. 1%); sedation and physical restraint were also more frequently required. Overall, patients in the titrated dose cohort had a shorter length of stay, less atropine toxicity, and improved patient outcome. Mortality rates were similar in both groups following adjustment for the pesticide ingested (Perera et al, 2008).
b) One retrospective study of 34 patients evaluated atropine maintenance dosage required to treat muscarinic features of severe organophosphate poisoning. When red cell acetylcholinesterase activity (RBC-AChE) was between 10% to 30% of normal, an atropine dose of 0.005 mg/kg/hr was adequate. Higher doses of atropine up to 0.06 mg/kg/hr were required to treat cholinergic crisis only when RBC-AChE was completely inhibited (Thiermann et al, 2011).

E) IPRATROPIUM

1) Endotracheal ipratropium 0.5 mg every 6 hours was associated with improvement in rales in one case of organophosphate poisoning (Shemesh et al, 1988).

F) PRALIDOXIME

1) INDICATIONS

a) PRALIDOXIME/INDICATIONS

1) Severe organophosphate poisoning with nicotinic (muscle and diaphragmatic weakness, respiratory depression, fasciculations, muscle cramps, etc) and/or central (coma, seizures) manifestations should be treated with pralidoxime in addition to atropine(Prod Info PROTOPAM(R) Chloride injection, 2010).

b) PRALIDOXIME/CONTROVERSY

1) Human studies have not substantiated the benefit of oxime therapy in acute organophosphate poisoning (Eddleston et al, 2002; de Silva et al, 1992); however oxime dosing in these studies was not optimized and methodology was unclear. Most authors advocate the continued use of pralidoxime in the clinical setting of severe organophosphate poisoning (Singh et al, 2001; Singh et al, 1998a).
2) It has been difficult to assess the value of pralidoxime in case studies because most of the patients have also received atropine therapy, or the pralidoxime was given late in the treatment or at a suboptimal dose (Peter et al, 2006; Rahimi et al, 2006).
3) More recent observational studies have indicated that acetylcholinesterase inhibited by various organophosphate (OP) pesticides varies in its responsiveness to oximes; diethyl OPs (eg, parathion, quinalphos) appear to be effectively reactivated by oximes, while dimethyl OPs (eg, monocrotophos or oxydemeton-methyl) appear to respond poorly. Profenofos, an OP that is AChE inhibited by a S-alkyl link, was also found to not reactivate at all to oximes (Eddleston et al, 2008).

2) ADMINISTRATION

a) PRALIDOXIME/ADMINISTRATION

1) Pralidoxime is best administered as soon as possible after exposure; ideally, within 36 hours of exposure (Prod Info PROTOPAM(R) CHLORIDE injection, 2006). However, patients presenting late (2 to 6 days after exposure) may still benefit (Borowitz, 1988; De Kort et al, 1988; Namba et al, 1971; Amos & Hall, 1965) .
2) Some mechanisms which may account for pralidoxime efficacy with delayed administration include:

a) Poisoning with an agent such as parathion or quinalphos which produces "slow aging" of acetylcholinesterase (Eddleston et al, 2008).
b) Slow absorption of the organophosphate compound from the lower bowel or exposure to large amounts (Prod Info PROTOPAM(R) CHLORIDE injection, 2006).
c) Release of the organophosphate from fat stores (Borowitz, 1988).
d) Other actions of pralidoxime.

3) 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.

4) 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).

5) 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).

6) 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).

7) EFFICACY

a) One review article evaluated two randomized-controlled trials of 182 organophosphate-poisoned patients treated with pralidoxime. These studies reported that high-dose pralidoxime was associated with a worse outcome (an increased mortality rate, increased requirement for ventilation, and increased rate of Intermediate syndrome) and pralidoxime should not have a role in the routine management of patients with organophosphate poisoning. However, the effects of oximes on pneumonia, duration of ventilation, or significant persistent neurological injury were not obtained. These studies did not consider a number of issues important for outcome (baseline characteristics were not evenly balanced; lower oxime dose than recommended; substantial treatment delays; type of organophosphate was not taken into account), and the methodology was unclear. The authors of the review article concluded that the current evidence is insufficient to indicate whether oximes are harmful or beneficial in the management of organophosphate-poisoned patients (Buckley et al, 2005).
b) One review article evaluated 7 controlled trials (2 randomized controlled trials, 1 study with historical controls, 3 retrospective studies, a prospective trial of 3 groups) of oximes in human organophosphate poisoning. These trials used varying dosage schedules of pralidoxime or obidoxime, and examined the effects of oxime therapy on mortality rate, mechanical ventilation, incidence of intermediate syndrome, and need for intensive care therapy. Oxime therapy was not associated with a significant change in mortality (risk difference 0.09, 95% CI -0.08 to 0.27, p=0.31), ventilatory requirements (risk difference 0.16, 95% CI -0.07 to 0.38, p=0.17), or a reduction in the incidence of intermediate syndrome (risk difference 0.16, 95% CI -0.12 to 0.45, p = 0.26) ; however, it was associated with an increased need for intensive care therapy (risk difference 0.19, 95% CI 0.01 to 0.36, p=0.04). The authors concluded that oxime therapy was associated with either a null effect or possible harm (Peter et al, 2006).
c) One study used high doses of pralidoxime to evaluate the biochemical profile of butyrylcholinesterase (BuChE) reactivation in both treated and untreated cases of moderate and severe organophosphate poisonings. Mortality, ICU stay, and type I and II paralysis and its correlation to BuChE profile were also studied. Twenty-one cases (11 moderately severe [6 in placebo and 5 in treatment group] and 10 severe cases [5 in placebo and 5 in treatment group) were included. In both groups, the BuChE levels increased gradually over several days (6-7 days). The BuChE levels were not different in control and treatment groups. There was no correlation between BuChE levels and severity of poisoning, the incidence of Type I and II paralysis, complications, ICU stay, number of days ventilated or mortality (Cherian et al, 2005).

G) OBIDOXIME CHLORIDE

1) SUMMARY

a) At the time of this review, obidoxime chloride is not available in the United States.

