Flora and fauna: Hazardous biotoxins for pets (Proceedings)

Plants

While scores of potentially toxic plants may be ingested, relatively few plants account for the majority of exposures. In cases of plant exposure, plants should be positively identified in order to determine their potential toxicity. Whole plant samples are preferred for identification, but it may be possible to identify a plant based upon examination of plant parts either from the environment of the animal or from vomitus. With few exceptions, treatment of toxic plant ingestions involves symptomatic and supportive care.

Recently, ingestion of grapes or raisins by dogs has been associated with acute renal failure (ARF). The proximate toxin has not been identified and not all dogs that ingest grapes or raisins are affected. In addition, there is no apparent relationship between the number of grapes or raisins ingested and the occurrence of ARF. Clinical signs of intoxication include anorexia, emesis, diarrhea, lethargy, abdominal pain, and oliguria followed by anuria. Histopathologic lesions include proximal renal tubule degeneration and necrosis. Diagnosis of intoxication relies on a history of recent ingestion of grapes or raisins. Treatment includes early GI decontamination and symptomatic and supportive care. Hemodialysis should be considered if available. The prognosis is poor based upon reported cases to date.

Mushrooms

A variety of mushrooms are toxic. However, the most poisonous mushrooms contain cyclopeptide toxins, especially amanitin. Several genera of mushrooms contain amanitin, but ingestion of Amanita spp. and Galerina spp. are most often involved in intoxication. Ingestion of amanitin-containing mushrooms results in fulminant liver failure. Renal failure and coagulopathy can also occur. Amanitin toxins inhibit protein synthesis by ribosomes within hepatocytes. Following mushroom ingestion, there can be a latent period before the onset of clinical signs. Clinical signs include hyperglycaemia following by hypoglycaemia, coagulation abnormalities, ataxia, listlessness, bradycardia and shock. Antemortem diagnosis of Amanita intoxication relies on a history of recent mushroom ingestion and, if testing is available, detection of amanitin in serum, urine or GI contents. Whether amatoxin testing is available or not, an attempt should be made to identify the genus and species of mushroom ingested. Unfortunately, mushroom identification often requires specialized expertise that may or may not be readily available and fresh samples are necessary.

Once liver damage has occurred, treatment is often unrewarding. GI decontamination is warranted if early after an ingestion. Multiple doses of activated charcoal are indicated due to enterohepatic recirculation of the toxins. Penicillin G and silymarin (derived from Silybum marianum or milk thistle) have been used, but their efficacy is uncertain. Silymarin at a total dose of 1.4 to 4.2 g per day can be given orally for 4 to 5 days. Alternatively, N-acetylcysteine at doses similar to those for treating acetaminophen intoxication can be administered. Silymarin and N-acetylcysteine are hepatoprotective. Vitamin K1 and blood transfusions are indicated in cases with coagulopathy.

Mycotoxins

Mycotoxins are secondary fungal metabolites that can intoxicate humans and animals. There are a number of mycotoxins that have been characterized and cause animal disease. However, two major classes of mycotoxins are responsible for the majority of small animal intoxications: aflatoxins and tremorgenic mycotoxins.

Aflatoxins are produced by certain fungal species in the genus Aspergillus in corn, peanuts and other agricultural products during warm and humid conditions. Four major aflatoxins are produced (aflatoxins B1, B2, G1 and G2) under natural conditions, with aflatoxin B1 being both the most prevalent and toxic. Aflatoxins are metabolized by the liver to reactive epoxides which bind covalently with cellular macromolecules such as DNA, RNA and proteins. Such binding results in damage to hepatocytes leading to impaired liver function, bile duct proliferation, bile stasis and liver fibrosis. Cases have occurred in dogs but have not been reported in cats.

In dogs, most reported cases have resulted in acute liver failure. Signs can include weakness, depression, anorexia, emesis, diarrhea, icterus and signs associated with coagulopathy. Hemorrhage secondary to protein synthesis inhibition and resulting clotting factor deficiency is often the immediate cause of death. Liver enzymes, ammonia and bilirubin concentrations are increased in serum and coagulation times can be prolonged. Testing of biological specimens for aflatoxins is not widely available. An antemortem diagnosis relies on occurrence of characteristic signs, ruling out other causes of acute liver failure and detection of aflatoxins in representative food items. Recognition of aflatoxicosis is often not sufficiently early for GID procedures to be useful. Treatment is symptomatic and supportive. The prognosis is related to the severity of the liver damage. If liver damage is extensive, the prognosis is poor.

