Organic Chemical Neurotoxicities

Organophosphates and Carbamates

Etiology and Epidemiology

Organophosphate and carbamate pesticides are commonly found on farms. They are used to treat livestock for internal and external parasites, and to protect soil and crops from insect pests.

Pathogenesis

Organophosphates and carbamates exert their toxic effects by competitive inhibition of acetylcholinesterase, the enzyme ordinarily responsible for the degradation of the neurotransmitter acetylcholine. This inhibition leads to accumulation of acetylcholine at neuromuscular junctions,

Table 5.6 Toxicity of some organophosphate, carbamate, and chlorinated hydrocarbon insecticides for goats.

autonomic ganglia, and effector cells, and causes an increased, prolonged stimulation of skeletal muscle, the entire parasympathetic nervous system, and the postgangli­onic cholinergic nerves of the sympathetic system.

In sheep, a delayed neurotoxicity caused by the organo­phosphate anthelmintic haloxon is recognized. The patho­genesis of delayed neurotoxicity is believed to involve an inherited esterase deficiency in Suffolk sheep. A distal axonopathy with dying back of neurons, particularly long axons in the spinal cord, develops several weeks after administration of haloxon. The clinical picture is one of progressive, symmetrical, spastic paresis of the hindlimbs. This syndrome was suspected in Angora goats, but no addi­tional documentation has emerged (Wilson et al. 1982).

Clinical Findings

The clinical signs of acute toxicity in goats are similar to those seen in other species, and include restlessness, froth­ing at the mouth, dyspnea, tremors, frequent urination and defecation, bloat, head pressing, teeth grinding, lacrima­tion, staggering gait, intermittent convulsions, paresis, and, finally, recumbency and death (Mohamed et al. 1989, 1990).

Clinical Pathology and Necropsy

Identifying a marked decrease in acetylcholinesterase activity in blood supports the diagnosis of organophos­phate and carbamate poisoning. Sample submission requirements of the receiving laboratory should be con­firmed before submitting samples. Based on the testing methodology employed, whole blood in heparin, whole blood in ethylenediaminetetraacetic acid (EDTA), sepa­rated serum, or heparanized plasma may be the preferred sample. When carbamates are suspected, blood must be refrigerated immediately and tested as soon as possible, because inhibition of acetylcholinesterase by carbamate is reversible. The laboratory should be notified of your suspi­cion of carbamates, so that test methods that require dilu­tion of the sample are not used. Samples of tissue, rumen content, blood, and urine can also be taken for direct detec­tion of the insecticides involved. Given the potential costs, these samples can be held pending the results of acetylcho­linesterase activity, which, if below the laboratory’s refer­ence interval, suggests organophosphate or carbamate toxicity.

Detection of dialkyl phosphates in the urine of goats proved to be a reliable indicator of exposure to diazinon over a range of challenge doses (Mount 1984). The test was more sensitive than measurement of blood cholinesterase activity in goats not showing clinical signs of toxicity.

There are no specific necropsy findings in organophos­phate or carbamate poisoning. Chemical analysis of tissues is often unrewarding, because organophosphate and carba­mate insecticides are rapidly metabolized. Analysis of stomach or rumen content, suspected feeds, or other for­mulations for insecticide content is preferred.

Diagnosis

Diagnosis is based on the characteristic signs of acute toxi­cosis in conjunction with documentation of decreased or absent acetylcholinesterase activity. In the absence of labo­ratory support, a favorable clinical response to atropine or oxime therapy supports the diagnosis. Other acute poison­ings, such as cyanide, nitrate, and urea toxicosis, and ana­phylactic reactions must be considered in the differential diagnosis. The pyrethroid insecticide fenvalerate has been shown to produce clinical signs suggestive of organophos­phate toxicosis when administered orally to Nubian goats at doses more than 112.5 mg/kg (Mohamed and Adam 1990).

Treatment and Control

Treatment can be successful, especially with early inter­vention. The treatment of choice to counteract signs of toxicosis is atropine sulfate given at a dose of 0.6-1 mg/kg bw. One-fourth to one-third the total dose should be given IV and the remainder SC or IM. The higher end of the dose range can be used in severe cases. Repeated dosing may be necessary every four to five hours for as long as two days in severe cases, but dosage should be cut back when possible to avoid serious bloat.

