Organophosphate Toxicosis in Animals

The toxicity of OP and carbamate insecticides is due to inhibition of the AChE enzyme within the nervous tissue and at the neuromuscular junction. The OPs inhibit AChE irreversibly by phosphorylation, and carbamates inhibit AChE reversibly by carbamylation. As a result of AChE inhibition, accumulation of acetylcholine (ACh) occurs, which overstimulates muscarinic ACh receptors (mAChRs) and nicotinic ACh receptors (nAChRs). Overstimulation of these receptors leads to signs of hypercholinergic preponderance, such as hypersecretions (salivation, lacrimation, urination, and diarrhea), convulsions, and muscle fasciculations. Seizures and death ensue due to noncholinergic mechanisms involving hyperstimulation of N-methyl-D-aspartate (NMDA) receptors, adenosinergic, gamma-aminobutyric acid (GABA-ergic), monoaminergic systems, and others. The persistence of excitotoxicity for more than an hour can lead to oxidative and nitrosative stress, neuroinflammation and neurodegeneration in the cortex, amygdala, and hippocampus, which are areas of the brain primarily involved in initiation and propagation of convulsions and seizures. Finally, death occurs due to respiratory failure.

In general, OP pesticides have a narrow margin of safety, and the dose-response curve is quite steep. Signs of OP poisoning are those of cholinergic overstimulation, which can be grouped into three categories: muscarinic, nicotinic, and central.

Muscarinic signs, which are usually first to appear, include hypersalivation, miosis, frequent urination, diarrhea, vomiting, colic, and dyspnea due to bronchoconstriction and increased bronchial secretions.

Nicotinic effects include muscle fasciculations and weakness.

The central effects include nervousness, ataxia, apprehension, and seizures. Cattle and sheep commonly show severe CNS depression. In dogs and cats, CNS stimulation usually progresses to convulsions. Some OPs (eg, amidothioates) do not enter the brain easily, so CNS signs are mild.

Onset of signs after exposure is usually within minutes to hours but may be delayed for >2 days in some cases. Severity and course of intoxication is influenced principally by the dose and route of exposure. In acute poisoning, the primary clinical signs may be respiratory distress and collapse, followed by death due to respiratory muscle paralysis. In addition to brain and skeletal muscles, OPs are known to adversely affect other organ systems, including the cardiovascular, respiratory, hepatic, reproductive and developmental, and immune systems.

An important diagnostic aid for OP poisoning is the determination of AChE activity in blood and brain. Unfortunately, the degree of decrease in blood AChE activity does not necessarily correlate with the severity of poisoning. Clinical signs are observed when brain AChE activity is inhibited >70%. The key factors appear to be the degree and rate at which the AChE activity is reduced. Neither OPs or their metabolites persist in the body for more than 24 hours. Chlorinated OP compounds have a greater potential for tissue residue. Frozen stomach and rumen contents should be analyzed for the pesticide residue by use of gas chromatography–mass spectrometry (GC-MS) for identification, confirmation, and quantitation. Blood or serum and urine can also be analyzed for residue of OPs or their metabolites. More than 70% of OPs produce one or more of the six dialkylphosphates (dimethyl phosphate, diethyl phosphate, dimethyl thiophosphate, diethyl thiophosphate, dimethyl dithiophosphate, and diethyl dithiophosphate).

Three categories of drugs are used to treat OP poisoning:

• Muscarinic receptor–blocking agents

• Cholinesterase reactivators

• Emetics, cathartics, and adsorbents to decrease further absorption

Atropine sulfate blocks the central and peripheral muscarinic receptor–associated effects of OPs. It is administered to effect in dogs and cats, usually at a dosage of 0.2–2 mg/kg (cats at the lower end of the range), every 3–6 hours or as often as clinical signs indicate. For horses and pigs, the dosage is 0.1–0.2 mg/kg, IV, repeated every 10 minutes as needed; for cattle and sheep, the dosage is 0.6–1 mg/kg, one-third given IV, the remainder IM or SC, and repeated as needed. Atropinization is adequate when the pupils are dilated, salivation ceases, and the animal appears more alert. Animals initially respond well to atropine sulfate; however, the response diminishes after repeated treatments. Overtreatment with atropine should be avoided. Atropine does not alleviate the nicotinic cholinergic effects, such as muscle fasciculations and muscle paralysis, so death from massive overdoses of OPs can still occur. Experimentally, inclusion of diazepam in the treatment was shown to reduce the incidence of seizures and increase survival rate in nonhuman primates.

An improved treatment combines atropine with the cholinesterase-reactivating oxime pralidoxime chloride, or 2-pyridine aldoxime methochloride (2-PAM). The dosage of 2-PAM is 20–50 mg/kg, given as a 5% solution IM or by slow IV (over 5–10 minutes), repeated at half the dose as needed; 2-PAM should be administered IV at a very slow rate. Response to AChE reactivators decreases with time after exposure. Therefore, treatment with oximes must be instituted as soon as possible (within 24–48 hours). The rate at which the AChE-OP complex becomes unresponsive to reactivators (due to the aging phenomenon) varies with the particular OP pesticides.

Removal of the poison from the animal also should be attempted as soon as possible. If exposure was dermal, the animal should be washed with detergent and room-temperature water but without scrubbing and irritating the skin. Emesis should be induced if oral exposure occurred < 2 hours previously; emesis is contraindicated if the animal is showing neurologic signs (CNS depression or convulsions). Oral administration of mineral oil decreases absorption of insecticides from the GI tract. Activated charcoal (1–2 g/kg as a water slurry) adsorbs OPs and helps elimination in the feces. This is particularly recommended in cattle. Continued absorption of OPs from the large amount of ingesta in the rumen has caused prolonged toxicosis in cattle. Artificial respiration or administration of oxygen may be required. Phenothiazine tranquilizers, barbiturates, and morphine are contraindicated.