- Azinphos-methyl (or -ethyl):
- Ethyl 4-Nitrophenyl Phenylphosphonothioate (EPN):
- Methyl parathion:
- Ronnel (Fenchlorphos):
- Tetraethyl pyrophosphate (TEPP):
- Clinical Findings:
- Intermediate Syndrome
The organophosphates (OPs) are derivatives of phosphoric or phosphonic acid. OPs have replaced the banned organochlorine compounds and are a major cause of animal poisoning. They vary greatly in toxicity, residue levels, and excretion. Many have been developed for plant and animal protection, and in general, they offer a distinct advantage by producing little tissue and environmental residue. Some of the OPs developed initially as pesticides are also used as anthelmintics. Five such compounds include dichlorvos, trichlorfon, haloxon, naphthalophos, and crufomate. The first two are primarily used against parasitic infestations in horses, dogs, and pigs; the latter three are used against parasites in ruminants.
Many of the OPs now used as pesticides (eg, chlorpyrifos, diazinon, fenitrothion, malathion, parathion, etc) are not potent inhibitors of cholinesterase until activated in the liver by microsomal oxidation enzymes; they are generally less toxic, and intoxication occurs more slowly. Certain OP preparations are microencapsulated, and the active compound is released slowly; this increases the duration of activity and reduces toxicity, but the toxic properties are still present.
Carbophenothion has been used as a spray for fruit trees and as a dip or spray for sheep blowfly, keds, and lice. Dairy calves <2 wk old sprayed with water-based formulations showed poisoning at concentrations ≥0.05%, and adult cattle were poisoned by spraying with 1%. Sheep and goats have been poisoned by 22 mg/kg, PO, but not by 8 mg/kg. In sheep, 0.1% as a dip produces no signs of poisoning. The LD50 for rats is ~31 mg/kg; a daily dosage of 2.2 mg/kg for 90 days produced poisoning. Dogs tolerated a diet containing 32 ppm for 90 days. A single application of a powder containing 1% of carbophenothion is lethal to cats.
The oral LD50 is 500 mg/kg in goats and 941 mg/kg in rats. In comparison with calves, steers, and cows, bulls (particularly of the exotic breeds) are highly susceptible to a single dose of chlorpyrifos. The maximum tolerated dose of chlorpyrifos in sheep is 750 mg/kg. Sheep given 850 mg/kg died 5 days after dosing, those given 900 mg/kg died on the third day, and a dose of 1,000 mg/kg was lethal within 30 hours. Onset of poisoning signs is usually delayed compared with that of many other commonly used organophosphates because of the conversion of chlorpyrifos to the active cholinesterase inhibitor chlorpyrifos-oxon. Chlorpyrifos produces reproductive and developmental toxicity.
Coumaphos is used against cattle grubs and a number of other ectoparasites and for treatment of premises. The maximum concentration that may be safely used on adult cattle, horses, and pigs is 0.5%. Young calves and all ages of sheep and goats must not be sprayed with concentrations >0.25%; 0.5% concentrations may be lethal. Adult cattle may show mild toxicity at 1% concentrations. The minimum lethal dose for calves appears to be between 10 and 40 mg/kg. A dose of 25 mg/kg is usually fatal in sheep. The oral LD50 in rats is 13 mg/kg.
Crotoxyphos is used as a spray or powder for the control of ectoparasites on cattle and pigs. Crotoxyphos is of rather low toxicity; however, Brahman cattle are markedly more susceptible than European breeds. Cattle (except as above), sheep, goats, and pigs all tolerate sprays containing crotoxyphos at 0.5% levels or higher. Crotoxyphos is safe at a level of 1%, although skin lesions have been found in pigs. Toxic doses appears to be in the 2% range, except for in Brahman cattle, in which 0.144%–0.3% may be toxic.
Demeton is used as a systemic insecticide against sucking insects and mites. Demeton is used mainly as a foliage spray and has a relatively long residual life. It is a mixture of demeton-O and demeton-S and is highly toxic to mammals. The oral LD50 is 8 mg/kg in goats and 2 mg/kg in rats; the dermal LD50 in rats and rabbits is 8 mg/kg. Demeton-O poisoning developed in several hundred cattle grazing near cotton treated with this insecticide. The corresponding analogues of demeton (demeton-O-methyl and demeton-S-methyl) are also used for similar purposes but are less toxic than demeton.
Young calves appear to tolerate 0.05% spray but are poisoned by 0.1% concentrations. Adult cattle may be sprayed at weekly intervals with 0.1% concentrations without inducing poisoning. Young calves tolerate 0.44 mg/kg, PO, but are poisoned by 0.88 mg/kg. Cattle tolerate 8.8 mg/kg, PO, but are poisoned by 22 mg/kg. Sheep tolerate 17.6 mg/kg but are poisoned by 26 mg/kg. The oral LD50 in rats is 300 mg/kg, and the dermal LD50 in rabbits is 379 mg/kg.