Oximes, such as trimedoxime bromide, 2-pyridine aldoxime methiodide (2-PAM), and pralidoxime chlo­ride, will free acetylcholinesterase from organophos - phate, but not from carbamate complexes. They are particularly useful in combination with atropine for the treatment of coumaphos, ronnel, dimethoate, and crufo - mate toxicity, where atropine alone is not always effec­tive (Osweiler et al. 1984). The use of these drugs in goals is not reported. In other ruminants, recommended doses are as follows: 2-PAM, 50-100 mg/kg bw; trimedoxime bromide, 10-20 mg/kg bw; and pralidoxime chloride, 20 mg/kg bw IV.

When poisoning is by the oral route, oral administration of 1 g/kg bw activated charcoal per adult goat by orogastric tube may help to reduce the additional uptake of insecti­cide. When exposure is dermal, washing animals with soap and water helps to reduce additional absorption. Handlers should wear masks and rubber gloves. Control of these toxicoses is difficult, because most outbreaks involve acci­dental exposure. Certainly, these chemicals should be han­dled with respect and used only according to directions. They should be stored securely where animal contact is impossible.

Chlorinated Hydrocarbons

Etiology and Epidemiology

These insecticide compounds, also known as organochlo- rines, have been used widely in agriculture for treatment of soils, water supplies, crops, seeds, and livestock. Methoxychlor, lindane, dichlorodiphenyltrichloroethane (DDT), aldrin, dieldrin, chlordane, and toxaphene are com­mon examples. Use of these insecticides directly on live­stock is increasingly restricted due to environmental and public health concerns. Nevertheless, accidental exposures and inappropriate use still lead to toxicities in livestock, including goats. Information on toxic doses of various chlorinated hydrocarbons for goats is given in Table 5.6. Because goats are used for both meat and milk production, the potential for relay toxicity to humans from consump­tion of goat products is similar to that from cattle.

Pathogenesis

The pathogenesis of toxicity for these compounds is not completely known and may be different for each. At least for chlorophenothane, the compound acts on axonal mem­branes to prolong the depolarized state by interfering with sodium influx and potassium efflux. Poisoning can occur by single large-dose exposure or chronic lower-dose expo­sure, due to the ability of these insecticides to accumulate in tissues. Absorption of these chemicals can occur through the skin, or by oral ingestion, aspiration, or inhalation. Neurologic signs in all cases are the usual clinical manifestation.

Clinical Findings

Clinical signs are similar in all species. Hypersensitivity, apprehension, and/or aggressiveness are frequent early signs, followed by fasciculation of muscles, especially in the head and neck, that extends to muscular spasms over the entire body. Snapping of the eyelids and continuous chewing or teeth grinding are common, sometimes with excessive salivation. Moderate bloating may occur. Loss of coordination with staggering gait, aimless wandering, or circling may be observed. Severe and prolonged convul­sions frequently develop. It is not unusual for animals to have a high fever due to seizure activity. Though animals may die during convulsions, death is usually preceded by terminal coma.

The severity of signs is to some extent dose dependent. Experimental poisoning with aldrin at a daily oral dose of 2.5 mg/kg bw led to clinical signs of depression, anorexia, teeth grinding, salivation, staggering gait, and hypersensi­tivity in one goat after 18 days of dosing, but no signs of toxicity in three others (Singh et al. 1985). Goats given daily aldrin orally at a dose of 20 mg/kg showed signs of hyper­excitability, incoordination of movement, muscle tremors, and convulsions by the ninth day of dosing, and died one to three days later (Omer and Awad Elkarim 1981).

Clinical Pathology and Necropsy

Clinicopathologic data is generally not helpful in the diag­nosis before death. There are no specific necropsy findings, although pulmonary congestion and ecchymotic hemor­rhages of the heart and other serosal surfaces may be observed. When there have been severe prolonged convul­sions with fever, the intestines may have a blanched or cooked appearance.

Diagnosis

Presumptive diagnosis depends on a history of exposure to chlorinated hydrocarbons, followed by the development of typical clinical signs. Definitive diagnosis depends on iden­tification of the offending agent by laboratory analysis of hair samples, rumen content, fat biopsies, or milk samples ante mortem or of tissue samples post mortem, especially liver, brain, and fat. Concentrations of the various chlorin­ated hydrocarbons considered diagnostic of toxicity in goat tissue are not well documented. Analyses are complex and costly, so there should be some notion of the specific chem­ical being searched for.