2) OBIDOXIME/INDICATIONS

a) Obidoxime dichloride, Toxogonin(R), may be a less toxic and more efficacious alternative to pralidoxime in poisonings from organophosphates containing a dimethoxy or diethoxy moiety.
b) Clinical experience with this compound is limited (Kassa, 2002; Willems, 1981; De Kort et al, 1988; Barckow et al, 1969).
c) It is apparently favored over pralidoxime in clinical practice in Belgium, Israel, The Netherlands, Scandinavia, and Germany and is the only oxime available in Portugal. It is currently not available in the US, but may be available through Merck in some countries.

3) ADULT DOSE

a) INITIAL: Obidoxime may be given as an intravenous bolus of 250 milligrams and may be repeated once or twice at 2 hour intervals (Prod Info TOXOGONIN(R) IV injection, 2007). It is more effective if given early, and the manufacturer recommends that it not be administered more than after 6 hours following organophosphate intoxication (Prod Info TOXOGONIN(R) IV injection, 2007), however in clinical practice it is often used in patients presenting more than 6 hours after poisoning (Thiermann et al, 1997).
b) ALTERNATIVE DOSING: For the treatment of organophosphorous pesticide poisoning, administer 250 milligrams of obidoxime as an intravenous or intramuscular bolus, followed by a continuous intravenous infusion of 750 milligrams/day (Antonijevic & Stojiljkovic, 2007; Thiermann et al, 1997).
c) CONTINUOUS INFUSION: To achieve a 4 microgram/milliliter threshold plasma level of obidoxime for the treatment of nerve agent intoxication, the following loading and maintenance doses are suggested: LOADING DOSE: 0.8 milligram/kilogram. INFUSION RATE: 0.5 milligram/kilogram/hour (Kassa, 2002).

4) PEDIATRIC DOSE

a) Children may be given single doses of 4 to 8 milligrams/kilogram, followed by an intravenous infusion of 0.45 milligrams/kilogram/hour (Prod Info TOXOGONIN(R) IV injection, 2007; Antonijevic & Stojiljkovic, 2007; Thiermann et al, 1997) not to exceed 250 milligrams, usual adult dose, in older children (Prod Info Toxogonin(R), obidoxime chloride, 1989).

5) DURATION:

a) More severely poisoned patients generally require a longer duration of infusion (Thiermann et al, 1997). If cholinergic signs or symptoms worsen or if cholinesterase concentrations decline after obidoxime is discontinued, therapy should be reinstituted.

6) ADVERSE EFFECTS

a) Mild, transient liver dysfunction has been noted with obidoxime use (Finkelstein et al, 1989).

7) A study of 63 patients with organophosphate poisoning found that high doses of obidoxime (8 mg/kg followed by 2 mg/kg/hour) were hepatotoxic compared to high dose pralidoxime (30 mg/kg followed by 8 mg/kg/hour). There were no fatalities in the group receiving pralidoxime while mortality was 50% in the obidoxime group (Balali-Mood & Shariat, 1998).

H) ASOXIME CHLORIDE

1) SUMMARY

a) Asoxime chloride is currently not available in the United States.
b) HI-6 is an oxime that was developed to treat organophosphate poisoning, and appears to be effective against the diethoxy group of organophosphates, which age more slowly than the dimethoxy portion (Kusic et al, 1991). It has been used increasingly in auto-injectors because it has been found to be a more effective reactivator of acetylcholinesterase inhibited by nerve agents compared with pralidoxime and obidoxime (Roberts & Aaron, 2007)

I) BENZODIAZEPINE

1) SUMMARY

a) Administer benzodiazepines to patients with severe poisoning or seizures.

2) DOSE

a) Starting doses for agitation or seizures are: 5 to 10 mg diazepam IV (0.05 to 0.3 mg/kg/dose); 2 to 4 mg lorazepam IV (0.05 to 0.1 mg/kg/dose); or 5 to 10 mg midazolam IV (0.15 to 0.2 mg/kg/dose) (Roberts & Aaron, 2007).

3) ANIMAL DATA

a) In animal models of organophosphate nerve agent poisoning, administration of diazepam along with oximes increased survival and decreased the incidence of seizures and neuropathy (Kusic et al, 1991; Lotti, 1991; Murphy et al, 1993). Diazepam may also decrease cerebral damage induced by organophosphate related seizures (McDonough et al, 1989; Sidell & Borak, 1992).

J) 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).

K) HYPOTENSIVE EPISODE

1) SUMMARY

a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.

2) DOPAMINE

a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).

3) NOREPINEPHRINE

a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
b) DOSE

1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).

L) CONDUCTION DISORDER OF THE HEART

1) Three phases of cardiac toxicity have been observed following OP poisoning (Bar-Meir et al, 2007):

1) Initial Phase: Hypertension and sinus tachycardia are present due to nicotinic effects.
2) Prolonged Phase: Sinus bradycardia and hypotension secondary to extreme parasympathetic overflow along with ST-T segment changes and AV conduction disturbances; alterations are based on the severity of the intoxication
3) Final Phase: QT prolongation, torsades de pointes, and sudden cardiac death can occur. This phase can begin within a few hours to 1 to 15 days after exposure. Signs of clinical intoxication may have resolved. The occurrence of late arrhythmias is poor clinical indicator, even if initial clinical treatment was adequate.

M) TORSADES DE POINTES

1) QT prolongation may develop with severe OP poisoning. In one study, patients with a QTc greater than 0.58 s were at high-risk for a fatal dysrhythmia and patients with a QTc of greater than 0.60 s developed potentially fatal dysrhythmias. In most cases, torsades de pointes occurred with QTc values of more than 0.50 s (Bar-Meir et al, 2007).
2) SUMMARY

a) Withdraw the causative agent. Hemodynamically unstable patients with Torsades de pointes (TdP) require electrical cardioversion. Emergent treatment with magnesium (first-line agent) or atrial overdrive pacing is indicated. Detect and correct underlying electrolyte abnormalities (ie, hypomagnesemia, hypokalemia, hypocalcemia). Correct hypoxia, if present (Drew et al, 2010; Neumar et al, 2010; Keren et al, 1981; Smith & Gallagher, 1980).
b) Polymorphic VT associated with acquired long QT syndrome may be treated with IV magnesium. Overdrive pacing or isoproterenol may be successful in terminating TdP, particularly when accompanied by bradycardia or if TdP appears to be precipitated by pauses in rhythm (Neumar et al, 2010). In patients with polymorphic VT with a normal QT interval, magnesium is unlikely to be effective (Link et al, 2015).

