Bromethalin-based rodenticides: Mode of action, toxicity, clinical effects, and treatment efficacy in rats, dogs, and cats
Dorman, David Christopher
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Permalink
https://hdl.handle.net/2142/22060
Description
Title
Bromethalin-based rodenticides: Mode of action, toxicity, clinical effects, and treatment efficacy in rats, dogs, and cats
Author(s)
Dorman, David Christopher
Issue Date
1990
Doctoral Committee Chair(s)
Buck, William B.
Department of Study
Veterinary Biosciences
Discipline
Veterinary Biosciences
Degree Granting Institution
University of Illinois at Urbana-Champaign
Degree Name
Ph.D.
Degree Level
Dissertation
Keyword(s)
Health Sciences, Pharmacology
Biology, Veterinary Science
Language
eng
Abstract
The purpose of these studies was to define the toxicity of bromethalin-based rodenticides, develop treatments, and determine new modes of action of bromethalin. Bromethalin-based rodenticides are highly neurotoxic to cats (bait LD$\sb{50}$ 0.54 mg bromethalin/kg) and dogs (bait LD$\sb{50}$ 3.56 mg bromethalin/kg). Bromethalin poisoning in the dog and cat produced a dose dependent delayed toxic syndrome. Sublethal doses of bromethalin to dogs and cats resulted in delayed CNS depression, hindlimb ataxia, paresis, and paralysis. Higher doses given to dogs resulted in rapid severe muscle tremors and generalized seizures. Bromethalin toxicosis was also associated with increased cerebrospinal fluid pressure and cerebral edema. Bromethalin toxicosis produces acute and chronic EEG changes. Predominant abnormal EEG changes included: spike and spike-and-wave EEG patterns; high voltage slow wave activity; photoconvulsive or photoparoxysmal irritative responses, and marked voltage depression. Histologic lesions included diffuse white matter spongiosis, mild microgliosis, and optic nerve vacuolization. Ultramicroscopic examination of brainstem revealed occasional swollen axons, intramyelenic vacuolization, and myelin splitting at the intraperiod line. Bromethalin was detected in kidney, liver, fat, and brain tissues using gas chromatography with electron capture detection. Bromethalin caused increased feline hepatic cytochrome P-450 and cytochrome b$\sb5$ concentrations and decreased microsomal aminopyrine N-demethylase and 4-nitrophenetole-O-deethylase activities.
Repeated oral administration of a superactivated charcoal/sorbitol (SAC) product was an effective therapy for bromethalin toxicosis in the dog. The administration of combined mannitol/dexamethasone were ineffective therapies in dogs or cats given lethal bromethalin doses. Delayed administration of SAC was ineffective in bromethalin-dosed cats. Extract of Gingko biloba (EGB) given (100 mg/kg) to adult male Sprague-Daley rats immediately after bromethalin (1.0 mg/kg) administration was associated with a decreases in clinical sign severity, brain malonaldehyde concentration, brain % water, and brain sodium concentration.
Bromethalin binding to cytochrome P-450 was associated with a modified Type II binding spectrum that had a peak at 420 nm and a trough at 390 nm. Hepatic cytochrome P-450 from the microsomal fractions isolated from cats given bromethalin had a similar difference spectrum (peak at 420 nm, trough at 390 nm) when compared to control cat cytochrome P-450.
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