In: Veterinary Toxicology, V. Beasley (Ed.

)
Publisher: International Veterinary Information Service (www.ivis.org), Ithaca, New York, USA.

Toxicants Associated with Seizures (9-Aug-1999)

P. A. Volmer
Department of Veterinary Biosciences, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Urbana,
IL, USA.

Chapter Sections
Strychnine
Calycanthus - Bubby Bush
Gelsemium - Yellow or Carolina Jessamine
Tetanus
Metaldehyde
Fluoroacetate-1080
5-Fluorouracil
Additional Toxicants

Strychnine

Major Species Usual Time of Onset Usual Duration (if survives) Full Table for
Toxicants Associated
All, esp.dogs Minutes to Hours Hours to few days with Seizures

Sources

z Strychnine is a bitter tasting alkaloid extracted from the seeds of an Indian tree, Strychnos-nux vomica.
z Present in "Nux Vomica" medications and homeopathic preparations.
z Supposed ruminatoric but is ineffective. Not a ruminatoric. There is no logical therapeutic use.
z Present in pesticides to control:
z Gophers, moles (subsoil use) - most products, especially those available OTC.
z Rats.
z Coyotes (not leagal in the USA).
z Infrequently relay toxicosis; may be more of a problem in raptors (Redig et al., 1982).
z Often dyed - red or green.
z Restricted in some states more than others.
z OTC availability - 0.5% (or 0.3%) or lower concentrations for subsoil use in the United States.
z All species are sensitive; problems mainly occur in small animals, especially dogs.
z Both accidental and malicious poisonings occur.

Strychnine
Toxicity

z Approximate lethal doses. (Primarily from Kirk's Current Veterinary Therapy, Volume VIII, p. 98. ).
z Bovine 0.5 mg/kg
z Equine 0.5 - 1.0 mg/kg
z Porcine 0.5 - 1.0 mg/kg.
z Canine 0.75 mg/kg.
z Feline 2.0 mg/kg.
z Rat 3.0 mg/kg.
z Fowl 5.0 mg/kg.
z Mallard ducklings 2 mg/kg.
z Pheasants 24.7 mg/kg.
z Thus based on 0.3% bait, 3 grams of bait would be potentially fatal to a 12 kg dog.
z Steep dose-response curve so that any animal displaying clinical signs must be carefully attended.

Absorption, Distribution, Metabolism and Excretion (ADME)

z Ionized in acid medium (pk1 = 6.0, pk2 = 11.7) and therefore absorbed in small intestine, but absorption is rapid.
z Metabolism of parent compound in liver; metabolites excreted in urine.
z Highest tissue concentrations occur in blood, liver, and kidney. Does not concentrate in nervous tissues. At death, the
highest concentrations are usually present in stomach contents.

Mechanism of Action

z Strychnine acts by competitively and reversibly antagonizing the inhibitory neurotransmitter glycine at postsynaptic
neuronal sites in the spinal cord and medulla.
z Result is unchecked reflex stimulation, with predominance of more powerful extensors which results in rigidity.

Strychnine Competes with Glycine

Signs

z Onset: 10 to 120 minutes after ingestion.

z Even sublethal doses may cause elevated blood pressure and heart rate.
z Usually no vomiting.
z Anxiety, stiffness.
z Violent tetanic seizures.
z Spontaneous or initiated by numerous stimuli, which is a diagnostic feature, however it can be hazardous (and
lethal) to deliberately initiate such seizures. Initiation of seizures is therefore contraindicated.
z Saw-horse stance.
z Opisthotonus and persistent rigid extension of all four limbs.
z Generally, there are no paddling and no running movements, masticatory activity, or salivation.
z Facial musculature contraction causes strained expression.
z Rigidity inhibits respiration, apnea results.
z Periods of relaxation gradually become fewer and shorter.
z Rarely loss of consciousness.
z Death from anoxia and exhaustion.
z Myoglobinuria possible.

Lesions

z Rapid rigor, rapid relaxation.

z Cyanosis, possible traumatic evidence of seizures.
z Birds that died (dunlin and killdeer) exhibited an unusual posture with the wings folded over their back, straightened
toes, with their bill in the soil and excreta extruded from their vent.

Diagnosis

z Food or bait usually in stomach if recently exposed.

z Analysis of:
z Baits.
z Frozen stomach contents obtained by lavage or at necropsy in lethal cases are most useful.
z Frozen liver.
z Frozen urine. Urine is the primary route of elimination but some animals may die too fast to detect
strychnine in the urine.
z Histopathology on brain should reveal normal tissue or perhaps changes consistent hypoxia.