3) MAGNESIUM SULFATE

a) Magnesium is recommended (first-line agent) for the prevention and treatment of drug-induced torsades de pointes (TdP) even if the serum magnesium concentration is normal. QTc intervals greater than 500 milliseconds after a potential drug overdose may correlate with the development of TdP (Charlton et al, 2010; Drew et al, 2010). ADULT DOSE: No clearly established guidelines exist; an optimal dosing regimen has not been established. Administer 1 to 2 grams diluted in 10 milliliters D5W IV/IO over 15 minutes (Neumar et al, 2010). Followed if needed by a second 2 gram bolus and an infusion of 0.5 to 1 gram (4 to 8 mEq) per hour in patients not responding to the initial bolus or with recurrence of dysrhythmias (American Heart Association, 2005; Perticone et al, 1997). Rate of infusion may be increased if dysrhythmias recur. For persistent refractory dysrhythmias, a continuous infusion of up to 3 to 10 milligrams/minute in adults may be given (Charlton et al, 2010).
b) PEDIATRIC DOSE: 25 to 50 milligrams/kilogram diluted to 10 milligrams/milliliter for intravenous infusion over 5 to 15 minutes up to 2 g (Charlton et al, 2010).
c) PRECAUTIONS: Use with caution in patients with renal insufficiency.
d) MAJOR ADVERSE EFFECTS: High doses may cause hypotension, respiratory depression, and CNS toxicity (Neumar et al, 2010). Toxicity may be observed at magnesium levels of 3.5 to 4.0 mEq/L or greater (Charlton et al, 2010).
e) MONITORING PARAMETERS: Monitor heart rate and rhythm, blood pressure, respiratory rate, motor strength, deep tendon reflexes, serum magnesium, phosphorus, and calcium concentrations (Prod Info magnesium sulfate heptahydrate IV, IM injection, solution, 2009).

4) OVERDRIVE PACING

a) Institute electrical overdrive pacing at a rate of 130 to 150 beats per minute, and decrease as tolerated. Rates of 100 to 120 beats per minute may terminate torsades (American Heart Association, 2005). Pacing can be used to suppress self-limited runs of TdP that may progress to unstable or refractory TdP, or for override refractory, persistent TdP before the potential development of ventricular fibrillation (Charlton et al, 2010). In a case series overdrive pacing was successful in terminating TdP associated with bradycardia and drug-induced QT prolongation (Neumar et al, 2010).

5) POTASSIUM REPLETION

a) Potassium supplementation, even if serum potassium is normal, has been recommended by many experts (Charlton et al, 2010; American Heart Association, 2005). Supplementation to supratherapeutic potassium concentrations of 4.5 to 5 mmol/L has been suggested, although there is little evidence to determine the optimal range in dysrhythmia (Drew et al, 2010; Charlton et al, 2010).

6) ISOPROTERENOL

a) Isoproterenol has been successful in aborting torsades de pointes that was resistant to magnesium therapy in a patient in whom transvenous overdrive pacing was not an option (Charlton et al, 2010) and has been successfully used to treat torsades de pointes associated with bradycardia and drug induced QT prolongation (Keren et al, 1981; Neumar et al, 2010). Isoproterenol may have a limited role in pharmacologic overdrive pacing in select patients with drug-induced torsades de pointes and acquired long QT syndrome (Charlton et al, 2010; Neumar et al, 2010). Isoproterenol should be avoided in patients with polymorphic VT associated with familial long QT syndrome (Neumar et al, 2010).
b) DOSE: ADULT: 2 to 10 micrograms/minute via a continuous monitored intravenous infusion; titrate to heart rate and rhythm response (Neumar et al, 2010).
c) PRECAUTIONS: Correct hypovolemia before using; contraindicated in patients with acute cardiac ischemia (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).

1) Contraindicated in patients with preexisting dysrhythmias; tachycardia or heart block due to digitalis toxicity; ventricular dysrhythmias that require inotropic therapy; and angina. Use with caution in patients with coronary insufficiency (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).

d) MAJOR ADVERSE EFFECTS: Tachycardia, cardiac dysrhythmias, palpitations, hypotension or hypertension, nervousness, headache, dizziness, and dyspnea (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
e) MONITORING PARAMETERS: Monitor heart rate and rhythm, blood pressure, respirations and central venous pressure to guide volume replacement (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).

7) OTHER DRUGS

a) Mexiletine, verapamil, propranolol, and labetalol have also been used to treat TdP, but results have been inconsistent (Khan & Gowda, 2004).

8) AVOID

a) Avoid class Ia antidysrhythmics (eg, quinidine, disopyramide, procainamide, aprindine), class Ic (eg, flecainide, encainide, propafenone) and most class III antidysrhythmics (eg, N-acetylprocainamide, sotalol) since they may further prolong the QT interval and have been associated with TdP.

