Methamidophos 51

most patients. Cases of edema have been described. Methadone appears to increase prolactin levels and can lead to gynecomastia.

In Vitro Toxicity Data

In Drosophila studies, methadone has not been shown to be mutagenic.

other opioid antagonists, with limited usefulness, similar to naloxone but with longer half-life and may be considered as an alternative to naloxone. The duration of naloxone effect is much shorter than that of methadone and relapse of opioid symptoms are common. For this reason naloxone infusion may be necessary and symptomatic patients should be monitored for 2 days.

Clinical Management
Activated charcoal is the preferred method of decontamination. The use of syrup of ipecac is contraindicated because of the potential for serious CNS and respiratory depression. Naloxone, a specific opioid antagonist, should be used to reverse signicant respiratory depression. Nalmefene and naltroxone are

See also: Heroin; Morphine.

Further Reading
Wolff K (2002) Characterization of methadone overdose: Clinical considerations and the scientific evidence. Therapeutic Drug Monitoring 24(4): 457470.

Methamidophos
Kevin N Baer
& 2005 Elsevier Inc. All rights reserved.
*

CHEMICAL ABSTRACTS SERVICE REGISTRY NUMBER: CAS 10265-92-6 SYNONYMS: O,S-Dimethyl phosphoramidothioate; Tamaron; Tamanox; Monitor; Acephate-met CHEMICAL/PHARMACEUTICAL/OTHER CLASS: Organophosphorus insecticide CHEMICAL STRUCTURE:
CH3O O P CH3S NH2

of methamidophos (replacement of covalent sulfur with oxygen) is accomplished primarily by liver microsomal enzymes. A variety of hydrolysis reactions to alkyl phosphates and various leaving groups can occur. Methamidophos is fairly well distributed throughout the tissues, with marked accumulation in the liver, kidney, and adipose tissue. Excretion in the urine is the major elimination pathway. Methamidophos is formed from biotransformation of another organophosphorus insecticide, acetphate.

Mechanism of Toxicity
Methamidophos is a potent, direct acetylcholinesterase inhibitor that acts by interfering with the metabolism of acetylcholine. As a result, acetylcholine accumulates at neuroreceptor transmission sites. Some evidence suggests that biotransformation of methamidophos may produce a more potent anticholinesterase.

Uses
Methamidophos is used as an insecticide and acaricide. In the United States, cotton, potatoes and tomatoes are the principal crops for methamidophos use.

Exposure Routes and Pathways

Poisonings can occur from inhalation, skin absorption, or ingestion.

Acute and Short-Term Toxicity (or Exposure)

Animal

Toxicokinetics
Methamidophos can be readily absorbed through the skin, lung, and gastrointestinal tract. The bioactivation

Methamidophos has high mammalian toxicity. The oral LD50 value in rats is B20 mg kg 1. Dermal LD50 values in rats and rabbits are about 100 mg kg 1. The no-observed-adverse-effect level (NOAEL) from an acute neurotoxicity study based

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Methamidophos

on inhibition of plasma, erythrocyte, and brain cholinesterase in rats was 0.3 mg kg 1 day 1.
Human

Classic signs of acute toxicity include pinpoint pupils, muscular fasciculations, slow pulse, excessive salivation and lacrimation, and gastrointestinal symptoms (nausea, abdominal cramps, diarrhea, and loss of sphincter control). In severe cases, convulsions, coma, and heart block are common. Death is generally attributed to respiratory insufciency caused by the combination of respiratory center depression, paralysis, and increased bronchial secretions. In children, the classic signs described previously may be infrequent, with the major symptoms being central nervous system depression, stupor, accidity, dyspnea, seizures, and coma.

establishment and maintenance of adequate airway and ventilation. Atropine sulfate in conjunction with 2-PAM (PAM, Pralidoxime) can be administered as an antidote. Atropine by intravenous injection is the primary antidote in severe cases. Test injections of atropine (1 mg in adults and 0.15 mg kg 1 in children) are initially administered, followed by 2 4 mg (in adults) or 0.0150.05 mg kg 1 (in children) every 1015 min until cholinergic signs (e.g., diarrhea, salivation, and bronchial secretions) decrease. High doses of atropine over several injections may be necessary for effective control of cholinergic signs. If lavage is performed, endotracheal and/or esophageal control is suggested. At rst signs of pulmonary edema, the patient should be placed in an oxygen tent and treated symptomatically.

Chronic Toxicity (or Exposure)

Animal

Ecotoxicology
Methamidophos may cause harm to nontarget species with approved applications. Field studies indicate bird mortality can occur with methamidophos use. Methamidophos residues on food that birds may eat (e.g., leaves, insects, invertebrates) show high acute and persistent exposure. In addition, residue data on food that wild mammals may eat indicate that there would be sufcient persistent residues to cause adverse chronic effects. Methamidophos is highly toxic to bees and some benecial insects. Freshwater and estuarine invertebrate aquatic species may be affected with normal use of methamidophos but acute risks to sh are minimal.

Methamidophos can cause delayed neurotoxicity in hens. The NOAEL from a long-term dosing study in rats was 0.03 mg kg 1 day 1 based on brain cholinesterase inhibition.
Human

Cholinesterase inhibition may persist for 26 weeks. Signs of delayed neuropathy in humans have been reported following dermal and/or inhalation exposures. Progressive distal weakness, ataxia, accid paralysis, or quadriplegia may ensure. Additional chronic toxicities, such as memory impairment, language defects (slowed speech and slurring), and behavior disorders have been reported.

Exposure Standards and Guidelines

The acute reference dose is 0.001 mg kg 1 and the chronic reference dose is 0.0001 mg kg 1 day 1.

Clinical Management
For exposure to eyes, eyelids should be held open and the eyes ushed with copious amounts of water for 15 min. For exposure to skin, affected areas should be washed immediately with soap and water. Medical attention is necessary if irritation develops and persists. For exposure through inhalation, the victim should be removed to fresh air and, if not breathing, given articial ventilation. The victim should receive medical attention as soon as possible. For ingestion victims, vomiting should be induced, keeping in mind the possibility of aspiration of solvents. Gastric decontamination should be performed within 30 min of ingestion to be most effective. Initial management of acute toxicity is

See also: Cholinesterase Inhibition; Organophosphates; Pesticides.

Further Reading
Gallo MA and Lawryk NJ (1991) Organic phosphorus pesticides. In: Hayes WJ Jr. and Laws ER Jr. (eds.) Handbook of Pesticide Toxicology, vol. 3, pp. 917972, 1090. San Diego: Academic Press.

Relevant Website
http://www.epa.gov United States Environmental Protection Agency.