Penitrem A and roquefortine are two mycotoxins produced by Penicillium spp. Toxigenic Penicillium spp. have been found on moldy dairy products, bread, walnuts and compost. Penitrem A and roquefortine affect the CNS. Penitrem A may act via presynaptic changes in acetylcholine release, decreased production of glycine or via GABA receptor agonism; the mechanism of action of roquefortine is unknown.

Most reported cases of intoxication involve dogs. Signs of intoxication in dogs include emesis, increased irritability, weakness, muscle tremors, rigidity, hyperactivity, sensitivity to noise, panting and hyperthermia. Tremors can become severe and opisthotonus, seizures, nystagmus, recumbency and paddling can occur. Rhabdomyolysis, dehydration and metabolic acidosis are potential complicating factors. Onset of signs can occur within 30 minutes of ingestion of contaminated materials or be delayed for several hours. A diagnosis of intoxication relies on a history of ingestion of moldly materials, occurrence of characteristic signs and detection of penitrem A and roquefortine in samples such as food items, GI contents, serum or urine. A number of other poisons such as metaldehyde, organophosphate and carbamate insecticides, pyrethrin/pyrethroid insecticides, bromethalin and illicit drugs cause similar clinical signs, so obtaining a detailed history and performing analyses on appropriate samples are keys to confirming mycotoxin exposure. Treatment involves GID if instituted early after a suspected exposure. Additional therapy involves controlling seizures and hyperthermia, correcting metabolic acidosis and maintaining hydration and urine flow.

Cyanobacterial Toxins

Cyanobacteria or blue-green algae are commonly found in fresh or salt water in temperate regions of the world. Under favourable environmental conditions, algae can undergo rapid proliferation resulting in algal "blooms" and elaborate extremely toxic compounds. Blooms can become concentrated along shorelines as a result of wind or wave action. Pets are exposed to the toxins when they ingest bloom material secondary to water ingestion. Microcystis and Nodularia spp. can produce hepatotoxins and Anabaena, Aphanizomenon, Lyngbya and Oscillatoria spp. can produce neurotoxins. The hepatotoxicants include microcystins or nodularin while the neurotoxicants include anatoxin-a or anatoxin-as.

Microcystins and nodularin inhibit protein phosphatases within hepatocytes which leads to rapid and massive hepatic necrosis, intrahepatic hemorrhage and shock. Anatoxin-a is a postsynaptic depolarizing blocking agent and anatoxin-as is an acetylcholinesterase inhibitor. Clinical signs associated with hepatotoxicant ingestion include emesis, diarrhea, lethargy, weakness, pallor and circulatory shock. Anatoxin-a causes acute onset of muscle rigidity, tremors, seizures, paralysis and respiratory paralysis. Anatoxin-as causes rapid onset of signs associated with muscarinic receptor stimulation (DUMBELS), seizures and respiratory paralysis. Confirmation of exposure relies on a history of access to contaminated water, observation of bloom material on the haircoat or around the mouth, detection of an odor suggestive of exposure to stagnant water, occurrence of compatible clinical signs, identification of toxigenic algal species in water samples or GI contents and identification of specific toxins in water samples or GI contents.

Treatment includes standard GID procedures if initiated soon after exposure to bloom material and symptomatic and supportive care. Circulatory shock is of immediate concern in animals exposed to hepatotoxicants, while seizure control and respiratory support are critical for animals exposed to the neurotoxicants. Atropine will reverse the muscarinic signs associated with anatoxin-as intoxication. The prognosis is poor for symptomatic animals and the rapidity of onset of clinical signs often precludes effective therapeutic intervention.