N) ACUTE LUNG INJURY

1) ONSET: Onset of acute lung injury after toxic exposure may be delayed up to 24 to 72 hours after exposure in some cases.
2) NON-PHARMACOLOGIC TREATMENT: The treatment of acute lung injury is primarily supportive (Cataletto, 2012). Maintain adequate ventilation and oxygenation with frequent monitoring of arterial blood gases and/or pulse oximetry. If a high FIO2 is required to maintain adequate oxygenation, mechanical ventilation and positive-end-expiratory pressure (PEEP) may be required; ventilation with small tidal volumes (6 mL/kg) is preferred if ARDS develops (Haas, 2011; Stolbach & Hoffman, 2011).

a) To minimize barotrauma and other complications, use the lowest amount of PEEP possible while maintaining adequate oxygenation. Use of smaller tidal volumes (6 mL/kg) and lower plateau pressures (30 cm water or less) has been associated with decreased mortality and more rapid weaning from mechanical ventilation in patients with ARDS (Brower et al, 2000). More treatment information may be obtained from ARDS Clinical Network website, NIH NHLBI ARDS Clinical Network Mechanical Ventilation Protocol Summary, http://www.ardsnet.org/node/77791 (NHLBI ARDS Network, 2008)

3) FLUIDS: Crystalloid solutions must be administered judiciously. Pulmonary artery monitoring may help. In general the pulmonary artery wedge pressure should be kept relatively low while still maintaining adequate cardiac output, blood pressure and urine output (Stolbach & Hoffman, 2011).
4) ANTIBIOTICS: Indicated only when there is evidence of infection (Artigas et al, 1998).
5) EXPERIMENTAL THERAPY: Partial liquid ventilation has shown promise in preliminary studies (Kollef & Schuster, 1995).
6) CALFACTANT: In a multicenter, randomized, blinded trial, endotracheal instillation of 2 doses of 80 mL/m(2) calfactant (35 mg/mL of phospholipid suspension in saline) in infants, children, and adolescents with acute lung injury resulted in acute improvement in oxygenation and lower mortality; however, no significant decrease in the course of respiratory failure measured by duration of ventilator therapy, intensive care unit, or hospital stay was noted. Adverse effects (transient hypoxia and hypotension) were more frequent in calfactant patients, but these effects were mild and did not require withdrawal from the study (Wilson et al, 2005).
7) However, in a multicenter, randomized, controlled, and masked trial, endotracheal instillation of up to 3 doses of calfactant (30 mg) in adults only with acute lung injury/ARDS due to direct lung injury was not associated with improved oxygenation and longer term benefits compared to the placebo group. It was also associated with significant increases in hypoxia and hypotension (Willson et al, 2015).

O) BRONCHOSPASM

1) SUMMARY

a) Bronchospasm may occur after inhalation exposure to organophosphates, or as part of the pattern of pharmacological muscarinic effects after systemic absorption.
b) Inhaled nebulized sympathomimetic bronchodilators and anticholinergics (eg, atropine, glycopyrrolate, ipratropium) may be effective in treating bronchospasm.

2) GLYCOPYRROLATE

a) Glycopyrrolate, a quaternary ammonium compound, has been used in the treatment of organophosphate poisoning because of its better control of secretions, less tachycardia, and fewer CNS effects.

1) DOSE (INHALATION): Racemic glycopyrrolate by inhalation is a long acting anticholinergic bronchodilator. It has been found to have a prolonged bronchodilator response and protection against bronchospasm in patients with asthma (Hansel et al, 2005). In one study, metered-dose glycopyrrolate aerosol in doses of 240, 480 and 960 micrograms, produced significant improvement in airway obstruction for 20 adult asthmatic patients for up to 12 hours. The 480 microgram dose appeared to produce the maximal bronchodilation without significant side effects (Schroeckenstein et al, 1988).
2) DOSE (INFUSION): In one small study, 7.5 mg of glycopyrrolate was added to 200 mL saline and titrated until mucous membranes were dry and secretions were minimal, heart rate was greater than 60 beat/minute with an absence of fasciculations. Except for a trend to fewer respiratory tract infections among those treated with glycopyrrolate, no significant differences in outcome were noted when comparable groups of organophosphate poisoned patients were treated with either atropine or glycopyrrolate (Bardin & Van Eeden, 1990). Glycopyrrolate may be given intramuscularly or intravenously, without dilution (Prod Info ROBINUL(R) injection, 2006).
3) A combination of glycopyrrolate/atropine therapy has been used successfully to treat two cases of acute organophosphorus poisoning (Tracey & Gallagher, 1990).

3) INHALED NEBULIZED IPRATROPIUM

a) IPRATROPIUM BROMIDE, an anticholinergic (parasympatholytic) bronchodilator agent, which is a quaternary ammonium compound chemically related to atropine. Each 3 mL vial contains 3.0 mg (0.1%) of albuterol sulfate (equivalent to 2.5 mg (0.083%) of albuterol base) and 0.5 mg (0.017%) of ipratropium bromide in an isotonic, sterile, aqueous solution containing sodium chloride. Usual dose: one 3 mL vial administered 4 times a day via nebulization with up to 2 additional 3 mL doses as necessary (Prod Info DUONEB(R) inhalation solution, 2005).

P) PULMONARY ASPIRATION

1) Many organophosphate compounds are found in solution with a variety of hydrocarbon-based solvents.
2) Aspiration pneumonitis may occur if these products are aspirated into the lungs.
3) Bronchopneumonia may develop as a complication of organophosphate-induced pulmonary edema.

Q) DRUG INTERACTION

1) NEUROMUSCULAR BLOCKER

a) Do NOT administer SUCCINYLCHOLINE (SUXAMETHONIUM) or other cholinergic medications.
b) Prolonged neuromuscular blockade may result when succinylcholine is administered after organophosphate exposure (Perez Guillermo et al, 1988; Selden & Curry, 1987).

R) EXPERIMENTAL THERAPY

1) ALKALINIZATION

a) SODIUM BICARBONATE: In one study, constant infusion of high doses of sodium bicarbonate (5 to 6 mEq/kg in 1 hour followed by 5 to 6 mEq/kg every 20 to 24 hours until recovery/death) appeared to be effective in patients (n=27) with acute organophosphate pesticide poisoning. Although no significant differences on the atropine doses required on admission and during the first 24 hours between the groups was noted, the total atropine used in the test group was significantly (p=0.048) lower than in the control group (n=26; 93.4 +/- 59.1 mg and 129.5 +/- 61 mg, respectively). In addition, the mean hospitalization period was significantly (p=0.037) lower in the test group than in the controls (4.33 +/- 1.99 and 5.59 +/- 1.97 days, respectively). No statistically significant differences on AchE activity was observed during treatment between the groups (Balali-Mood et al, 2005).