Treatment

z Primary goal - prevent asphyxia.

z Pentobarbital - the preferred drug for relaxation; given to effect with care. It is essential to be ready to intubate and
administer artificial ventilation in severely affected animals.
z Robaxin (methocarbamol) at 150 mg/kg, IV, repeat doses of 90 mg/kg as needed has been recommended by some
authors. NOTE: unnecessary when using pentobarbital.
z Inhalation anesthetics.
z May have to maintain in anesthetized state up to 48 hours.
z Contraindicated:
z Ketamine - due to motor stimulatory effects.
z Morphine - due to respiratory depression, possible stimulation of spinal cord.
z Artificial respiration if hypoxic.
z Detoxification - can shorten course - lessen severity.
z Emetics are generally contraindicated due to the risk of initiation of a seizure and aspiration.
z Enterogastric lavage.
z Activated charcoal and a saline or osmotic cathartic.
z Fluids, forced diuresis with 5% mannitol in 0.9% normal saline at 7 mg/kg/hour.
 z Ammonium chloride (100 mg/kg, BID, po) to acidify urine thereby increasing protonation of strychnine to
reduce its reabsorption across the renal tubular membrane. NOTE: Ammonium chloride is infrequently needed
and is contraindicated if the animal is acidotic from exertion or from respiratory failure due to tetany of the
muscles of respiration or when myoglobinuria is present.
z If the animal has a severe metabolic acidosis, the slow infusion of fluids with added bicarbonate is indicated.
If acidosis is of respiratory origin, administration of bicarbonate is inappropriate.
z Experimentally, Sargiah (1985) found that diazepam, glycine, and beta-alanine given IP raised the seizure
threshold in mice. However, in another report, glycine given to mice in high doses (1 - 6 g/kg, IP) caused
hypothermia and sedation but was incapable of preventing strychnine convulsions (Lapin, 1981). Further
evaluation of glycine and other amino acids is required before they can be recommended.
z Cardiovascular effects, if they occur, can be abolished by combinations of alpha- and beta-adrenergic blocking
agents and can be reduced significantly by diazepam. Specific therapy depends on EKG and clinical signs.
z Care must be taken with any manipulation of the patient due to the excessive muscle stimulation and reflex rigidity
that may readily occur.

Key Features

z Baits, malicious poisoning.

z Strychnine in stomach contents.
z Interferes with glycine at postsynaptic neuronal sites in spinal cord.
z Tetanic seizures, asphyxia, opisthotonus, rapid onset and progression in most cases.
z Pentobarbital or other anticonvulsant treatment combined with detoxification using activated charcoal and
(sometimes) acidification of the urine while avoiding contraindicated drugs.

Calycanthus - Bubby Bush

Calycanthus - C. fertilis (Problem plant, a wild shrub); C. floridus (Ornamental plant)

Major Species Usual Time of Onset Usual Duration (if survives) Full Table for
Toxicants Associated
Herbivores, esp. cattle Minutes to Hours Few days; often lethal with Seizures

Common Names

z Carolina allspice
z "Bubby" bush
z Sweet shrub
z Hairy allspice
z Pale sweet shrub
z Smooth allspice
z Strawberry bush
z Indian toothpick

Description

Height: 6 - 10 feet; circumference 6 - 12 feet; summer foliage dark green, fall foliage is yellow. Leaves alternate, 2
1/2 inches, somewhat rough above, generally egg-shaped with blunt or pointed tips. Flowers brown - maroon and
fragrance suggesting strawberries. Fruit is like a rose hip. Seed pods, brownish, urn-shaped receptacle containing
many 1-seeded brown achenes. In some species, stems are pubescent; in others, they are hairless. Pest resistant. Bark
has been used as a subsitute for cinnamon.
Distribution

Most reports of poisoning are apparently from Tennessee. Also reported in bulletins from Georgia, North Carolina,
and Alabama.

Toxic Principle

Calycanthine, an indole alkaloid found in the seeds, with a pathophysiological action similar to strychnine.

Signs

z Unexpected deaths.
z Cows laying on side with severe tetanic spasms.
z Muscle fasciculations.
z Injected sclera, pupillary dilation.
z When touched, the animals develop rigid extension, opisthotonus, and convulsions.
z Respiratory rates elevated, such as 100 and 108.
z Urinalysis, CBC, and routine blood chemistry panels within normal limits.
z May seizure while standing in the field.
z Rapid death.

Lesions

No lesions, but in rumen can find seed pods (husks) and seeds typical of the Calycanthus shrub.

Diagnosis

z The leaves may be undisturbed, but there may be no seed pods present, presumably indicating that they had been
eaten.
z Presence of Calycanthus seeds in the rumen contents.
z Tentative diagnosis made using the history, signs, evidence of consumption of the shrub (seeds) and the lack of any
other CNS stimulant or other explanation.

Treatment

z A successful approach used on bovine animals was comprised of a quiet stall, mineral oil orally, and thiamine, given
intravenously the first day and then intramuscularly. Calves responded well and were released after 3 days. The
remaining calves on pasture responded to no therapy and made an uneventful recovery.
z Based on extrapolation from strychnine toxicosis, repeated administration of activated charcoal, minimal stimulation
and sedation with chloral hydrate (50 - 70 mg/kg, IV, to effect) or pentobarbital (30 mg/kg, IV, to effect) may be
appropriate in ruminants. Prolonged anesthesia would generally be impractical in most ruminant cases.