Treatment and Control

Therapy is primarily supportive. When topical poisoning is involved, animals should be washed thoroughly with soap and water. Handlers should wear masks and rubber gloves. In cases of ingestion, activated charcoal should be given at a dose of 1 g/kg bw per adult goat as soon as possible after exposure. Seizures may need to be controlled by use of long-acting barbiturates. Daily oral dosing of recovered animals with small volumes of mineral oil may help to clear chlorinated hydrocarbons from the intestinal tract, but will have little or no effect in mobilizing the agents in tissue. Specific guidelines for the safety of meat and milk products from goats recovered from poisoning are not available. Because of the potential harmful effects in humans, the consumption of meat or milk from these recovered animals should be discouraged. Control essen­tially involves client education concerning the danger, proper usage, and safe storage of chlorinated hydrocarbons.

Miscellaneous Organic Chemical Toxicities

Levamisole, a widely used caprine anthelmintic, is one of the most common potential causes of neurotoxicity in goats. When overdosed, it can produce a clinical syndrome very similar to nicotine poisoning, with signs including anxiety, hyperesthesia, increased urination and defecation, muscle tremors, staggering gait, and convulsions. More information on levamisole use and toxicity in goats is given in Chapter 10.

Urea toxicosis has been reported in goats. The syndrome is characterized by abdominal pain, bloat, dyspnea, and frothy salivation; neurologic signs include ataxia, tremors, hyperesthesia, and struggling. The condition is discussed in detail in Chapter 19.

Both cyanide and nitrate poisoning can produce signs of nervous dysfunction including excitement, muscle trem­ors, staggering gait, and dilated pupils secondary to sys­temic anoxia. These conditions are discussed in detail in Chapter 9.

Diesel fuel poisoning has been reported in goats when the animals drank from a small pond containing fuel from an overturned tank truck (Toofanian et al. 1979). Goats drank the tainted water readily. Clinical signs developed within hours and included anorexia, depression, diarrhea, dyspnea, and a mucopurulent nasal discharge. The breath and the urine smelled strongly of diesel fuel. Affected goats progressively worsened; developed neurologic signs includ­ing incoordination, tremors, head pressing, aimless wan­dering, pica, abnormal vocalization, and recumbency; and died, presumably due to respiratory compromise.

Nitrofurans are a class of antibacterials that were for­merly in common use for control of enteric infections in young calves and pigs. Due to public health concerns about their carcinogenicity, the use of nitrofurans in food ani­mals is now severely restricted in many countries, includ­ing the United States, where parenteral use was first banned in 1991 and topical use was banned in 2002. The toxicity of furazolidone in Nubian goats has been reported (Ali et al. 1984). At oral daily doses as low as 40 mg/kg for as long as 10 days, goats showed signs of anorexia, weight loss, restlessness, incoordination, and hyperexcitability, with constant chewing movements, tail wagging, foot stamping, backward walking, and circling. At daily oral doses of 160 or 320 mg/kg, similar signs were more severe and accompanied by frothy salivation, grunting, and bel­lowing, and death within one week of the onset of treatment.

Dinitro compounds such as dinitrophenol and dinitro­cresol are used as herbicides and fungicides and are toxic to goats immediately after application to foliage, but not once the residue has dried (Guss 1977). When goats feed on sprayed foliage there may be yellow discoloration of skin and hair around the mouth and nose associated with feed­ing activity. Clinical signs of toxicity include fever, dysp­nea, tachycardia, and convulsions. The clinical course is short and death rapidly ensues. Even with early interven­tion, the prognosis is guarded. No specific therapies have been reported, but use of antipyretics, anticonvulsants, and supportive care may be of some value.

Pentachlorophenol is commonly used as a wood pre­servative for lumber. It is toxic to livestock via the mecha­nism of uncoupling oxidative phosphorylation. It is readily absorbed through the skin, via inhalation, or by ingestion. As a general precaution, pentachlorophenol- treated wood should not be used in goat buildings because of the well-known wood chewing and swallowing behav­ior of goats. Of particular concern is freshly treated wood that has not yet dried or cured. Clinical signs of toxicity can include muscular weakness and lethargy, fever, sweating, dehydration, tachypnea, collapse, and death, with rapid onset of rigor mortis. Convulsions have been reported in goats before death (Guss 1977). There is no specific treatment.

Chlorpromazine and piperazine produce a fatal drug interaction when given to goats. The drug combination resulted in immediate, severe clonic convulsions and rapid respiratory arrest when chlorpromazine was given IV at a dose of 10 mg/kg after oral administration of piperazine at a dose of 220 mg/kg (Boulos and Davis 1969).