Zootoxins

Latrodectus spp. or black widow spiders are globose black spiders with an hour-glass red-orange abdominal pattern. They are widely distributed in the US. Single bites are potentially fatal especially to sensitive species such as cats. Clinical signs include progressive muscle fasiculations, severe pain, muscle cramping, abdominal rigidity without tenderness, restlessness, hypertension, bronchorrhea, regional numbness and hypersalivation. The venom of black widow spiders contains several biologically active proteins one of which, α-latrotoxin, induces neurotransmitter release from nerve terminals. Acetylcholine, noradrenaline, dopamine, glutamate and enkephalin systems are all affected. There are no confirmatory tests that are available. One clue in cats: they may vomit up the spider. Early identification of bites is difficult unless the bite is actually witnessed. Treatment includes the administration of a specific antivenin (Lyovac®, equine origin from Merck) by slow i.v. infusion. Allergic and anaphylactic reactions can occur. If antivenin is not available, 10% calcium gluconate can be used to help alleviate muscle cramping and pain.

Loxosceles spp. also inhabit many areas of the US. They have a violin-shaped marking on the dorsum of the cephalothorax. A single bite is potentially lethal. The site of the bite can be difficult to detect initially. However, a severe dermonecrotic lesion characterized by erythema, bulla formation, sloughing and scabbing often results. Severe systemic signs are uncommon. A number of biologically active components of the venom have been identified including hyaluronidase, esterase, alkaline phosphatase, lipase, 5'-ribonucleotide phosphorylase and sphingomyelinase D. There is no specific antidote available. Case management is directed toward treating the local cutaneous reaction and systemic manifestations. Dapsone, a leucocyte inhibitor, has shown efficacy in treating dermal lesions in animal models. Anti-inflammatory, antipyretic and analgesic agents can be useful although use of agents that potentially interfere with normal clotting should be avoided.

Fireflies of the genus Photinus have been documented to be poisonous to bearded dragons (Pogona spp.) and perhaps other reptiles. These fireflies contain toxins called lucibufagins, which are structurally related to cardiotoxins found in toads and plants (bufodienolides and cardenolides, respectively). The toxins serve as a means of protection from predators. In two documented cases, owners fed fireflies to their lizards. Acute onset of clinical signs occurred including head-shaking movements, pronounced oral gaping that became more severe with time, sever dyspnea and color changes resulted. The target organ appears to be the cardiovascular system.

The Colorado River toad (Bufo alvarius) and marine or cane toad (B. marinus) are most often implicated in toxicoses. When attacked or disturbed, these toads release toxic substances from their dorsally-located parotid glands. Biologically active substances include dopamine, catecholamines, bufotenine, bufagenins (digitalis-like compounds), bufotoxins and indole alkylamines. Absorption of the toxins is generally via the mucous membranes. The main target organs are the heart, peripheral vasculature, and CNS. Clinical signs include hypersalivation, pawing at the mouth, brick-red mucous membranes, hyperthermia, ataxia, collapse and seizures. Sinus tachycardia, sinus bradycardia, and ventricular arrhythmias can occur. Electrolytes disturbances are the most common clinical pathologic finding (↑ potassium and calcium, ↓ phosphorus, sodium and chloride). There is no confirmatory test of exposure or intoxication. Treatment consists of flushing the oral cavity, controlling seizures, treating arrhythmias and providing supportive care. Differential diagnoses include heat stroke, neuropathies and seizure disorders, metaldehyde, methylxanthines, oleander and OP/carbamate insecticides.

Dietary Supplements

Guarana is the dried paste made from the crushed seeds of Paullinia cupana or P. sorbilis, a fast growing shrub native to South America. Currently, the most common forms of guarana include syrups, extracts and distillates used as flavoring agents and as a source of caffeine for the soft drink industry. More recently, it has been added to weight loss formulations in combination with ephedra. Caffeine concentrations in the plant range from 3 to 5%, which compares to 1 to 2% for coffee beans. Oral lethal doses of caffeine in dogs and cats range from 110 to 200 mg/kg body weight and 80 to 150 mg/kg body weight, respectively. A case series involving intoxication of dogs following ingestion of a weight loss product containing guarana (caffeine) and ma huang (ephedrine) was recently reported. Estimated doses of the respective plants associated with adverse effects were 4.4 to 296.2 mg/kg and 1.3 to 88.9 mg/kg. Symptomatology included hyperactivity, tremors, seizures, behavioral changes, emesis, tachycardia and hyperthermia. Ingestion was associated with mortality in 17% of the cases.