Comment

There are numerous references citing the Calycanthus Shrub as being "thought to be toxic or dangerous, but rarely
eaten". Nearly all references are directed to Dr. Chestnut's work in 1898 when, in his "Summary of Toxic Plants", he
mentioned some unconfirmed poisonings in Tennessee. The older livestock owners in the Tennessee mountains and
the Plateau area have long recognized the shrub as poisonous and have called it "Bubby".
Gelsemium - Yellow or Carolina Jessamine
Gelsemium sempervirens - Yellow jessamine, false jessamine; Trumpetflower, Carolina jessamine

Major Species Usual Time of Onset Usual Duration (if survives) Full Table for
Toxicants Associated
Herbivores, fowl Minutes to several days Few days; often lethal with Seizures

Images

Yellow Jessamine - U.S. G.S. Northern Prairie Wildlife Research Center. - To view this image in full size go to the
IVIS website at www.ivis.org . -
Gelsimium sempervirens - Google Image Search. - To view this image in full size go to the IVIS website at
www.ivis.org . -

Description

Twining or trailing plant, evergreen, woody perennial. Ten to 20 ft in length. Adult plant may have stem up to 1 inch
in diameter; younger stems are red-brown, wiry and tangled; very highly branched. Leaves are opposite, simple,
glossy and short petioled, 2 - 4 inches long. Flowers in late winter or early spring; short axillary clusters; yellow,
fragrant and funnel shaped.

Habitat

Virginia to Florida, Texas, and Central America. Coastal plain and lower piedmont from Virginia to Texas. In low
ground and thickets of mountains, fencerows, woods, and fields; usually climbing on trees. Also used to cover
porches and trellises.

Toxic Principle

Alkaloids of indole configuration, related to strychnine: gelsemine and gelseminine.

Toxicity

z Among the 10 poisonous plants which cause the most problems in North Carolina.
z Flowers, leaves, roots, and nectar are poisonous, also cause dermatitis.
z Honey from flowers may also be toxic.
z Rootstock and nectar most toxic.
z Livestock losses occur in winter when shortage of other forage exists.

Susceptible Species

Cattle, sheep, goats, horses, fowl, humans.

Signs

z Livestock on range often found in prostrate condition.

z Die within 24 - 48 hours after going down.
z Intense abdominal cramps.
z Muscle weakness.
z Convulsive movements of head, front legs, and sometimes rear legs.
z Slow respiration.
 z Hypothermia.

Diagnosis

z Death due to respiratory paralysis.

z Fowl fed green leaves died in 5 - 11 days.

Lesions

Nonspecific.

Treatment

Terminate exposure, activated charcoal and saline cathartic; symptomatic and supportive care.

Tetanus

Major Species Usual Time of Onset Usual Duration (if survives) Full Table for
Toxicants Associated
All species, esp. horses Days to weeks Days to months; potentially lethal with Seizures

Sources

z Tetanus toxin is produced by Clostridium tetani a gram-positive, spore-forming bacillus under anaerobic conditions.
z C. tetani spores are also commonly present in the feces of domestic animals, especially those of horses, and in soil
contaminated by the feces.
z C. tetani spores may persist in soil for many years and are resistant to many standard disinfection processes, including
steam heat (100º C for 15 minutes).
z Poisoning is known to result from clostridial growth in contaminated wounds in which anaerobic conditions
predominate. The usual incubation period is 1 - 3 weeks. It is possible for the original point of entry to heal without
any evidence of infection and for subsequent trauma, even months later to set up the necessary environment for
clostridial growth and toxin production.
z Animals given appropriate preventative measures (toxoid and antitoxin) are at low risk of developing tetanus.
z The usual portal of entry in horses is deep puncture wounds. Clinical toxicosis is most likely when there is sufficient
accompanying tissue damage to result in an anaerobic environment favorable to clostridial growth. Umbilical
infections also occur in foals that receive no maternal immunity.
z The usual portal of entry in cattle is via the reproductive tract at parturition. Outbreaks of tetanus in cattle have
suggested that the toxin may have been produced in the gut or ingested preformed in the feed. Grazing of rough,
fibrous feeds before such outbreaks is a common factor in the history, and it is possible that infection may have begun
via wounds in the oral cavity. Castrating and dehorning with elastic bands can also result in clostridial infection.
z In pigs, castration wounds are the most common point of infection.
z In lambs and adult sheep, infection is most often associated with castration, docking, or shearing. Docking with
elastic bands is one of the most common causes of tetanus in lambs.

Mechanism

z Three exotoxins are produced by the vegetative form of C. tetani: tetanospasmin (causes clinical signs); tetanolysin
(increases local tissue necrosis); and nonspasmogenic toxin (importance unknown).
z Tetanus toxin (tetanospasmin) is a protein (2 polypeptide fragments; total MW approximately 150,000). Transport to
the CNS occurs retrograde within nerves and via the bloodstream. The course of axons in tissues can be traced, in a
research setting, by applying a nontoxic fragment of tetanus toxin to a nerve terminal and, after allowing time for
 retrograde transport, staining tissue sections with an immunological probe for the toxin fragment. The toxin binds to
gangliosides in the brain stem or spinal cord. It blocks inhibitory synaptic input, especially at glycine mediated sites,
by binding to the presynaptic membrane and blocking the release of glycine, resulting in spastic paralysis. It may
also inhibit release of GABA and other amino acid neurotransmitters.
z Tetanus toxin may also cause paralysis by inhibiting the release of acetyl choline at neuromuscular junctions
(probably less important than inhibitory effect on release of glycine).
z Constant muscular spasticity may be produced and normally innocuous stimuli cause exaggerated responses.
z Death occurs as a result of rigidity of the muscles of respiration and associated asphyxia.
z Tetanus toxin may also cause "cardiovascular symptoms in patients whose spastic paralysis was controlled".
z Nonspasmogenic toxin is poorly understood and is thought to cause paralysis of the peripheral nervous system.
z Tetanolysin is antiphagocytic and enhances local tissue necrosis.

