Small Animal Toxicology Essentials (Poppenga/Small Animal Toxicology Essentials) || Insecticides

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<ul><li><p>127</p><p> 18 Insecticides AMITRAZ </p><p> Sources/Formulations Amitraz is a formamidine acaricide with activity against ticks, mites, and lice. It is used in veterinary medicine for the control and eradication of demodex mites and for the prevention of tick infestations. For small animals amitraz is commercially available under the trade names Mitaban dip (19.9% for dilution), Preventic collar (9.0%), and ProMeris topical solution (15%). It is also available as an emulsifi able concentrate (12.5% for dilution) for use on pigs and cattle. </p><p> Kinetics Amitraz is rapidly absorbed following oral administration of technical material. Clinical signs can be seen by 1 hour of ingestion and peak plasma concentrations occur by 5 hours. The elimination half - life is approximately 23.4 hours (Hugnet et al. 1996 ). Absorption and duration of effects following ingestion of amitraz - impregnated collars tend to be prolonged due to slow release of the active ingredient from the collar. Although dermal absorption is low, intoxication has been reported following topical application in dogs (Paradis 1999 ). </p><p> Mechanism of Action The alpha - 2 adrenergic agonist characteristics of amitraz account for its sedative and hyperglycemic effects. The effects on blood glucose are thought to be due to alpha - 2 mediated inhibition of insulin release (Plumb 2005 ). </p><p> Toxicity Amitraz is classifi ed by the EPA as slightly toxic to mammals if ingested orally. The oral LD 50 for amitraz in rats is 523 800 mg/kg and for mice is greater than 1600 mg/kg. The dermal LD 50 for rats and rabbits is greater than 1600 mg/kg and greater than 200 mg/kg, respectively (Extoxnet 1995 ). Cats tend to be more sensitive than dogs to the effects of amitraz. </p><p> Clinical Effects Signs Signs of amitraz toxicosis can begin within 1 to 4 hours, but can be delayed as long as 12 hours. Intoxicated dogs and cats exhibit vomiting, depression, somnolence, ataxia, disorientation, ileus, bradycardia, hypertension, or hypo-tension, coma, hypothermia, and seizures. Some of the neurological signs might be attributed to the xylene carrier found in dip formulations. Equids may display similar neurological signs and are at risk of developing life - threatening ileus and impaction. </p><p> Laboratory Biochemical changes include hyperglycemia and elevated hepatic enzymes. </p><p> Differential Diagnosis Toxicants causing central nervous system depression should be considered. These include ethanol, methanol, isopropanol, the avermectins, marijuana, ethylene glycol, </p><p>Small Animal Toxicology Essentials, First Edition. Edited by Robert H. Poppenga, Sharon Gwaltney-Brant. 2011 John Wiley and Sons, Inc. Published 2011 by John Wiley and Sons, Inc.</p><p> Petra A. Volmer </p></li><li><p>128 Section 3 / Specifi c Toxicants</p><p>ingested. However, if surgery is required to remove collar pieces, activated charcoal can obscure the surgical fi eld. Yohimbine and atipamezole might hasten passage of collar fragments from the gastrointestinal tract by revers-ing depressed GI motility. Saline cathartics can also enhance elimination. </p><p> Prognosis Animals receiving prompt, aggressive treatment have a good prognosis. Animals exhibiting severe signs such as coma or seizures, have a guarded to poor prognosis. </p><p> ORGANOCHLORINES </p><p> Sources/Formulations The organochlorine insecticides (OCs) (also referred to as chlorinated hydrocarbons ) reached the height of their popularity as insecticides from approximately the 1950s to the 1970s. They were prized because of their effective-ness as insecticides and relatively low acute mammalian toxicity (compared to the organophosphorus and carba-mate compounds at the time). Additionally they were lipo-philic and slow to degrade, requiring fewer applications. These characteristics, however, also contributed to their environmental persistence and biomagnifi cation through the food chain. Because of this, the OCs have been replaced by newer and safer insecticides. However, old containers may resurface from storage in sheds, barns, and other structures, thus posing a hazard. </p><p> There are three main categories of OCs based on chemi-cal structure. The diphenyl aliphatic compounds include agents such as DDT, methoxychlor, perthane, and dicofol. The aryl hydrocarbons include lindane, mirex, kepone, and paradichlorobenzene. The cyclodiene insecticides include aldrin, dieldrin, endrin, chlordane, heptachlor, and toxa-phene. Although DDT and most of the other OCs have been banned from use in the United States, lindane topical products are still available as second line treatments for scabies and head lice in humans if fi rst line treatments are not effective. Lindane - based dips for dogs, though not popular, continue to be available. </p><p> Kinetics The OCs are well absorbed through most exposure routes. Blood concentrations initially increase following absorp-tion, but