5-hydroxytryptophan, also known as Griffonia seed extract, is a popular dietary supplement that is available over-the-counter for a variety of conditions including depression, chronic headaches, obesity and insomia in humans. A retrospective study by the ASPCA National Animal Poison Control Center reported 21 cases of accidental ingestion of products containing 5-HTP by dogs between 1989 and 1999. Clinical signs of intoxication developed in 19 of the 21 dogs and consisted primarily of seizures, depression, tremors, hyperesthesia, ataxia and hyperthermia. Vomiting and diarrhea were also frequently reported. The pharmacologic and toxicologic action of 5-HTP is believed to be due to increased concentrations of serotonin in the CNS. The estimated minimum toxic oral dose from the NAPCC study was 23.6 mg/kg while the minimum lethal oral dose was estimated to be 128 mg/kg. Three of the 19 symptomatic dogs died, while 16 of 17 dogs receiving symptomatic and supportive care recovered.

Melaleuca oil is derived from the leaves of the Australia tea tree (Melaleuca alternifolia); it often referred to as tea tree oil. The oil contains terpenes, sesquiterpenes and hydrocarbons. A variety of commercially available products contain the oil and shampoos and the pure oil have been sold for use on dogs, cats, ferrets and horses. Tea tree oil toxicosis has been reported in dogs and cats (Villar, 1994; Bischoff, 1998). A recent case report describes the illness of three cats exposed dermally to pure melaleuca oil for flea control (Bischoff, 1998). Clinical signs in one or more of the cats included hypothermia, ataxia, dehydration, nervousness, trembling and coma. There were moderate increases in serum ALT and AST concentrations. Two cats recovered within 48 hours following decontamination and supportive care. However, one cat died ~ 3 days following exposure. The primary constituent of the oil, terpinen-4-ol, was detected in the urine of the cats. Another case involved the dermal application of 7 to 8 drops of oil along the backs of two dogs as a flea repellant. Within ~ 12 hours one dog developed partial paralysis of the hindlimbs, ataxia and depression. The other dog only displayed depression. Decontamination (bathing) and symptomatic and supportive care resulted in rapid recovery within 24 hours.

Pennyroyal oil is a volatile oil derived from Mentha pulegium and Hedeoma pulegiodes. Pennyroyal oil has a long history of use as a flea repellant and has been used to induce menstruation and abortions in humans. There is one case report of pennyroyal oil toxicosis in the veterinary literature in which a dog was dermally exposed to pennyroyal oil at ~ 2 g per kg. Within 1 hr of application, the dog became listless and within 2 hr began vomiting. Thirty hr after exposure, the dog exhibited diarrhea, hemoptysis and epistaxis. Soon thereafter, the dog developed seizures and died. Histopathologic examination of liver tissue showed massive hepatocellular necrosis. The toxin in pennyroyal oil is thought to be pulegone, which is bioactivated to a hepatotoxic metabolite called menthofuran.

References

Hooser SB, Talcott PA (2006): Cyanobacteria. In: Small Animal Toxicology, eds. ME Peterson and PA Talcott, pp. 685-689, Elsevier Saunders, St. Louis.

Mazzaferro EF, Eubig PA, Hackett TB, Legare M, Miller C, Wingfield WE and Wise L (2004) Acute renal failure associated with raisin or grape ingestion in 4 dogs. Journal of Veterinary Emergency and Critical Care 14, 203-212.

Poppenga RH (2006) Hazards associated with the use of herbal and other natural products. In: Small Animal Toxicology, eds. ME Peterson and PA Talcott, pp. 312-344, Elsevier Saunders, St. Louis.

Puschner, B (2002) Mycotoxins. The Veterinary Clinics of North America 32, 409-419.

Spoerke D (2006) Mushrooms. In: Small Animal Toxicology, eds. ME Peterson and PA Talcott, pp. 860-887. Elsevier Saunders, St. Louis.