Susceptible Species

z Although all species of domestic animals are susceptible to tetanus, most cases appear to occur in the horse.
z Horses are the domestic species most sensitive to tetanus toxin.
z Pigs, cattle and sheep are less sensitive and dogs and cats are fairly resistant but are sometimes affected. Poultry are
more resistant.
z Generally, tetanus occurs in individual animals although outbreaks have been described in cattle, young pigs, and
lambs.

Signs

z Tetany, the predominant clinical sign of tetanus, is characterized by sustained tonic contractions of muscle without
twitching.
z Incubation period varies from days to months. Infrequently the incubation period can be long, and in those cases,
diagnosis may be difficult.
z Signs are referable to hyperesthesia, tetany and convulsions with eventual rigidity of the muscles of respiration,
asphyxia, and death.
z Clinical signs may include a sawhorse stance, protrusion of the third eyelid, rigidity of the generalized musculature,
"sardonic grin", and secondary postural effects which diminish defecation and urination. Rigidity with extension of
the tail has been described for cats "pump-handle tail".
z Opisthotonus and persistent rigid extension of all four limbs.
z Stiff gait.
z Horses, spasms of the masseter muscles occur early in the disease, "lockjaw" results.
z If paralysis of laryngeal and pharyngeal musculature occurs, aspiration pneumonia may develop.
z Excitation or loud noises may elicit convulsions in hyperesthetic animals.
z Excess stimulation of sympathetic nervous system can occur with sweating, tachycardia, arrhythmias,
vasoconstriction, colic.
z Complications due to recumbency occur, e.g., pressure induced neuropathy, decubital ulcers.
z As the dose of toxin is increased, paralysis can result.
z Localized tetanus involving only the muscle groups closest to the site of injury is relatively uncommon.

Characteristic "sawhorse" stance of a dog with generalized tetanus showing stiff, outstretched tail and contracted
facial musculature.
Lesions

z The only lesions which assist in the diagnosis of tetanus are the finding of appropriate wounds. Culture of the
organism may be attempted.
z CSF normal.

Differential Diagnosis and Diagnosis

z Hypomagnesemia encephalitis, eclampsia, strychnine toxicosis.

z Culture is often unrewarding.
z EMG - normal nerve conduction velocities, persistent electrical discharges occur.

Treatment

z Keep animal in dark quiet room.

z Offending wound should be located and meticulously debrided.
z IV antitoxin [only after a test dose (SQ) to check for hypersensitivity reactions] will reduce uptake of toxin by nerves.
z Administration of tetanus antitoxin will not reverse the clinical signs.
z Suggested dosages of antitoxin range from 10 - 220 IU/kg. Probably 5,000 - 10,000 IU given IV or IM in an adult
horse is adequate.
z Tetanus toxoid is administered concurrently.
z Local infiltration of wounds with antitoxin has been recommended (Blood, Henderson).
z Intrathecal administration of antitoxin has been described in humans and horses (Muylle et al.). Controversial.
Greatest benefits early in disease course.
z Antibiotics (e.g., penicillin) are used to decrease bacterial numbers.
z Muscle relaxants most often used include guaifenesin guiacolate (5% to effect, keep standing), methocarbamol (10 -
20 mg/kg, q8h), and diazepam (0.05 - 0.4 mg/kg).
z Tranquilizers may be required. Promazine (0.5 - 1.0 mg/kg, IM) may provide 4 - 8 hours of relaxation.

Prognosis

z Many animals become dysphagic which necessitates intensive support measures.

z If animal is recumbent, generally the prognosis is poor. There is presently a 50% mortality rate for horses displaying
neurologic signs at presentation.

Potential route of spread of tetanus toxin into the CNS. Figures from Greene ibid.
Key Features

z Clostridium tetani anaerobically produces toxin in wounds and umbilical tissues.

z Transfer to CNS via nerves and/or blood.
z Inhibition of release of glycine.
z Rigidity, tetany, debilitation.
z Therapy: antitoxin, antibiotics, sedation, support.
z Prevention: toxoid, antitoxin, good wound management, colostrum, antitoxin for foals.

Metaldehyde

Major Species Usual Time of Onset Usual Duration (if survives)

All species, esp. Full Table for

z Minutes to hours (neurologic or respiratory z One to two days; often Toxicants Associated
dogs effects). lethal with Seizures
z Days (liver failure). z Days to months; liver
failure rare.

Sources

z Molluscicide - slug and snail baits - polymer of acetaldehyde. Occasional baits contains cereals: increases palatability.
z Pellets. Snarol, Buggetta.
z Liquid. Dead-line (sticky liquid).
z Bait usually 3.5% metaldehyde.
z Some products contain arsenic or carbamate (insecticidal compounds) which are usually of less toxicologic
importance than the metaldehyde present.
z Poisoning - coastal areas and south (especially in California).
z Used as a fuel in small heaters.
z Incidence in the early 1970's in California:
z 4.5 cases/month/small animal practice - Sacramento area.
z Some emergency clinics averaged 20 - 30 cases/week.