1) One review article evaluated 5 studies to determine the efficacy of alkalinization (eg; sodium bicarbonate) for the treatment of organophosphate poisoning. Because of the poor quality of these studies (eg; uncontrolled; randomized but poorly concealed; marked heterogeneity between subjects and treatment), the authors determined that there is insufficient evidence to support the routine use of plasma alkalinization for the treatment of organophosphate poisoning (Roberts & Buckley, 2005).
2) Although the exact mechanism of action of alkalinization (including sodium bicarbonate) in the treatment of organophosphate poisoning is unknown, the following mechanisms have been proposed, based on in vitro, animal and human studies (Roberts & Buckley, 2005):

1) Enhanced pesticide clearance from the body through non-enzymatic and/or enzymatic hydrolysis
2) Volume expansion with improved tissue perfusion
3) Improved efficacy of oximes
4) Direct effect on neuromuscular function
5) Bicarbonate-induced release of lactate into the circulation

2) MAGNESIUM SULFATE

a) One single center, single-blind prospective control trial evaluated the use of magnesium sulfate in the management of patients (n=45) with organophosphate poisoning. Eleven of 45 patients were given magnesium sulfate (4 grams/day IV continued for only the first 24 hours after admission) in a systematic sampling (every fourth eligible patient). Although there was no significant difference between the two groups in terms of daily oxime or atropine requirements, the magnesium-treated group had a significantly lower mortality rate (0% vs 14.7% in control group) and duration of hospitalization (2.9 days vs 5 days in control group) compared to those who had not received magnesium sulfate (P<0.01). The authors suggested that magnesium sulfate inhibits acetylcholine release from motor nerve terminals and can antagonize the effects of organophosphates. In addition, it was proposed that intravenous use of magnesium sulfate can control premature ventricular contractions and it can counteract the direct toxic inhibitory action of organophosphate on sodium potassium AT-Pase (Pajoumand et al, 2004).

3) FRESH FROZEN PLASMA

a) In a prospective study of 33 patients with organophosphate poisoning, 20 patients received atropine and pralidoxime, 11 received atropine, pralidoxime and fresh frozen plasma (FFP) (2 of these had already developed intermediate syndrome before receiving FFP) , 1 received only atropine and one received atropine and FFP. Although approximately 29% of patients receiving pralidoxime without FFP developed intermediate syndrome, none of the patients receiving FFP developed intermediate syndrome after FFP was initiated. The mortality rates in the pralidoxime group and FFP/atropine/pralidoxime group were 14.3% and 0%, respectively. BuChE concentration in FFP was 4069.5 +/- 565.1 International Units/L. An increase in BuChE activity of approximately 461.7 +/- 142.1 International Units/L was observed for every two bags of fresh frozen plasma administered (Guven et al, 2004).
b) In a randomized clinical trial, 56 patients with organophosphate (OP) poisoning were randomly assigned to either receive fresh frozen plasma (FFP) (4 packs as stat dose at the start of therapy) or control group. All patients also received atropine (max stat dose: 25 mg; mean and median doses, 927 +/- 3016 mg and 77 mg; range, 26 to 244 mg, respectively) and patients with moderate to severe poisoning received pralidoxime (3 mg/kg/hr; mean and median doses, 7093 +/- 7539 mg and 4000 mg; range, 2000 to 11500 mg, respectively). It was determined that the use of FFP had no significant effect on atropine and pralidoxime doses, hospitalization length, and the mortality of OP poisoned patients (Pazooki et al, 2011).

4) EXTRACORPOREAL PERFUSION

a) Extracorporeal cardiopulmonary support, including intraaortic balloon pumping and percutaneous cardiopulmonary support, were used to treat a 50-year-old woman with respiratory arrest, refractory circulatory collapse, coma, and severe hypothermia, after ingesting 100 mL of an insecticide containing 35% fenitrothion and 15% malathion. The patient gradually improved following hemodynamic support and active rewarming. Nineteen hours after admission the patient was alert with evidence of severe muscle weakness. Intubation was required for more than 23 days. The patient was transferred on day 67 for further treatment for depression (Kamijo et al, 1999).

S) EXTRAPYRAMIDAL SIGN

1) SCOPOLAMINE: A 17-year-old girl developed extrapyramidal signs (cogwheel rigidity of the extremities, bradykinesia, bradyarthria, mask face, drooling), and coma within 36 hours of ingesting 150 mL of chlorpyrifos. She had not been treated with atropine because of lack of initial cholinergic manifestations. She responded immediately to intravenous scopolamine (0.5 mg). In addition, she received obidoxime 250 mg intravenously and then both drugs were repeated after 6 hours. She was discharged 4 days later without further sequelae (Kventsel et al, 2005).
2) AMANTADINE: Five days after ingesting a raw eggplant sprayed with dimethoate (Rogor), a 14-year-old boy developed overt extrapyramidal parkinsonism (a resting tremor, expressionless face, lack of blinking along with marked cogwheel rigidity and a stooped, slow gait, agitation) after recovering from the acute cholinergic crisis. He was treated with 100 mg of amantadine three times daily with complete recovery within 1 week. He continued to receive 100 mg of amantadine twice daily for 3 additional months (Shahar et al, 2005).
3) One study reported 27 patients with basal ganglia impairment after acute organophosphate insecticide poisoning. Twenty-one patients recovered; half of them were treated with various medications (eg; trihexyphenidyl, benzehexol, bromocriptine, biperidine, diphenhydramine, levodopa/carbidopa, and haloperidol). Four patients had persistent parkinsonism (Shahar et al, 2005).

Inhalation Exposure

6.7.2)

A) BRONCHOSPASM

1) Bronchospasm may occur after inhalation exposure to organophosphates, or as part of the pattern of pharmacological muscarinic effects. Inhaled sympathomimetic bronchodilators or atropine may be effective in treating bronchospasm.

B) SUPPORT

1) See ORAL exposure for further information on therapy.

C) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Eye Exposure

6.8.2)

A) SUPPORT

1) Systemic toxicity is unlikely following ocular exposure only. However, see ORAL exposure if there is clinical evidence of systemic absorption.

B) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Dermal Exposure

6.9.2)

A) SUPPORT

1) See ORAL exposure for further information on therapy.

B) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Enhanced Elimination

1) Hemoperfusion, hemodialysis, and exchange transfusion have not been shown to affect outcome or duration of toxicity in controlled trials of organophosphate poisoning.

1) Exchange transfusions and/or hemoperfusion with activated carbon have been effective in lowering plasma concentrations of parathion, but it is not clear that these procedures affect outcome or speed of recovery (Windler et al, 1983; de Monchy et al, 1979).

1) CASE REPORT: After accidental dermal exposure to fenitrothion, a 62-year-old man developed nausea and vomiting, miosis, excess salivation, fasciculation and aspiration pneumonia. His conditions deteriorated during atropine and pralidoxime (PAM) therapies. On day 5, he developed sepsis and plasmapheresis was performed. Plasma cholinesterase was decreased initially and continued to decline even with high doses of atropine and PAM; however, it normalized after plasma exchange. He was discharged from the ICU without further sequelae (Guven et al, 2004a).

1) Hemoperfusion with coated activated charcoal or amberlite XAD-4 has been effective in clearing parathion, Demeton-S-methyl sulfoxide and dimethioate from human blood. Hemodialysis was less effective (Okonek et al, 1979).
2) In a retrospective study, use of hemoperfusion in patients with severe organophosphate poisoning appeared to be associated with a more rapid rise in plasma acetylcholinesterase concentrations, although this did not correlate with more rapid resolution of cholinergic manifestations or improved outcome (Altintop et al, 2005).
3) Several in vitro studies have shown acceptable clearances of parathion with hemoperfusion. Burgess & Audette (1990) reported that charcoal hemoperfusion is an efficient means to improve clearance of malathion on a short-term basis (the first 30 minutes); however, its effectiveness is limited by the short duration of effective removal (120 minutes), afforded by the column and the wide distribution of malathion in the body. Over a prolonged time in severe, acute malathion poisoning, the authors recommended that the column should be changed when it becomes saturated with the pesticide (Burgess & Audette, 1990).
4) Recurrence of toxicity after apparent improvement has been described after hemoperfusion for fenitrothion poisoning (Yoshida et al, 1987).

1) Hemoperfusion was NOT successful in removing clinically relevant amounts of organophosphates in one study of 42 patients. The amount removed was less than 0.1% of total absorbed poison (Martinez-Chuecos et al, 1992).
2) In a study of 108 patients with dichlorvos poisoning, treatment with charcoal hemoperfusion in addition to standard care (atropine, pralidoxime) was associated with a reduced cumulative dose of atropine, reduced need for mechanical ventilation, lower mortality rate, decreased duration of coma and altered mental status, and shorter ICU stay. Hemoperfusion also improved serum ChE activity and reduced dichlorvos concentration (Peng et al, 2004).
3) EXTRACORPOREAL CARBOHEMOPERFUSION (ECHP): Prehospital use of an activated charcoal intravenous bypass, in the ambulance or at home, was used in 16 patients with ingestion of "lethal" amounts of carbophos. All patients survived and required less atropine and artificial ventilation than a comparison group treated without ECHP. Eight of 30 patients in the control group died within 2 hours after admission (Afanasiev et al, 1992).

Abstracts

Range Of Toxicity

Summary

Therapeutic Dose

7.2.1)

A) HEAD LICE - Apply malathion lotion to dry hair in an amount sufficient to wet both the hair and scalp. Allow hair to dry naturally; do not use electrical heat. Shampoo hair 8 to 12 hours after applying lotion. Rinse hair and use a fine tooth comb to remove dead lice and eggs. May repeat in 7 to 9 days if lice are still present (Prod Info OVIDE(R) topical lotion, 2005).

7.2.2)

A) HEAD LICE - The safety and effectiveness of malathion lotion in children less than 6 years of age have not been established (Prod Info OVIDE(R) topical lotion, 2005). However, a study comparing 0.5% malathion gels and lotion to permethrin for treatment of head lice included 50 subjects 2 to 6 years-old. No major adverse effect were reported (Meinking et al, 2007).
B) Children 6 years of age or older: treatment should be done only under direct supervision of an adult (Prod Info OVIDE(R) topical lotion, 2005).
C) The American Academy Pediatrics suggests the cautious use of malathion in the treatment of head lice because of the potential risk of human toxicity if ingested, and the flammability of the product because of its alcohol base. It is recommended that over-the-counter products such as pyrethroids be tried initially (Frankowski, 2004).

Minimum Lethal Exposure

Maximum Tolerated Exposure

1) There is a body of clinical experience that suggests that humans are more susceptible to the toxic effects of malathion than are rats; however, there have been repeated demonstrations of the relative safety of malathion to humans (ACGIH, 1991; Hathaway et al, 1996):
2) All organophosphate esters undergo hydrolysis in water; generally the water-soluble products of hydrolysis are less toxic than the parent compound (Minton & Murray, 1988).
3) No effect on blood cholinesterase was found when malathion was fed to human volunteers for 47 days at the rate of 16 mg/man/day (ACGIH, 1991).
4) Volunteers dosed dermally with malathion had no change of blood cholinesterase or other injury while excreting an average of 47 mg/man/day and a maximum of 220 mg/man/day (ACGIH, 1991).

1) Delayed respiratory failure developed in a 53-year-old man 30 hours after ingesting about 300 mL of 50% malathion. Following supportive care, including atropine and pralidoxime treatment, his condition gradually improved and he was extubated on day 13 and transferred to the psychiatric service 5 days later (Berman et al, 2015).
2) An adult developed severe toxicity but survived after ingesting 60 mL of a 50% malathion solution (Bentur et al, 2003).
3) An adult developed severe toxicity but recovered after ingesting 100 ml of 15% malathion (Dive et al, 1994).
4) In a group of workers with an average exposure of 3.3 mg/m(3) for 5 hours (maximum of 56 mg/m(3)), the cholinesterase levels in the blood were not significantly decreased, and none exhibited signs of cholinesterase inhibition (Hathaway et al, 1996).
5) In a human experiment in which four men were exposed 1 hour daily for 42 days to an airborne concentration of 84.8 mg/m(3), there was moderate irritation of the nose and conjunctiva, but there were no cholinergic signs or symptoms (Hathaway et al, 1996).
6) Non-lethal intoxication has occurred in agricultural workers, but has usually been the result of gross exposures with concomitant skin absorption (Hathaway et al, 1996).

