INTRODUCTION

Bromethalin (2,4-dinitro-N-methyl-N-[2,4,6-tribromophenyl]-6-[trifluoromethyl] benzenamine) was discovered in the mid-1970s¹ and has subsequently been incorporated into a number of rodenticide products. Bromethalin inhibits brain adenosine triphosphate (ATP) production and can be used to control warfarin-resistant rats and mice. As with other rodenticides, accidental poisoning of dogs, cats, and other companion animals with bromethalin is not uncommon.

SOURCES

Bromethalin-containing rodenticides have been marketed under a variety of trade names, including Assault (PM Resources, Inc) and Fastrac (Bell Laboratories, Inc). Bromethalin-based products usually contain 0.01% bromethalin and are often manufactured in a pelleted or paraffin bait block form. Pelletized products are often sold as individual paper or plastic “place pack” envelopes that contain 16 to 42.5 g (0.57 to 1.5 oz) of bait. The size and weight of the rodenticide pellets vary depending on manufacturer and product use. Bromethalin is also sold to commercial pest control operators in bulk and as a concentrated (2% to 10%) solution.

TOXIC DOSE

Among the common experimental animal species evaluated to date, only guinea pigs have been demonstrated to be resistant to bromethalin toxicosis. The basis for this resistance stems from the relative inability of guinea pigs to metabolize bromethalin to its toxic N-demethylated metabolite.² The reported oral median lethal dose (LD₅₀) of bromethalin is greater than 1000 mg/kg in the guinea pig.² In all other species examined to date, the acute (single-dose) oral LD₅₀ ranges from approximately 1 to 15 mg/kg. Cats appear to be one of the species most sensitive to the toxic effects of bromethalin. For example, the oral LD₅₀ of powdered bromethalin bait was found to be 0.54 mg/kg in experimental cats, whereas the LD₅₀ in dogs was 3.7 mg/kg.^3,4 These acute LD₅₀s provide an estimate of the amount of bromethalin required to be ingested to induce toxicity in dogs and cats. It is possible that individual cats and dogs could develop severe clinical signs following exposure to lower doses (e.g., greater than or equal to 1/10 of an LD₅₀), especially with repeated exposure. Secondary poisoning (relay toxicity) of animals resulting from the ingestion of bromethalin-poisoned rodents has not been demonstrated experimentally.⁵ The author is, however, aware of cases in which relay toxicosis most likely accounted for the animals’ exposure.

TOXICOKINETICS

Most of the information about the metabolism and toxicokinetics of bromethalin has been obtained from experimental studies conducted with rats.² On ingestion, bromethalin is rapidly absorbed from the gastrointestinal tract. The absorption half-life is approximately 2.7 hours. Peak plasma concentrations occur within 4 hours of ingestion. Bromethalin is rapidly metabolized by liver mixed-function oxygenases to its more toxic N-demethylated metabolite, desmethyl bromethalin.

Desmethyl bromethalin formation appears to play a crucial role in the development of toxicity since animal species (e.g., guinea pigs) that are unable to metabolize bromethalin to desmethyl bromethalin are resistant to its toxic effects. Bromethalin and its metabolite are readily distributed throughout the body and reach their highest concentrations in body fat.⁵ Bromethalin is excreted from the body relatively slowly with a plasma excretion half-life of approximately 6 days in the rat.² Urinary excretion of bromethalin is minimal and accounts for less than 3% of an oral dose; thus therapies directed at enhancing renal excretion (e.g., diuresis) are ineffective at altering bromethalin pharmacokinetics. Excretion of bromethalin occurs primarily through the bile. Total biliary excretion can account for 5% to 25% of an orally administered dose. Reabsorption of bromethalin excreted into the bile by the gastrointestinal tract probably occurs with subsequent cycling between the hepatobiliary system and the gastrointestinal tract. Interruption of the enterohepatic recirculation of bromethalin is a mainstay of decontamination therapy and relies on the repeated oral administration of activated charcoal.

MECHANISM OF TOXICITY

The presumed biochemical mechanism of action of bromethalin and its active metabolite, desmethyl bromethalin, is uncoupling of oxidative phosphorylation. Uncoupling of oxidative phosphorylation has been demonstrated to occur in vitro in brain and liver mitochondria isolated from normal rats.² Uncoupling of oxidative phosphorylation results in decreased tissue ATP concentrations and reduced activity of ATP-dependent sodium and potassium ion channel pumps. The brain is the primary target site for the biochemical effects of bromethalin, most likely because of its enhanced dependence on oxidative phosphorylation. Inhibition of ATP production leads to impaired ion pump function, subsequent brain electrolyte imbalances, and the associated movement of fluid into the myelinated regions of the brain and spinal cord. Increased cerebral lipid peroxidation also occurs following bromethalin ingestion and may likewise contribute to the development of clinical signs.⁶

CLINICAL SIGNS

The primary target for bromethalin is the central nervous system (CNS), and most clinical signs are generally referable to that system. Clinical signs in affected animals can vary tremendously, depending on the amount of bromethalin ingested and the stage of intoxication in which the animal is observed. Most animals that ingest a potentially toxic dose of bromethalin remain asymptomatic for the first several hours. The subsequent onset of clinical signs is dose dependent. Animals that ingest a supralethal dose (greater than or equal to LD₅₀) of bromethalin often develop clinical signs within 2 to 24 hours of ingestion. This acute-onset syndrome is characterized by severe muscle tremors, hyperthermia, extreme hyperexcitability, running fits, hyperesthesia, and focal motor and/or generalized seizures that appear to be precipitated by light or noise.^3,4 In many respects, the clinical signs induced by high-dose bromethalin exposure resemble toxic syndromes induced by strychnine or monosodium fluoroacetate (compound 1080) ingestion. Fortunately, such supralethal ingestions infrequently occur; thus this acute-onset syndrome is rarely reported.

More commonly, dogs and cats are exposed to lower doses of bromethalin (i.e., ingestion of a dose equal to LD₅₀), which produces a more delayed onset of neurological signs. In these circumstances, it is not unusual for clinical signs to develop first within several days of ingestion and then progress throughout a 1- or 2-week period.^3,4 Clinical signs observed in poisoned dogs and cats with this slower onset syndrome usually include hindlimb ataxia and paresis wih associated decreased conscious proprioception of the hindlimbs (Figure 34-1). Severely affected animals eventually develop hindlimb paralysis followed by a diminished or absent deep pain response, patellar hyperreflexia, and upper motor neuron bladder paralysis. Mild to severe CNS depression is usually present in animals having bromethalin-induced ataxia and paresis, with severely affected animals developing semicoma or coma. Abdominal distention is occasionally observed in poisoned cats and has been characterized radiographically by the presence of enlarged bowel loops. Additional clinical signs that can be seen include vomiting, anorexia, anisocoria, behavioral changes (“dementia”), positional nystagmus, abnormal postures (e.g., Schiff-Sherrington syndrome and forelimb extensor rigidity), loss of bark, opisthotonos, and fine muscle tremors.^3,4,7 Focal motor or generalized seizures also occur in the latter stages of this syndrome. Severely poisoned dogs and cats often develop a decerebrate posture (Figure 34-2) during the terminal phases of the syndrome.

Figure 34-1 Hindlimb ataxia with decreased conscious proprioception in a cat 5 days after administration of bromethalin (0.45 mg/kg).

(From Dorman DC: Emerging neurotoxicities. In August JR (ed): Consultations in Feline Internal Medicine 2, Philadelphia, 1994, WB Saunders, pp 429-436.)

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