Structure of Metaldehyde

Susceptible Species

Dogs, cats, sheep, humans, others.

Toxicity

z Toxic oral dose of metaldehyde for most species is from 60 - 500 mg/kg.
z Minimum oral lethal dose metaldehyde.
z Dog: 100 mg/kg.
z Horse: 60 - 360 mg/kg.
z Cow: 200 mg/kg.
z Reported LD50
z Dog: LD50 oral: 100 - 1000 mg/kg.
z Cat: LD50 oral: 207 mg/kg.
z Guinea pig: LD50 oral: 175 mg/kg.
z Mouse: LD50 oral: 200 mg/kg.
z Rat: LD50 oral: 227 mg/kg.
z Rabbit: LD50 oral: 290 mg/kg.
z 3 - 4 ounces of most pelleted baits would be toxic to average size dog, sheep.

Absorption, Distribution, Metabolism and Excretion (ADME)

z Acetaldehyde liberated by gastric hydrolysis of metaldehyde.

z Acetaldehyde - milder odor than formaldehyde.

Mechanism of Action

z Precise mechanism of action in mammals unknown.

z Acidosis presumably results from the subsequent metabolism of acetaldehyde and from other effects (tremors,
seizures, exertion).
z Acetaldehyde may or may not directly cause the problems occurring in metaldehyde toxicosis.
z Acetaldehyde not detected in tissue or serum from metaldehyde poisoned dogs.
z Brain concentration of 5-HT (5-hydroxytryptamine = serotonin) and noradrenaline are often inversely related to the
prevalence of seizures.
z A decrease in brain 5-HT and noradrenalin occurs in metaldehyde-poisoned animals.
z Intraperitoneal administration of acetaldehyde to mice did not result in significant depression of 5-HT.
z An increase in monoamine oxidase (MAO) activity occurs during metaldehyde toxicosis in mice. However, MAO
activity was unrelated to survivability of mice in this study. Conversely, MAO activity is decreased in acetaldehyde-
poisoned mice.
z Decreases in the important inhibitory neurotransmitter gamma amino butyric acid (GABA) also occur in metaldehyde
poisoned animals (mice). As GABA levels decreased so did survival rates.

Signs

z Cattle
z Salivation, ataxia, hyperpnea, tremors, convulsions (convulsions may start at posterior end and progress
forward). These may pitch cattle forward on their muzzles if severe. Frothy diarrhea sometimes occurs.
Cyanosis. Loss of "blink" reflex and blindness. May overreact to external stimuli.
z Sheep and Goats
z "CNS signs tremors fore and hind limbs, ataxia, convulsions, nystagmus, cyanosis, liver damage (pale and
friable) in goats and sheep.
z Uncommon cause of poisoning.
z Horses
z Colic.
z Mild leg tremors, hyperesthesia, diarrhea, sweating, hyperpnea (severely fluted nostrils).
z Tachycardia, clonic spasms, incoordination, extended head, convulsive spasms.
z Violent muscle spasms and ventroflexion of the spinal column just before death.
z Dogs
z Often eat all the snail bait available to them.
 z Onset of signs - almost immediate up to 3 hours.
z Sequence:
z Increased heart rate, anxiety, nystagmus.
z Mydriasis, hyperpnea, panting, hypersalivation (may be frothy) stiff legs, ataxia.
z May be rapidly followed by muscle tremors, then vomiting, hyperesthesia, continuous convulsions,
cyanosis, acidosis, diarrhea, dehydration, hyperthermia (to 108º F).
z Convulsions more continuous than in strychnine poisoning. Also, external stimuli do not have the
marked effect as seen in strychnine toxicosis.
z Later stages may have depression followed by narcosis.
z If death occurs, it is usually from respiratory failure and takes place from 4 - 24 hours after exposure. If animal
survives this period, it may succumb to liver failure within 2 to 3 days.
z Possible to have temporary blindness (which may last weeks) with normal pupillary reflexes.
z Feline (toxicosis not reported frequently):
z Similar to canine except nystagmus may be more prevalent.
z Depression, dyspnea, convulsions, tachycardia.
z Birds
z Poisoning reported in ducks and geese.
z Lethal dose ducks 300 mg/kg.
z Signs include ataxia, opisthostonus, dyspnea, polypnea, tremors.

Lesions

z Cattle
z Blood may fail to clot.
z Dark, congested lungs.
z Petechia in airways, throughout body.
z Sometimes enteritis and massive endocardial hemorrhages.
z Horse
z Lesions not diagnostic (not sufficiently specific).
z Epicardial hemorrhage.
z Moderate pulmonary congestion.
z Swollen red liver.
z Slight hyperemia of upper gastrointestinal mucosa.
z Birds
z Engorged vessels in mesentery and intestinal serosa.
z Petechiation gizzard.
z Lungs congested, bloody fluid in air sacs.
z Swollen hepatocytes with coagulative degeneration.
z Dogs
z Nonspecific lesions:
z Hepatic, renal, pulmonary congestion, subendocardial, subepicardial hemorrhages.
z Gastrointestinal hemorrhages.
z Any species
z Acetaldehyde odor in stomach/gastrointestinal tract may help in diagnosis.

