Organophosphate poisoning
Poisoning from organophosphates causes cholinergic crisis and significant mortality.
Organophosphate poisoning results from exposure to organophosphates, compounds used as insecticides, medications, and nerve agents. It is one of the most common causes of poisoning worldwide, with nearly three million poisonings annually and about two hundred thousand deaths. The condition arises from inhibition of acetylcholinesterase, leading to acetylcholine accumulation and a range of cholinergic symptoms.
Quick Facts
- Field
- Emergency medicine
- Symptoms
- Increased saliva
- diarrhea
- small pupils
- muscle tremors
- confusion
- Onset
- Within 12 hours
- Causes
- Organophosphates
- Diagnosis
- Based on symptoms and confirmed by butyrylcholinesterase
- Differential
- Carbamate poisoning
- Prevention
- decreasing access
- Medication
- Atropine
- oximes
- diazepam
Facts from the source article.
Signs and symptoms
Symptoms include muscle weakness, fatigue, cramps, fasciculation, paralysis, hypertension, and hypoglycemia. Overstimulation of central nicotinic receptors produces anxiety, headache, convulsions, ataxia, respiratory and circulatory depression, tremor, general weakness, and potential coma. Muscarinic overstimulation causes visual disturbances, chest tightness, wheezing from bronchoconstriction, increased bronchial secretions, salivation, lacrimation, sweating, peristalsis, and urination. The mnemonics SLUDGEM (salivation, lacrimation, urination, defecation, gastrointestinal motility, emesis, miosis) and MUDDLES (miosis, urination, diarrhea, diaphoresis, lacrimation, excitation, salivation) describe muscarinic effects but omit CNS and nicotinic signs. Onset and severity depend on the specific chemical, exposure route, dose, and individual PON1 enzyme activity. Reproductive effects in males include poor semen quality, reduced seminal volume, decreased motility, and lower sperm count. In females, menstrual disturbances, longer pregnancies, spontaneous abortions, stillbirths, and developmental effects in offspring have been linked to OP exposure. Prenatal exposure is associated with impaired fetal growth and development, delayed mental development, pervasive developmental disorder, and morphological abnormalities in the cerebral surface.
Pathophysiology
Excess acetylcholine at nerve synapses and neuromuscular junctions underlies the health effects, as organophosphates inhibit acetylcholinesterase, the enzyme that normally breaks down acetylcholine. This inhibition may be reversible or irreversible depending on whether covalent bonding, termed aging, occurs. Organophosphates phosphorylate the serine hydroxyl residue on AChE, inactivating it and causing disturbances across cholinergic synapses; reactivation is very slow or absent. Paraoxonase 1 (PON1) is a key enzyme that can inactivate some OPs through hydrolysis, acting on active metabolites such as chlorpyrifos oxon, diazoxon, and nerve agents like soman, sarin, and VX. PON1 gene polymorphism leads to variation in enzyme levels and catalytic efficiency, influencing individual susceptibility. Higher plasma PON1 activity provides greater protection; rats injected with purified PON1 were more resistant to acute cholinergic activity, while PON1 knockout mice are more sensitive to pesticides like chlorpyrifos. The degree of protection depends on the compound and PON1's catalytic efficiency. PON1 activity is much lower in neonates, making them more sensitive. In 2006, up to a 13-fold variation in adult PON1 levels was observed, with similar variance in sensitivity to diazoxon.
Treatment
Current antidotes include pretreatment with carbamates to protect AChE and post-exposure anti-cholinergic drugs. Atropine, a muscarinic antagonist, is used with pralidoxime or other pyridinium oximes, though meta-analyses have found oximes to be of no benefit or possibly harmful. Atropine blocks peripheral acetylcholine action; these antidotes prevent lethality but may not prevent post-exposure incapacitation, performance deficits, or permanent brain damage. Clinical experience with pralidoxime has raised doubts about its efficacy. Enzyme bioscavengers, particularly human serum BChE (HuBChE), are being developed as pretreatments to sequester OPs before they reach targets. HuBChE offers broad protection against soman, sarin, tabun, and VX, has long retention in circulation, and does not provoke immunological responses. It is being assessed for inclusion in protective regimens. PON1 has potential for treating sarin exposure, but recombinant variants with higher catalytic efficiency are needed. Class III anti-arrhythmic agents are being researched because they block potassium currents in cardiac cells, relevant to OP-induced cardiac toxicity. Plasma alkalinisation lacks sufficient evidence to support its use.
Society and culture
Under a 1988 amendment to the Federal Insecticide, Fungicide and Rodenticide Act, the U.S. EPA regulates organophosphate pesticides, initially focusing on food crop uses. No pesticide may be sold in the United States without EPA review and a determination of no unreasonable risk. The 1996 Food Quality Protection Act required reassessment of all pesticide tolerances with consideration for children, leading to a 10-year review of health and environmental effects starting with organophosphates. In 1999, the EPA banned methyl parathion and restricted azinphos methyl on foods consumed by children. The review concluded in 2006, eliminating or modifying thousands of uses. Non-governmental groups, researchers, and the EPA's Office of Inspector General have expressed concerns that the review did not consider possible neurotoxic effects on fetuses and children. EPA scientists sent a letter to the administrator decrying the lack of developmental neurotoxicity data. Restrictions have been controversial; for example, in 1999 the EPA restricted household use of chlorpyrifos but not agricultural use, and it remains widely used. In 2013, the EPA requested comment on risks to children from volatilization of chlorpyrifos from treated crops.
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