"Natural" does not mean "safe" (Proceedings)

Unfortunately, many people equate natural and safe. Thus, this may explain in part the current popularity of products containing "all natural" active ingredients. However, some of the most toxic compounds known to man are naturally-occurring (botulism, cyanogenic glycosides, ricin). This presentation will discuss several toxins (poisonous substances occurring naturally) that represent potential hazards to companion animals. They are chemically diverse and affect a variety of organ systems. In several cases, the toxin or toxins responsible for tissue damage have not been identified.

Mycotoxins

Vomitoxin or deoxynivalenol has been found in dog foods containing corn, wheat, barley or oats contaminated with toxin-producing Fusarium spp. molds. Clinical signs in affected animals include sudden onset of feed refusal and emesis. In experimental feeding trials with dogs, feed refusal has occurred at vomitoxin concentrations of ~ 4 to 5 ppm. Differential diagnosis includes other causes for anorexia and emesis (viral, bacterial or parasitic), which are very non-specific signs. There are no specific clinical pathologic or post-mortem findings. Exposure is confirmed by analysis of suspect feed; most veterinary diagnostic laboratories offer vomitoxin analysis. Treatment involves removal from suspect feed and symptomatic and supportive care. The prognosis is excellent.

Several Penicillium spp. of molds produce penitrem A and/or roquefortine. Penitrem A poisoning has been reported in dogs that have ingested moldy food items (moldy cheese, bread or English walnuts). Roquefortine poisoning has been documented in dogs ingesting such moldy material as dairy products or compost. The mechanism of toxicity is not known, but penitrem A may act by interfering with central inhibitory neurons or influencing presynpatic transmitter release. Clinical signs include early restlessness, panting, and hypersalivation followed by mild to moderate whole body muscle tremors. At high doses, tremors can be severe and seizures may occur. Affected animals may be hyperesthetic. Secondary signs include hyperthermia, exhaustion, dehydration, metabolic acidosis and rhabdomyolysis. Diagnosis can be confirmed by analysis of vomitus, gastric lavage washings or stomach contents. Treatment is directed toward appropriate gastrointestinal decontamination procedures and symptomatic and supportive care. Diazepam is recommended for initially controlling agitation, muscle tremors, or seizures. If unsuccessful, methocarbamol may be tried. The majority of patients recover within 24 to 48 hours with appropriate care. Differential diagnoses includes strychnine, metaldehyde, methylxanthines, pyrethrins/pyrethroids, organophosphates/carbamates and eclampsia in pregnant animals.

Zootoxins

Spiders

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 fasiciculations, 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

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.

Amphibians

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.

Plant Toxins

Lilium spp. Lilium spp. and hybrid lilies such as Easter lily, Asiatic lily, and star-gazer lily are potentially toxic to cats. Blooms and leaves are considered toxic. The toxin has not been identified but ingestion of the plant causes acute renal failure. Clinical signs are secondary to renal impairment and include anorexia, emesis and depression. On post-mortem examination, there is extensive proximal tubular degeneration and necrosis. Treatment consists of early decontamination and standard acute renal failure interventions. Prevention is the best medicine.

Ricinus communis. The castor bean plant is often encountered as a garden ornamental. It contains ricin, which is a glycoprotein. Ricin is exceedingly toxic; a reported lethal dose for rodents and dogs is 1 μg/kg body weight. One castor bean seed contains up to 1 mg ricin. Ricin acts at the level of the ribosome by interfering with normal ribosome function. This results in cessation of protein synthesis. Metabolically active cells are especially sensitive to the effect of ricin. Clinical signs can be delayed after ingestion. The severity of signs and acuteness of their onset may be related to not only the number of seeds ingested but whether or not they are masticated first. Intact seeds can pass harmlessly through the GI system whereas those that are chewed rapidly release ricin. Signs include emesis, abdominal pain, bloody diarrhea, tenesmus, lethargy, cyanosis, seizures, circulatory collapse, renal failure and death. Antemortem diagnosis can be difficult since few laboratories test for ricin. Detection of seeds or other plant fragments might be possible in vomitus or on postmortem examination. Treatment involves very early GI decontamination and symptomatic and supportive care.

Taxus spp. There are several yew species that are highly toxic including the Japanese and English yews. All parts of the plant are considered toxic except the red, fleshy aril around the seed. Ingestion of several tablespoons to a handful of needles can be fatal. Yews contain taxines and bioflavenoids which have cardiovascular and CNS depressant activities. Clinical signs include dizziness, abdominal discomfort, mydriasis, shallow breathing, initially tachycardia followed by bradycardia, hypotension, respiratory paralysis, cardiac arrest, coma and death. Exposure/intoxication can be confirmed by detection of the characteristic leaves in vomitus or detection of taxines in stomach contents samples. Treatment involves early decontamination and symptomatic and supportive care.