Diagnosis

z Acetaldehyde in stomach content, lavage washings, tissues: Submit frozen. Freeze rapidly. Acetaldehyde smells
similar to formaldehyde.
z Metaldehyde in baits can be analytically detected.
z Metaldehyde in liver, urine, and plasma. Urinary excretion is low.

Treatment

z Seizure control : Diazepam 2 - 5 mg/kg IV to effect may be preferred over barbiturates because barbiturates compete
 with an enzyme that degrades acetaldehyde. Phenobarbital or pentobarbital may be required for unresponsive cases.
z Horses : Xylazine with acepromazine has been recommended.
z Artificial respiration.
z Enterogastric lavage, activated charcoal.
z Severe cases : Gas anesthesia, fluids with bicarbonate.
z Fluid therapy to control dehydration, acidosis, electrolyte imbalances.

Key Features

z Especially California and Gulf Coast.

z Snail bait, polymer of acetaldehyde.
z Acidosis.
z Reduction in brain serotonin and norepinephrine.
z Tremors, seizures, not aggravated greatly by stimulation.
z May be followed by liver failure.
z Evacuate GI tract, activated charcoal, diazepam, barbiturates may be contraindicated (use only when not responding),
fluids and bicarbonate.

Acetaldehyde toxicity in dogs.

z 600 mg/kg acetaldehyde per os.

z Clinical signs included vomiting, tremors.
z Vomitus often bloody.
z All normal 24 hours after receiving acetaldehyde.

Fluoroacetate-1080

Major Species Usual Time of Onset Usual Duration (if survives) Full Table for
Toxicants Associated
All species, esp. carnivores, rodents (target species) Hours Few days; often lethal with Seizures

Sources

z Primarily used in commercial rodent control (e.g. by Pest Control Operators in very controlled conditions). Not
legally found in rodenticides for use in homes in the USA.
z Tasteless, odorless, colorless; dyed black.
z Relay toxicosis - especially in dogs, possible in other species.
z Coyote control.
z Large bait stations - used in past; now illegal.
z Occasional experimental coyote control permits.
z Toxic collars (various forms) on sacrificial sheep - on market now.
z Single lethal dose baits - proposed and studied but not marketed.
z Used for control of ground squirrels and rabbits in some countries.
z Still in use as a widely available rodenticide in some Latin American and other countries of the world. Sometimes
products are smuggled into the USA from Mexico.
z Characteristic lag period after ingestion, may limit the development of bait shyness.
z Fluoroacetic acid is the toxic principle in several poisonous plant species from South Africa, Australia, and Brazil
(see front index).
z Fluoracetate is an important toxic metabolite of some fluorinated ethanes that might be inhaled, e.g.: 1,2-
difluoroethane, 1-chloro-2-fluoroethane, 1-chloro-1,2-difluorethane, and 1-bromo-2-fluoroethane of
fluoroethylnitrosoureas. The enzyme involved in bioactivation is likely to be cytochrome P450 2E1.
 Sodium fluoroacetate (1080 )

Mechanism

z Classical Theory (Lethal synthesis) :

Fluoroacetate + Acetyl-Co-A → Fluoroacetyl-Co-A + Oxalacetate → Fluorocitrate
Inhibits Aconitase (Kreb's cycle inhibited, energy depleted), which results in accumulation of citric and lactic acids.

Tricarboxylic acid cycle

 Sites of action of aconitase

z Kun's hypothesis (not widely accepted).

z Fluorocitrate is formed as shown above and is the active (toxic) metabolite.
z Primary mechanism is not primarily due to inhibition of aconitase - but is due to inhibition of citrate transport
across the inner mitochondrial membrane.

Toxicity

z Oral lethal doses (LD50).

z Canine and feline 0.05 - 1.0 mg/kg of b.w.
z Rodent 0.2 - 8 mg/kg.
z Oral lethal doses:
z Cattle: 0.15 - 0.62 mg/kg.
z Sheep: 0.25 - 0.50 mg/kg.
z Goat: 0.30 - 0.70 mg/kg.
z Horse: 0.50 - 1.75 mg/kg.
z Pig: 0.30 - 0.40 mg/kg.
z Fowl: 10 - 30 mg/kg.
z Relay toxicoses possible. Occurs especially when canids consume poisoned rodents.

Signs

z Affects CNS and heart.

z Effects and signs vary with species.
z Latent period 1/2 to several hours.
z Cardiotoxic: cattle, horse, rabbit.
z Neurotoxic: dog, guinea pig.
z Both: pig, cat, monkey, sheep.
z Dogs
z Anxiety.
z Running in a straight line or around the perimeter of an enclosure.
z Wild barking.
z Vomiting. Vomiting generally occurs too late to save animal's life.
z Hyperthermia.
z Repeated defecation, urination - tenesmus (persistent).
z Seizures which are largely tetanic; increase in frequency and severity with time. Later, as animal becomes
exhausted seizures become weaker but even more frequent. Paddling occurs during seizures.
z Breathing ceases before heart stops.
z Death occurs within 2 - 12 hours after ingestion. Death may occur during seizures or from subsequent
respiratory paralysis.
 z Cats
z Excitation or depression, vocalization.
z Ropey salivation, possible evacuation of bowels, possibly diarrhea.
z Arrhythmia common.
z Generally do not display "running fits".
z Ruminants, herbivores
z Cardiac signs primarily noted : Arrhythmia, rapid weak pulse, ventricular fibrillation. Stagger, tremble,
collapse, grind teeth, terminal seizures.
z Horses
z Tremble, sweat. May die from ventricular fibrillation.
z Swine and sheep
z Cardiac and nervous syndromes.