Serum Plasma Blood Concentrations

7.5.1)

A) THERAPEUTIC CONCENTRATION LEVELS

1) THERAPEUTIC USE

a) Lice and their eggs (nits) were killed within 3 seconds by direct application of 0.003% and 0.06% malathion in acetone, respectively (Klaasen, 1990). One pharmaceutical preparation is provided in 78% isopropanol (Prod Info OVIDE(R) topical lotion, 2005).
b) One-hundred percent of 357 live lice isolated from the heads of school children were killed within one hour following application of a 0.5% malathion lotion (Chosidow et al, 1994).

7.5.2)

A) TOXIC CONCENTRATION LEVELS

1) EXPOSURE

a) Malathion was not detected in the blood of one patient who died following ingestion (Chaturvedi et al, 1989). In previously reported fatal cases, postmortem blood concentrations were 100 to 1880 milligrams/liter (Farago, 1967), 0.3 milligram/liter, and 1.89 milligrams/liter (Morgade & Barquet, 1982).

1) A blood malathion level of 23.9 mg/L, the highest reported in the literature (as determined by modern methods) was reported in a fatal case. Postmortem analysis revealed the blood ChE activity 12 days after exposure was less than 9% of normal (Zivot et al, 1993).
2) In a fatal suicidal malathion poisoning, postmortem blood and gastric contents levels were 1.8 and 978 micrograms/milliliter, respectively; malathion was not detectable in the liver (Thompson et al, 1998).

Workplace Standards

1) Editor's Note: The listed values are recommendations or guidelines developed by ACGIH(R) to assist in the control of health hazards. They should only be used, interpreted and applied by individuals trained in industrial hygiene. Before applying these values, it is imperative to read the introduction to each section in the current TLVs(R) and BEI(R) Book and become familiar with the constraints and limitations to their use. Always consult the Documentation of the TLVs(R) and BEIs(R) before applying these recommendations and guidelines.

a) Adopted Value

1) Malathion

a) TLV:

1) TLV-TWA: 1 mg/m(3)
2) TLV-STEL:
3) TLV-Ceiling:

b) Notations and Endnotes:

1) Carcinogenicity Category: A4
2) Codes: BEI(A), IFV, Skin
3) Definitions:

a) A4: Not Classifiable as a Human Carcinogen: Agents which cause concern that they could be carcinogenic for humans but which cannot be assessed conclusively because of a lack of data. In vitro or animal studies do not provide indications of carcinogenicity which are sufficient to classify the agent into one of the other categories.
b) BEI(A): The BEI notation is listed when a BEI is also recommended for the substance listed. Biological monitoring should be instituted for such substances to evaluate the total exposure from all sources, including dermal, ingestion, or non-occupational. Substances identified as Acetylcholinesterase Inhibiting Pesticides are part of this notation.
c) IFV: Inhalable fraction and vapor.
d) Skin: This refers to the potential significant contribution to the overall exposure by the cutaneous route, including mucous membranes and the eyes, either by contact with vapors or, of likely greater significance, by direct skin contact with the substance. It should be noted that although some materials are capable of causing irritation, dermatitis, and sensitization in workers, these properties are not considered relevant when assigning a skin notation. Rather, data from acute dermal studies and repeated dose dermal studies in animals or humans, along with the ability of the chemical to be absorbed, are integrated in the decision-making toward assignment of the skin designation. Use of the skin designation provides an alert that air sampling would not be sufficient by itself in quantifying exposure from the substance and that measures to prevent significant cutaneous absorption may be warranted. Please see "Definitions and Notations" (in TLV booklet) for full definition.

c) TLV Basis - Critical Effect(s): Cholinesterase inhib
d) Molecular Weight: 330.36

1) For gases and vapors, to convert the TLV from ppm to mg/m(3):

a) [(TLV in ppm)(gram molecular weight of substance)]/24.45

2) For gases and vapors, to convert the TLV from mg/m(3) to ppm:

a) [(TLV in mg/m(3))(24.45)]/gram molecular weight of substance

e) Additional information:

B) NIOSH REL and IDLH Values for CAS121-75-5 (National Institute for Occupational Safety and Health, 2007):

1) Listed as: Malathion
2) REL:

a) TWA: 10 mg/m(3)
b) STEL:
c) Ceiling:
d) Carcinogen Listing: (Not Listed) Not Listed
e) Skin Designation: [skin]

1) Indicates the potential for dermal absorption; skin exposure should be prevented as necessary through the use of good work practices and gloves, coveralls, goggles, and other appropriate equipment.

f) Note(s):

3) IDLH:

a) IDLH: 250 mg/m3
b) Note(s): Not Listed

C) Carcinogenicity Ratings for CAS121-75-5 :

1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): A4 ; Listed as: Malathion

2) EPA (U.S. Environmental Protection Agency, 2011): Not Assessed under the IRIS program. ; Listed as: Malathion
3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): 2A ; Listed as: Malathion

a) 2A : The agent (mixture) is probably carcinogenic to humans. The exposure circumstance entails exposures that are probably carcinogenic to humans. This category is used when there is limited evidence of carcinogenicity in humans and sufficient evidence of carcinogenicity in experimental animals. In some cases, an agent (mixture) may be classified in this category when there is inadequate evidence of carcinogenicity in humans and sufficient evidence of carcinogenicity in experimental animals and strong evidence that the carcinogenesis is mediated by a mechanism that also operates in humans. Exceptionally, an agent, mixture or exposure circumstance may be classified in this category solely on the basis of limited evidence of carcinogenicity in humans.