then they decline rapidly as distribution takes place to liver, kidney, brain, and lipid - rich tissues such as adipose where OCs are stored. Body fat may serve as a source of OC poisoning if weight loss occurs and stored OCs are released into the general circulation. Because of </p><p>barbiturates, benzodiazepines, opioids, and antidepres-sants. Other differentials include CNS trauma and primary CNS disease. </p><p> Diagnostics Antemortem Amitraz can be detected in stomach contents, urine, feces, and skin, although laboratories performing the analysis are limited. </p><p> Postmortem No specifi c gross or histopathological lesions are expected on necropsy. Tissue analysis for the presence of the com-pound can confi rm exposure. </p><p> Management of Exposures The most common routes of exposure are dermal and oral. In either case, patients should be stabilized if necessary, clinical signs treated, and further exposure prevented. </p><p> For dermal exposures, the animal should be stabilized according to clinical signs and then bathed in a liquid dish detergent to remove any product remaining on the skin. Care should be taken to prevent the development of hypo-thermia subsequent to bathing. Mild signs following label use often do not require treatment and resolve in 24 72 hours. For more severe signs, yohimbine and atipamizole are alpha - 2 adrenergic antagonists that effectively reverse bradycardia, CNS depression, hyperglycemia, and ileus (Plumb 2005 ). Atipamezole is thought to have fewer car-diorespiratory effects than yohimbine (Andrade and Sakate 2003 ). Atropine should not be used in the treatment of amitraz - induced bradycardia, because it can potentiate hypertension and ileus (Hsu et al. 1986 ). Seizures can be treated with diazepam or a barbiturate. Animals should be closely monitored for severe CNS depression following use of these drugs. In all cases exhibiting clinical signs, symptomatic and supportive care including IV fl uids and thermoregulation is indicated. </p><p> Oral exposures are usually the result of ingestion of either spot - on or concentrated dip formulations contain-ing volatile hydrocarbons, or from ingestion of an amitraz - containing collar. The induction of emesis should be avoided or done with care for products containing solvents due to the risk of aspiration and subsequent chemical pneumonitis. Emesis is recommended for asymptomatic animals that have ingested a collar. Acti-vated charcoal binds amitraz; however, administration may also aggravate an already upset stomach and cause vomiting and possible aspiration. Activated charcoal is more suitable for cases in which a collar has been </p></li><li><p> Chapter 18 / Insecticides 129</p><p> Diagnostics Confi rmation of an OC poisoning is based on history of exposure and appropriate clinical signs along with detec-tion of the compound in tissues. Samples for OC analysis should be collected and submitted in clean glass containers or wrapped in aluminum foil (dull side toward sample) to prevent contamination from plasticizers which can inter-fere with analysis. </p><p> Antemortem Blood, milk, or adipose tissue (from a biopsy), or suspect feed or product can be analyzed. However, fi nding OC residues is not alone diagnostic because of the widespread persistence of these compounds in the environment. </p><p> Postmortem Liver, brain, adipose tissue, and ingesta collected during necropsy can be analyzed. </p><p> Management of Exposures Treatment is aimed at controlling neurological signs and preventing further exposure. No specifi c antidote exists, so therapy is largely symptomatic and supportive. Neuro-logical stimulation can be addressed with antiseizure med-ications (e.g., diazepam, barbiturates, gas anesthetics, propofol, etc.) but may be diffi cult to control. For dermal exposures animals should be bathed with a liquid dish detergent. Activated charcoal is recommended for oral exposures. Personnel should use protective measures to prevent self - exposure. </p><p> Prognosis The prognosis is dependent upon the OC involved, the dose, and how quickly treatment is initiated. Those animals with few or mild signs and that receive prompt treatment have a good prognosis. Animals with prolonged or severe signs, or for which treatment has been delayed have a guarded prognosis. </p><p> ORGANOPHOSPHORUS AND CARBAMATE INSECTICIDES </p><p> Sources/Formulations This group of compounds is characterized by their ability to inhibit the enzyme acetylcholinesterase. There are a number of organophosphorus (OP) and carbamate insecti-cides developed for use on animals and crops, as well as around buildings or in structures such as ships and air-planes. The development of newer and safer insecticides has limited the use of this class of compounds to some </p><p>their lipophilicity, OCs will be secreted into milk and eliminated from the body via this route. Some OCs are excreted through the bile and reabsorbed (enterohepatic recirculation), contributing to persistence in the body. </p><p> Mechanism of Action The OCs exert their effects through two main mechanisms. In