Clinical Pathology

z Hyperglycemia (poor utilization - Kreb's cycle inhibited).

z Lactic acidosis.

Lesions

z Empty stomach, colon, urinary bladder.

z Cyanosis.
z Rapid rigor mortis.
z Congestion - liver, kidney.
z Heart- diastole with subepicardial hemorrhage (nonspecific lesion).
z Sheep that died acutely from fluoroacetate toxicosis had degeneration and necrosis of individual or small groups of
myocardial fibers.
z Cerebral edema and lymphocytic infiltration of the Virchow-Robin space have been described.

Diagnosis

z Signs
z History of exposure, negative tests for other agents help to rule out other causes.
z Analysis of:
z Baits, stomach contents, vomitus, liver, kidney. Few labs perform analyses; analysis difficult; best lab at
present is the State Diagnostic Laboratory in Fargo, North Dakota.
z False negatives at any lab, especially at inexperienced lab.

Treatment

z Do not use an emetic unless it is very early, no signs are observed, and the animal will be constantly monitored in
case of seizures. Perform enterogastric lavage if there is any likelihood of continued absorption.
z activated charcoal + saline cathartic.
z Most symptomatic treatments (when used alone) are not reliably effective after severe signs develop. Treatment often
fails but can permit some animals to survive.
z Barbiturates (pentobarbital to control presenting seizures followed by a prophylactic dose of Phenobarbital and
additional pentobarbital, repeat as needed) (Tourtellotte and Coon, 1950).
z Solutions containing 50% alcohol and 5% acetic acid have been given orally at 8.8 ml/kg. In almost all cases, this
therapy is ineffective. Moreover, combined therapy with ethanol and barbiturates was associated with prolonged
(days) anesthesia and a high incidence of pneumonia.
z Barbiturates alone are therefore preferred over barbiturates with ethanol and acetic acid. Barbiturates are far better
than ethanol and acetic acid alone.
z Calcium gluconate has been recommended to control tetany (0.2 - 0.5 ml/kg of 5% solution, IV, slowly in fluids).
z Monacetin (glyceryl monoacetate) at 0.55 gm/kg, IM. Apparently, the theory is to provide an available source of
acetate to compete with fluoroacetate and thereby increase the production of citrate.
 z Short shelf-life.
z May be difficult to obtain.
z Not very effective unless dose of 1080 is near or less than the LD50
z Antiarrhythmics may be of value in appropriate species; apparently these have not been tested for efficacy in 1080
poisoning.

Differential Diagnosis in 1080 Poisoning

z Initial considerations.
z Lead-running fits, convulsions, vomiting, but usually much slower onset.
z Hypomagnesemia, hypocalcemia, brain injury.
z Cardioglycoside toxicosis, Japanese yew (Taxus spp.) poisoning.
z Strychnine, organochlorine insecticide or methylxanthine toxicosis.

Key Features

z Often multiple deaths near source, rodenticide, coyote control.

z Mechanism(s) of action.
z Delayed onset, running, evacuation of GI tract, urinary bladder.
z Species differences (CNS vs. heart).
z Phenobarbital if seizuring, hyperexcitable, detoxification.
z Often poor response to therapy.

5-Fluorouracil

Major Species Usual Time of Onset Usual Duration (if survives) Full Table for
Toxicants Associated
All, esp.dogs Minutes to Hours Weeks often lethal with Seizures

Sources

z Chemotherapeutic anticancer therapy.

z Used for the treatment of solar keratoses, actinic keratoses, and superficial skin tumors in humans.
z Commonly prescribed forms of 5-fluorouracil (5-FU) include 2% and 5% Efudex solution and cream, 1% Fluoroplex
topical cream and solution.

5-fluorouracil
Toxicity

z Estimated toxic doses in dog 20 - 129 mg/kg.

z Estimated lethal doses 43 mg/kg.
z Oral LD50 5-FU - mice 500 mg/kg; Rat 100 mg/kg.

Absorption, Distribution, Metabolism and Excretion (ADME)

z Variable oral absorption in human clinical studies.

z Absorbed through intact skin.
z 5-FU is a pyrimidine antimetabolite which needs to be metabolized in order to produce cytotoxicity.
z Its complex metabolism involves intracellular conversion of 5-FU to either 5-fluoro-2'-deoxyuridine-5'-
monophosphate (FdUMP) or 5-fluorouridine-5'-triphosphate (FUTP).
z 5-FU readily diffuses across cell membranes, FdUMP does not readily diffuse. Extended bone marrow toxicity may
be related to delayed clearance of FdUMP from this site.