Dichlorvos has many uses on both plants and animals. It is rapidly metabolized and excreted, and residues in meat and milk are not a problem if label directions are followed. It is of moderate toxicity, with a minimum toxic dose of 10 mg/kg in young calves and 25 mg/kg in horses and sheep. The oral LD50 in rats is 25 mg/kg, PO, and the dermal LD50 in rabbits is 59 mg/kg. A 1% dust was not toxic to cattle. Flea collars containing dichlorvos may cause skin reactions in some pets. Cats wearing dichlorvos-impregnated collars can develop signs of ataxia-depression syndrome, followed by death.
Dimethoate is used extensively in horticulture as a systemic insecticide, but it also kills insects by contact. When administered PO, the minimum toxic dose for young dairy calves was ~48 mg/kg, while 22 mg/kg was lethal for cattle 1 yr old. Daily doses of 10 mg/kg for 5 days in adult cattle lowered blood cholinesterase activity to 20% of normal but did not produce poisoning. Horses have been poisoned by doses of 60–80 mg/kg, PO. When applied topically, 1% sprays have been tolerated by calves, cattle, and adult sheep. The oral LD50 in rats is 215 mg/kg, and the dermal LD50 in rabbits is 400 mg/kg.
Dioxathion is a nonsystemic acaricide and insecticide for the control of ticks. Dioxathion is a mixture of cis- and trans-isomers, usually in the ratio of 1:2. The cis-isomer is more toxic than the trans-isomer. Used on both plants and animals, it is rapidly metabolized and not likely to produce residues in meat greater than the 1 ppm official tolerance. Concentrations of ≥0.15% are generally used on animals. The minimum toxic dose in calves is 5 mg/kg. Sprays of 0.5% in cattle and sheep or 0.25% in goats and pigs are nontoxic. Sprays at concentrations up to 0.1% are usually safe for calves and lambs. Twice this concentration may produce signs of poisoning. Dioxathion at 8.8 mg/kg, PO, has killed young calves, and it produced intoxication at 4.4 mg/kg. Emaciated cattle with severe tick infestation are more frequently poisoned than healthy animals. Maximum residues of dioxathion in adipose tissue of cattle occur 2–4 days after dipping. The elimination half-life, after obtaining maximum concentrations, is ~16 days.
The maximum nontoxic oral dose is 0.88 mg/kg for young calves, 2.2 mg/kg for cattle and goats, and 4.8 mg/kg for sheep. Poisoning has occurred in cattle after consuming harvested forages previously sprayed with this insecticide. The oral LD50 in rats is 2 mg/kg, and the dermal LD50 in rabbits is 6 mg/kg. Chronic exposure to disulfoton may result in tolerance to toxicity.
EPN is a nonsystemic insecticide and acaricide structurally related to parathion. The acute oral LD50 in rats is 8–36 mg/kg. EPN at a dosage of 10 mg/kg was found to be nontoxic to adult cattle and sheep. The minimum oral toxic dose of EPN is 2.5 mg/kg in calves and 25 mg/kg in sheep and yearling cattle. Sprays containing 0.025%–0.05% EPN are toxic to young calves, and 0.25% EPN is lethal. Dogs were not poisoned at dosages >100 mg/kg.
The oral LD50 in rats is 35 mg/kg, and the dermal LD50 in rabbits is 2,730 mg/kg. The maximum nontoxic dose is 10 mg/kg in calves and 50 mg/kg in cattle, sheep, and horses. In general, Brahman cattle are especially susceptible to famphur toxicity. This compound is effective against warbles in cattle, but (as for all grubicides) directions must be followed as to time of application; larvae killed while migrating and the resultant local reaction can cause serious problems. In several instances, famphur poisoning occurred in birds (mainly magpies and robins) shortly after cattle had been treated with a pour-on preparation containing famphur.
Fenitrothion, also known as sumithion, is used as a contact insecticide in agriculture and horticulture. The oral LD50 in rats is 250 mg/kg, and the dermal LD50 in rabbits is 1,300 mg/kg. When applied to cattle, its metabolites are excreted at low levels in milk and urine. Fenitrothion produces reproductive and developmental toxicity in chickens.