general, the diphenyl aliphatics interfere with sodium channel kinetics, resulting in partial depolarization. The aryl hydrocarbons and cyclodienes act to inhibit the binding of GABA (an inhibitory neurotransmitter) to GABA receptors. For both of these mechanisms, clinical signs refl ect nervous stimulation. DDT metabolites also cause selective necrosis of the adrenal gland zona fasci-ulata and zona reticularis. The OCs have demonstrated potent estrogenic and enzyme - inducing properties, which interfere with fertility and reproduction in wildlife and laboratory animals. </p><p> Toxicity The acutely toxic dose varies depending upon the OC, but in general the group is less toxic than the organophospho-rus or carbamate insecticides. The one exception is endrin with a rat acute oral LD 50 of 3 mg/kg (Buck et al. 1976 ). </p><p> Clinical Effects Signs Signs can occur anywhere from minutes to days following exposure. Initial signs include salivation, nausea, vomit-ing, followed by agitation, apprehension, hyperexcitabil-ity, incoordination, nervousness, and tremors. These can progress to clonic - tonic seizures, opisthotonus, paddling, and clamping of the jaw. Seizure activity can persist for 2 3 days (due to lipophilicity and enterohepatic recircula-tion). Coma and death are possible. </p><p> Laboratory No diagnostic or suggestive changes occur. Although per-forming CBC and chemistry profi les will not rule in or out a diagnosis of an OC toxicosis, they are recommended to determine the overall health of the poisoned patient. </p><p> Differential Diagnosis Any agent or disease process causing neurological stimu-lation should be included in the differential diagnosis list. Such conditions include infectious encephalitis, lead poisoning, rabies, eclampsia, canine distemper, strychnine, metaldehyde, 4 - aminopyridine, methylxan-thines, and other toxicants causing seizures. </p></li><li><p>130 Section 3 / Specifi c Toxicants</p><p> The cholinesterase inhibitors are metabolized primarily in the liver. In most cases the metabolic process detoxifi es the compound but some organophosphorus insecticides may be activated or have an increase in activity following metabolism. In particular, phosphorothioates and phos-phorodithioates (sulfur - containing compounds) undergo oxidative desulfuration reactions to form the oxon deriva-tives that have increased potency. General oxidation and hydrolysis reactions, in particular the cleavage of the ester linkage, markedly reduce toxicity (Taylor 2001 ). Most OPs and carbamates are excreted as degradation products in the urine. </p><p> Mechanism of Action The OP and carbamate insecticides inhibit the enzyme acetylcholinesterase (AChE). AChE functions to break down the neurotransmitter acetylcholine (ACh) into acetate and choline, which are then recycled to form more acetylcholine. Acetylcholine is the neurotransmitter found between preganglionic and postganglionic neurons of the autonomic nervous system; at the junction of postgangli-onic parasympathetic neurons in smooth muscle, cardiac muscle, or exocrine glands; at neuromuscular junctions of the somatic nervous system; and at cholinergic synapses in the CNS. AChE is also found on the surface of red blood cells, although its function there is uncertain. Inhibition of AChE results in excess ACh at the postsynaptic receptor, </p><p>extent, but many of these products are still available and in use. Older formulations can turn up from storage in old outbuildings such as sheds and barns. Most OP and carba-mate insecticides are applied topically to the animal or plant, but some are designed to be absorbed and act sys-temically. The OPs and carbamates can be found in various formulations including dusts, wettable powders, and emul-sifi able concentrates. They have been used in dips, sprays, fl ea collars, shampoos, fl ea foggers, and ant and roach baits. </p><p> The organophosphorus insecticides are aliphatic carbon, cyclic, or heterocyclic phosphate esters. They can be iden-tifi ed by the presence of the terms phosphate , phosphoro-thioate , phosphoramidate , phosphonate , phosphoryl , or phosphorothiolate somewhere in their long chemical name. Carbamates are derivatives of carbamic acid and generally have the terms carbamate , or carbamoyl , some-where in their long chemical name. Tables 18.1 and 18.2 provide common and chemical names of some representa-tive OPs and carbamates, and their acute oral LD 50 . </p><p> Kinetics Ultimately, absorption is dependent upon lipid solubility and carrier formulation, but in general, the cholinesterase inhibitors tend to be well absorbed from any exposure route. They are rapidly distributed to tissues throughout the body. </p><p> Table 18.1. Common organophosphorus compounds </p><p> Compound Chemical Name Acute Oral LD 50 (mg/kg; rat) </p><p> Chlorpyrifos O,O - diethyl O - (3,5,6 - trichloro - 2 - pyridyl) phosphorothioate 135 Diazinon O,O - diethyl O - (2 - isopropyl - 4 - methyl - 6 - pyrimidyl) phosphorothioate 300 Dichlorvos 2,...</p></li></ul>

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