Mechanism of Action

z Toxicity of 5-FU is most pronounced in rapidly dividing cell lines.

z FdUMP inhibits intracellular enzyme, thymidylate synthetase. Thymidylate synthetase inhibition prevents the
conversion of 2'-deoxyuridine-5'-monophosphate (dUMP) to 2'-deoxyruidine-5'-monophosphate (dTMP). Inhibition
of dTMP synthesis results in impaired DNA synthesis.
z FUTP is incorporated into RNA, impairing post-transcriptional processing of ribosomal RNA (rRNA).
z 5-FU can also be converted to 5-fluorocytosine (5-FC) which is incorporated into messenger RNA (mRNA) in place
of cytosine, resulting in misreading as uracil.
z Normal RNA turnover may act as a slow release depot for 5-fluororidine-5'-monophosphate (FUMP) which can be
converted to FdUMP, with resultant prolongation of FdUMP-mediated blockade of thymidylate synthetase.
Incorporation of 5-FU does not necessarily lead to biologically significant alterations in RNA function.
z Postulated from experimental studies in cats that the development of cerebellar ataxia is due to production of
fluorocitrate and interference with Kreb's cycle as per toxicosis resulting from fluoroacetate.

Clinical Signs

z Since bone marrow stem cells and epithelial cells of the intestinal crypts have high mitotic index and growth rate,
these 2 organs are prime targets for 5-FU toxicity.
z In human patients leukopenia and thrombocytopenia most commonly develop 7 - 20 days following the
administration of the first 5-FU dose.
z Mucosal ulceration, diarrhea, and vomiting are common findings during 5-FU therapy in human patients.
Radiographic evidence of mucosal ulceration may be noted with the use of contrast media.
z Clinical signs in dogs developed within 45 - 60 minutes following accidental ingestion. Deaths occurred 6 - 16 hours
post-ingestion.
z The most commonly reported clinical signs in accidental 5-FU ingestion by dogs include vomiting, seizures, death,
hypersalivation, tremors, and ataxia.
z Less common clinical signs in dogs include respiratory distress, cyanosis, depression, lacrimation, alopecia,
bradycardia, tachycardia, personality changes - aggressiveness. Behavioral changes have been reported following
dermal exposure of a domestic cat to 5-FU.
z Less frequent signs reported in humans include lacrimation, cardiotoxicity, and alopecia which seem to parallel those
seen in dogs.
z 5-FU reported to be neurotoxic in man, dogs, and cats. Cerebellar ataxia is most commonly reported neurotoxic sign
in human patients receiving 5-FU therapy. Adverse reactions from intravenous 5-FU therapy in dog and cat includes
hyperexcitability, nervousness, muscle tremors, and ataxia.

Pathology

z Clinical pathological changes included mild elevations in serum SGPT, serum alkaline phosphatase, and creatinine
 phosphokinase 2 days postexposure.
z Pathological lesions include hemorrhagic colitis, gastrointestinal mucosal ulceration, desquamation of the
gastrointestinal tract, stomatitis. Pulmonary edema and congestion of the lungs, liver, thymus, kidneys, and small
intestine.

Treatment

z Emetic and activated charcoal if animal asymptomatic and recent (< 1 hour) ingestion.
z Symptomatic and supportive therapy including fluids, anticonvulsant therapy, and gastrointestinal protectants.
z Valium as an anticonvulsant was rarely effective for the control of 5-FU related seizures. Phenobarbital or
pentobarbital may be required as anticonvulsants.
z Phenothiazine tranquilizers are contraindicated. Focal motor and grand mal seizures have been associated with the use
of phenothiazine tranquilizers in human patients receiving 5-FU.
z Lithium carbonate (10 mg/kg PO BID) can be used to stimulate myelopoiesis if bone marrow toxicity develops.
Accidental ingestions of 5-FU in dogs have not been associated with bone marrow suppression to our knowledge.
Febrile neutropenic animals should have blood cultures performed and require bactericidal antibiotic therapy.
z Continuous subcutaneous infusion of uridine prevented lethal toxicity of 5-FU in experimentally dosed mice. In
humans, the proposed dose for uridine rescue is 2 grams/m2/hour as an intermittent infusion for 3 hours. A 3-hour
uridine-free or rest period is recommended between intermittent infusions to avoid risk of uridine-related fever. The
usefulness of uridine for the treatment of acute accidental ingestions of 5-FU is uncertain at this time.
z Allopurinol has been studied as an agent to reduce the dose-limiting toxicity of 5-FU. Some benefit in humans was
observed with high-dose continuous intravenous infusion. No clinical benefit was noted with bolus allopurinol.
Effectiveness of allopurinol in acute oral toxicity is unknown at this time.

Additional Toxicants

Usual Duration
Specific agents Major Species Usual Time of Onset
(if survives)
Castrix (crimidine) All species Minutes Hours; potentially lethal Full Table for
(rodenticide) Toxicants Associated with Seizures
Acute Fluoride Toxicosis See Toxicants that Affect the Teeth and Skeletal System
Japanese Yew (Taxus) in dogs See Toxicants that Affect the Heart

z Castrix (Crimidine)
z Acute Fluoride Toxicosis (See Toxicants that Affect the Teeth and Skeletal System)
z Japanese Yew (Taxus) in dogs (See Toxicants that Affect the Heart)
z Corynetoxins (due to ingestion of pasture grasses, such as Festuca rubra commutata, that have mature seedheads
infected by Clavibacter toxicus)

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