Dracaena spp. Although Dracaena spp. are not listed in many poisonous plant references, the NAPCC considers plants in this genus to be toxic, especially to cats. Common names include dracaena marginata, dracaena palm, dragon tree and corn plant. Clinical signs in cats include mydriasis, dyspnea, abdominal pain, tachycardia, and hypersalivation. Other signs include emesis +/- blood, depression, anorexia, weakness and ataxia. The toxic principle has not been identified. Treatment consists of early decontamination and symptomatic and supportive care.

Herbal Preparations

The increased use of herbal preparations and the potential for intoxication or adverse reactions following their use obligates the clinician to consider them in cases of suspected poisoning. It is important to point out that the incidence of animal intoxication or adverse reactions following the use of natural remedies has not been determined, but it is unlikely to be higher than the incidence from many orthodox pharmaceuticals.

Ephedra or ma huang: the dried young branches of ephedra (Ephedra spp.) have been used for their stimulating and vasoactive effects. In addition, ephedra has been employed in several products promoted for weight loss. The plant constituents responsible for biological activity are the alkaloids, ephedrine and pseudoephedrine. In commercial use, dried ephedra should contain no less than 1.25% ephedrine. Ephedrine and pseudoephedrine are sympathomimetics and acute intoxication is associated with insomia, restlessness, tachycardia and cardiac arrhythmias. Nausea and emesis are also reported to occur. 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. North American species of ephedra (also called Mormon tea) have not been shown to contain any pharmacologically active alkaloids.

The use of ephedra in humans has been associated with a greatly increased risk for adverse effects compared to other commonly used herbs. One study reported that products containing ephedra accounted for 64% of all reported adverse effects from herbs although they accounted for only 1% of herbal product sales. The actual frequency of adverse effects in patients using ephedra could not be determined since the study was based upon calls received by human poison control centers. However, based upon such studies the FDA initiated a ban on ephedra-containing products in April of 2004. This marked the first time that the FDA banned the sale of a dietary supplement since the passage of the DSHEA Act in 1994.

Citrus aurantium ("bitter orange" or "Seville orange") has appeared in many products labeled as "ephedrine-free" and also combined with caffeine and/or guarana. The primary active components are synephrine (structurally similar to epinephrine), octopamine (structurally similar to norepinephrine) and N-methyltyramine. The overall effect is that of stimulation. Studies in humans have shown that bitter orange–containing preparations cause tachycardia as well as increases in systolic and diastolic pressure. Signs of intoxication can be expected to be similar to those seen with ephedra.

Guarana: 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. See Ephedra for a discussion of a case series involving dogs ingesting a product containing guarana and ephedra.

5-hydroxytryptophan: 5-HTP, 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.

Additional Reading

Mycotoxins

Puschner, B. (2002). Mycotoxins. Veterinary Clinics of North America: Small Animal Practice, 32(2): 409-420.

Zootoxins

Eubig P.A. (2001). Bufo species toxicosis: big toad, big problem. Vet Med. 96(1):595-599. Fowler, M.E. (1993). Veterinary zootoxicology. pp. 41-46; 69-80; 81-86.

Gwaltney-Brant S., Dunayer EK, Youssef HJ. Terrestrial zootoxins. 2007. In: Gupta, R.C., editor. Veterinary Toxicology Basic and Clinical Principles, pp. 794-807.

Peterson, M.E. 1997. Spider venom toxicosis – brown recluse family. In: Tilley, L.P., Smith Jr., F.W.K., editors. 5-Minute Veterinary Consult, p. 1207.

Peterson, M.E. 2000. Toad venom toxicosis. In: Tilley, L.P., Smith Jr. F.W.K., editors. The 5-Minute veterinary consult Canine and feline. 2nd ed., pp. 1252-1253.

Reeves, M.P. 2004. A retrospective report of 90 dogs with suspected cane toad (Bufo marinus) toxicity. Aust Vet J 82(10):608-11.

Roberts, B.K., et al. 2000. Bufo marinus intoxication in dogs: 94 cases (1997-1998). J Am Vet Med Assoc 216(12):1941-1944.

Plants and Herbs

Barr, C. (2006). Household and Garden Plants. Small Animal Toxicology, 2nd ed. (Peterson, M.E. and Talcott, P.A. eds.), pp. 345-410.

Langston, C.E. (2002). Acute renal failure caused by lily ingestion in six cats. J Am Vet Med Assoc 220(1):49-52.

Hausner, E. and Poppenga, R. (2009). Herbal Hazards. Current Veterinary Therapy IV, pp. 149-155. Means, C. (2002). Selected herbal hazards. Veterinary Clinics of North America: Small Animal Practice, 32(2):367-382.