Malathion is one of the safest organophosphates because of its selective toxicity; it is highly toxic to insects but much less toxic to mammalian species. The oral LD50 in rats is 885 mg/kg, and the dermal LD50 in rabbits is 4,000 mg/kg. The oral acute toxic dose in calves is 10–20 mg/kg and in adult cattle and sheep is 50–100 mg/kg. In a chronic study in buffalo calves (6–9 mo old), daily oral administration of malathion at 0.5 mg/kg for 1 yr produced no biochemical or clinical effects. Dosages >1 mg/kg inhibited blood acetylcholinesterase (AChE) activity and increased liver enzymes (ALT and AST). A 20 mg/kg dose produced clinical signs after 10 days. The acute oral LD50 in buffalo calves is 53 mg/kg. Dermal application by spray containing 0.5% or 1% of malathion had no apparent effect on calves, but 5% spray caused death within 75 hr. Malathion at 0.5% or 1% should not be sprayed on calves for more than 3 consecutive days. Malathion is excreted in cow’s milk.
Methyl parathion is less toxic than parathion (diethyl parathion). The LD50 in rats from a single oral dose is 9–25 mg/kg, and the dermal LD50 in rabbits is 63 mg/kg. Methyl parathion at 2.5 mg/kg had no ill effect, but 10 mg/kg daily quickly led to toxic signs. The lethal dose in cattle is 100 mg/kg. Methyl parathion is excreted in cow’s milk. Methyl parathion produces reproductive and developmental toxicity.
Naled is essentially a dibrominated dichlorvos, which has the ability to act as a contact insecticide. It has a broad spectrum of insecticidal action. Because it has a short residual life, it poses relatively little hazard to fish and wildlife. The oral LD50 in rats is 191 mg/kg, and the dermal LD50 in rabbits is 390 mg/kg.
Parathion (diethyl parathion) is widely used for control of plant pests and is approximately one-half as toxic as tetraethyl pyrophosphate (see Tetraethyl pyrophosphate (TEPP)). The oral LD50 in rats is 3 mg/kg, and the dermal LD50 in rabbits is 6.8 mg/kg. It is used as a dip and spray for cattle in some countries (not in the USA). Most cases of occupational insecticide poisonings in people have been attributed to parathion or its degradation products. The minimum toxic dose in calves is 0.25–0.5 mg/kg and in cattle is 25–50 mg/kg. The minimum oral lethal dose in sheep is 20 mg/kg and in goats is 50 mg/kg. The LD50 in dogs is 23–35 mg/kg and in cats is 15 mg/kg. Dermal sprays containing 0.02%, 1%, and 1% of parathion are lethal to calves, sheep, and goats, respectively. Parathion is used extensively to control mosquitoes and insects in orchards and on market garden crops. Normally, because so little is used per acre, it presents no hazard to livestock. However, because of the potency of parathion, care should be taken to prevent accidental exposure. Parathion does not produce significant residues in animal tissues.
Phorate is closely related to demeton (see Demeton). It is a systemic insecticide and miticide. The oral LD50 in rats is 1.6 mg/kg, and the dermal LD50 in rabbits is 2.5 mg/kg. The minimum toxic dose PO is 0.25 mg/kg in calves, 0.75 mg/kg in sheep, and 1 mg/kg in cattle.
Ronnel is an excellent oral systemic insecticide. It is effective against many ecto- and endoparasitic arthropods, including cattle grubs, screw worms, and sucking lice. Ronnel is also used as a residual spray insecticide to control flies, fleas, and cockroaches. The oral LD50 in rats is 1,250 mg/kg, and the dermal LD50 in rabbits is 2,000 mg/kg. Ronnel produces mild signs of poisoning in cattle at 132 mg/kg, but severe signs do not appear until the dosage is >400 mg/kg. The minimum toxic dose in sheep is 400 mg/kg. Concentrations as high as 2.5% in sprays have failed to produce poisoning of cattle, young dairy calves, or sheep. Poisoning usually occurs in two stages. The animal first becomes weak and, although able to move about normally, may be placid. Diarrhea, often flecked with blood, may also be seen. Salivation and dyspnea then appear if the dose was high enough. Blood cholinesterase activity declines slowly over 5–7 days. Ronnel produces residues in meat and milk; strict adherence to label restrictions is essential. The residues may be removed by giving the animal activated charcoal for several days.
Ruelene is active both as a systemic and contact insecticide in livestock, has some anthelmintic activity, and has rather low toxicity. Dairy calves have been poisoned by 44 mg/kg, PO, while adult cattle require 88 mg/kg for the same effect. Sheep are moderately intoxicated by 176 mg/kg; Angora goats are about twice as sensitive. Pigs have been poisoned by 11 mg/kg and horses by 44 mg/kg. Most livestock tolerate a 2% topical spray.