4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed ; Listed as: Malathion
5) MAK (DFG, 2002): Not Listed
6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

D) OSHA PEL Values for CAS121-75-5 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):

1) Listed as: Malathion (Total dust)
2) Table Z-1 for Malathion (Total dust):

a) 8-hour TWA:

1) ppm:

a) Parts of vapor or gas per million parts of contaminated air by volume at 25 degrees C and 760 torr.

2) mg/m3: 15

a) Milligrams of substances per cubic meter of air. When entry is in this column only, the value is exact; when listed with a ppm entry, it is approximate.

3) Ceiling Value:
4) Skin Designation: Yes
5) Notation(s): Not Listed

Toxicity Information

7.7.1)

A) Bingham et al, 2001 Budavari, 2000 Hartley & Kidd, 1990 Hayes & Laws, 1991 HSDB, 2002 ITI, 1995 Lewis, 2000 OHM/TADS, 2002 RTECS, 2002

1) LD50- (INTRAPERITONEAL)MOUSE:

a) 193 mg/kg
b) 420 mg/kg (Bingham et al, 2001)
c) 420-474 mg/kg (HSDB, 2002)
d) 985 mg/kg (Hayes & Laws, 1991)

2) LD50- (ORAL)MOUSE:

a) 190 mg/kg
b) 400-500 mg/kg (Hayes & Laws, 1991)
c) 1025 mg/kg (Bingham et al, 2001)
d) 4000 mg/kg (OHM/TADS, 2002)
e) 4059 mg/kg (Hayes & Laws, 1991; HSDB, 2002)

3) LD50- (SKIN)MOUSE:

a) 2330 mg/kg

4) LD50- (SUBCUTANEOUS)MOUSE:

a) 221 mg/kg -- reactivates cholinesterase

5) LD50- (INTRAPERITONEAL)RAT:

a) 250 mg/kg
b) 340 mg/kg (ITI, 1995)
c) 750 mg/kg (Bingham et al, 2001; Hayes & Laws, 1991; OHM/TADS, 2002)

6) LD50- (ORAL)RAT:

a) 290 mg/kg
b) 599 mg/kg (ITI, 1995)
c) male, 1375 mg/kg (Bingham et al, 2001; Budavari, 2000; Hayes & Laws, 1991; OHM/TADS, 2002)
d) female, 1000 mg/kg (Bingham et al, 2001; Hayes & Laws, 1991)
e) 1156 mg/kg (OHM/TADS, 2002)
f) 1400 mg/kg (Hayes & Laws, 1991; ITI, 1995)
g) 1401 mg/kg (Hayes & Laws, 1991)
h) 2800 mg/kg (Hartley & Kidd, 1990)
i) male, 2830 (Hayes & Laws, 1991; OHM/TADS, 2002)
j) male, 5843 mg/kg (Hayes & Laws, 1991; HSDB, 2002)
k) 8000 mg/kg (Hayes & Laws, 1991)
l) 10,700 mg/kg (Hayes & Laws, 1991)
m) 12,500 mg/kg (Hayes & Laws, 1991)

7) LD50- (SKIN)RAT:

a) 4100 mg/kg (Hartley & Kidd, 1990)
b) male, 4444 mg/kg (Hayes & Laws, 1991)
c) female, 4444 mg/kg (Hayes & Laws, 1991)
d) >4444 mg/kg

8) LD50- (SUBCUTANEOUS)RAT:

a) 400 mg/kg -- lacrimation; muscle contraction/spasticity; true cholinesterase
b) 1000 mg/kg (HSDB, 2002; Lewis, 2000)

9) TCLo- (INHALATION)RAT:

a) 2300 mcg/m(3) for 4H/13W-intermittent -- endocrine changes; changes in blood cell count; true cholinesterase

Pharmacology Toxicology

Pharmacologic Mechanism

Toxicologic Mechanism

1) GENERAL - ORGANOPHOSPHATES

a) CARDIOTOXICITY - Mechanisms may include sympathetic and parasympathetic over-activity, hypoxemia, acidosis, electrolyte derangements, and a direct toxic effect of the compounds on the myocardium. Another source reported 3 phases of cardiotoxicity after organophosphate exposure: Phase 1 - a short period of increased sympathetic tone; Phase 2 - a prolonged period of parasympathetic activity; Phase 3 - QT prolongation, torsade de pointes, ventricular tachycardia, and then ventricular fibrillation. Myocardial damage may occur due to sympathetic and parasympathetic over-activity (Karki et al, 2004).
b) ACUTE PANCREATITIS - Following organophosphate exposure, acute pancreatitis may be caused by acetylcholine release from pancreatic nerves and prolonged hyperstimulation of pancreatic acinar cells (Guloglu et al, 2004). Several cases of acute pancreatitis have been reported with the ingestion of malathion-containing pesticides (Hsiao et al, 1996; Zamir & Novis, 1994).

Physicochemical

Physical Characteristics

Ph

1) No information found at the time of this review.

Molecular Weight

Animal Toxicology

References

General Bibliography

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MALATHION

Classification | Detailed evidence-based information

Therapeutic Toxic Class

Specific Substances

Available Forms Sources

Life Support

Clinical Effects

Laboratory Monitoring

Treatment Overview

Range Of Toxicity

Endocrine

Immunologic

Reproductive

Carcinogenicity

Summary Of Exposure

Vital Signs

Heent

Cardiovascular

Respiratory

Neurologic

Gastrointestinal

Genitourinary

Dermatologic

Musculoskeletal

Genotoxicity

Monitoring Parameters Levels

Methods

Life Support

Patient Disposition

Monitoring

Oral Exposure

Inhalation Exposure

Eye Exposure

Dermal Exposure

Enhanced Elimination

Summary

Therapeutic Dose

Minimum Lethal Exposure

Maximum Tolerated Exposure

Serum Plasma Blood Concentrations

Workplace Standards

Toxicity Information

Pharmacologic Mechanism

Toxicologic Mechanism

Physical Characteristics

Ph

Molecular Weight

General Bibliography