Temephos is used as an insecticide against mosquitoes and midges. It is of low toxicity to mammalian species. The oral LD50 for rats is 1 g (or more)/kg, while the dermal LD50 is >4 g/kg. Daily exposure of cattle for 1 yr at 1–1.5 mg/kg is known to produce clinical signs of poisoning and affect fertility in heifers.
Trichlorfon is used as a systemic insecticide and anthelmintic in domestic animals. It is also used as an acaricide in sheep at the dose rate of 80 mg/kg at weekly intervals for not more than 4 wk. The oral LD50 in rats is 630 mg/kg, and the dermal LD50 in rabbits is >2,000 mg/kg. As a spray, trichlorfon at a 1% concentration is tolerated by adult cattle; given PO, it is tolerated by young dairy calves at 4.4 mg/kg but produces poisoning at 8.8 mg/kg. Adult cattle, sheep, and horses appear to tolerate 44 mg/kg, while 88 mg/kg produces poisoning. Dogs were unaffected when fed 1,000 ppm of trichlorfon for 4 mo. Administration of trichlorfon at 75 mg/kg, PO, produces adverse clinical signs in dogs. Trichlorfon is metabolized rapidly.
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 increased bronchial secretions and bronchoconstriction. Nicotinic effects include muscle fasciculations and weakness. The central effects include nervousness, ataxia, apprehension, and seizures. Cattle and sheep commonly show severe depression. CNS stimulation in dogs and cats usually progresses to convulsions. Some OPs (eg, amidothioates) do not enter the brain easily, so that 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 dosage 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 acetylcholinesterase (AChE) activity in blood and brain. Unfortunately, the depression of blood cholinesterase does not necessarily correlate with the severity of poisoning; signs are seen when brain AChE activity is inhibited >70%, and the enzyme in blood reflects, only in a general way, the levels in nervous tissue. The key factors appear to be the degree and rate at which the enzyme activity is reduced. Analyses performed after exposure may be negative, because OPs do not remain long in tissues as the parent compounds. Chlorinated OP compounds have greater potential for tissue residue. Frozen stomach and rumen contents should be analyzed for the pesticide, using GC-MS for identification, confirmation, and quantitation. Blood/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: 1) muscarinic receptor–blocking agents, 2) cholinesterase reactivators, and 3) 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 hr or as often as clinical signs indicate. For horses and pigs, the dosage is 0.1–0.2 mg/kg, IV, repeated every 10 min 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. Including diazepam in the treatment reduced the incidence of seizures and increased survival of nonhuman primates experimentally.
An improved treatment combines atropine with the cholinesterase-reactivating oxime, 2-pyridine aldoxime methochloride (2-PAM, pralidoxime chloride). The dosage of 2-PAM is 20–50 mg/kg, given as a 5% solution IM or by slow IV (over 5–10 min), repeated at half the dose as needed. IV 2-PAM must be given very slowly to avoid musculoskeletal paralysis and respiratory arrest. Response to cholinesterase reactivators decreases with time after exposure; therefore, treatment with oximes must be instituted as soon as possible (within 24–48 hr). The rate at which the enzyme/organophosphate complex becomes unresponsive to reactivators (due to ageing phenomenon) varies with the particular pesticide.
Removal of the poison from the animal also should be attempted. If exposure was dermal, the animal should be washed with detergent and water (about room temperature) but without scrubbing and irritating the skin. Emesis should be induced if oral exposure occurred <2 hr previously; emesis is contraindicated if the animal is depressed. Oral administration of mineral oil decreases absorption of pesticide 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.
Organophosphate-induced intermediate syndrome (IMS) has been seen in people and animals (particularly dogs and cats) acutely poisoned with a massive dose of an OP insecticide. OPs known to cause IMS include bromophos, chlorpyrifos, diazinon, dicrotophos, dimethoate, disulfoton, fenthion, malathion, merphos, methamidophos, methyl parathion, monocrotophos, omethoate, parathion, phosmet, and trichlorfon. Clinically, IMS is characterized by acute paralysis and weakness in the areas of several cranial motor nerves, neck flexors, and facial, extraocular, palatal, nuchal, proximal limb, and respiratory muscles 24–96 hr after poisoning. IMS is a separate clinical entity from acute toxicity and delayed neuropathy. Generalized weakness, depressed deep tendon reflexes, ptosis, and diplopia are also evident. These symptoms may last for several days or weeks depending on the OP involved. Although the exact mechanism of action involved in IMS in unclear, the defect occurs at the neuromuscular junction (decreased AChE activity and expression of nicotinic receptors). Despite AChE inhibition, muscle fasciculations and hypersecretory activities are absent. There is no specific treatment; therapy relies on atropine sulfate and 2-PAM and should be continued for weeks.