LOCOWEED

The locoweeds, Astragalus and Oxytropis species, are found from the Rocky Mountains and Texas to California. Plants of both genera are perennial, herbaceous legumes with opposite, pinnately compound leaves. Flowers are purple to white racemes.²⁵ Seeds are borne in pods. Various species of Astragalus have different toxic chemicals and effects. Some species are nontoxic, whereas others have excessive selenium concentrations, 3-nitrocompounds, or swainsonine (the locoweed toxin, also found in Swainsona).^26-28 Swainsonine (locoweed) inhibits cellular α-mannosidases, leading to abnormal glycoprotein metabolism.^29,30

Locoweed is unpalatable to livestock and is initially ingested when other feed is lacking (during the winter and spring).³¹ In addition, evidence suggests that cattle may learn to ingest locoweed from one another.³² Once ingestion is initiated, however, animals apparently acquire a taste for the plant.³¹ Locoweed remains toxic when dry,³³ and it affects all classes of livestock. Locoweed ingestion (up to 90% of body weight of plant material) causes gradual onset of signs related to the production, metabolic, central nervous, reproductive, and cardiovascular systems.^31,33-38 Affected animals become emaciated, lethargic, dull, and ataxic, with an impaired sense of direction.^33,37 Animals are nervous despite the depression and, especially horses, may react violently to stimulation. Horses do not seem to recover from the tendency to react uncharacteristically to stimuli. Reproductive consequences of “locoism” include abortion, prolonged estrus, altered breeding behavior, decreased libido, inhibition of normal spermatogenesis, weak and docile newborns, and deformed limbs with flexed tendons and joint laxity.^{34,37,38,40,41} Locoweed ingestion predisposes calves to development of right-sided congestive heart failure at high altitudes (“high mountain disease”).^35,36

Sheep fed locoweed had clinical pathologic evidence of liver and renal (mild) damage, with increased serum concentrations of alkaline phosphatase (ALP), aspartate transaminase (AST), and blood urea nitrogen (BUN).^39,42 The major postmortem finding in locoweed intoxication is emaciation. Microscopically, locoweed (and swainsonine) causes widespread neurovisceral cytoplasmic vacuolation in animals and the fetus (if present).^43-45 The brain, liver, and kidney are the major affected organs. The vacuoles contain mannose-rich compounds.⁴⁶ Diagnosis of locoweed toxicosis is based on evidence of plant consumption, clinical signs, and lesions. No chemistry test is available for locoism. New tests are under development to stain tissues for mannose accumulation⁴⁶ and measure α-mannosidase activity in serum to indicate exposure to locoweed.⁴⁷

No antidote is available for locoweed poisoning. Exposure to the plant should be stopped and proper nutrition provided. Recovery from emaciation frequently occurs, but horses that have developed locoism cannot be trusted. Proper grazing management of rangeland, including using range when other, more palatable plants are present, is a recommended strategy to minimize losses caused by the plant.⁴⁸ Milk from animals exposed to locoweed can be toxic, suggesting that swainsonine is passed in milk.⁴⁹ Clearance studies suggest that poisoned animals should be given approximately 28 days to clear swainsonine because of an estimated half-life in livestock of 60 hours.^47,50

PYRROLIZIDINE ALKALOIDS

Losses from pyrrolizidine alkaloids occur throughout the United States, resulting from ingestion of various species (spp.) of plants from the families of Compositae (Senecio spp.), Leguminosae (Crotalaria spp.), and Boraginaceae (Cynoglossum and A. intermedia).⁵¹ S. jacobea is found in the northwestern United States, S. vulgaris (common groundsel) can be found throughout the western United States, Crotalaria is present in the Midwest, Cynoglossum is primarily in the Rocky Mountain region, and Amsinckia is in California. Toxin concentrations are highest in seeds, flowers, and leaves and are lower in stems. The most toxic pyrrolizidine alkaloids are diester rings with a 1,2 double bond and a branched ester group.⁵¹ The compounds are bioactivated in the liver to reactive pyrroles and trans-4-hydroxy-2-hexenal.^52,53 The reactive metabolites bind cell molecules and cross-link deoxyribonucleic acid (DNA), leading to necrosis, alteration of cell division, or carcinogenicity.⁵² The carcinogenicity of these compounds, which is a result of both genotoxic and promoting properties, is a reason for food safety concerns related to the pyrrolizidine alkaloids.^54,55

Plants with pyrrolizidine alkaloids are unpalatable. Most poisonings occur when animals are forced to graze the plant, or when the plant is masked in hay (Senecio spp. and A. intermedia) or grains (Crotalaria spp.; a major contaminant before the availability of herbicides for weed control).⁵¹ Toxicity is retained in dry hay and grains. All classes of livestock are affected. Small ruminants such as sheep are more resistant to the alkaloids than are cattle and horses. For example, ingestion of as little as 5% of their body weight of tansy ragwort (S. jacobea) in hay may be lethal to a cow or horse. Conversely, more than 100% of their body weight in plant material is needed to cause pyrrolizidine alkaloid poisoning in sheep and goats.⁵² The resistance of sheep to the alkaloids likely results from differences in liver biotransformation patterns.⁵¹ For example, sheep tend to have lower rates of hepatic production of toxic pyrroles plus higher levels of glutathione conjugation of toxic metabolites.⁵⁶ Interestingly, ingestion of pyrrolizidine alkaloids will enhance the toxicity of copper in sheep.⁵⁷ Although cattle and horses tend to have similar sensitivity to Senecio species, it is apparent that cattle tend to resist the hepatotoxic effects of Amsinckia at levels in hay that would be hazardous to horses (although Amsinckia may still cause nitrate toxicity in the cattle instead).

Animals with pyrrolizidine alkaloid toxicosis are usually presented with signs and lesions compatible with liver failure (see Chapter 33 for a complete description of signs and lesions).^51,52,58 In addition to liver effects, pulmonary disease also has been reported for Crotalaria poisoning.⁵¹ Signs may be delayed for months after ingestion of the plant, appearing after the liver damage has had an opportunity to become chronic.⁵⁹ Emaciation and hepatoencephalopathy often occur, leading to common names for the disease, such as “walking disease,” “walkabout,” and “hard liver disease.”

Diagnosis of pyrrolizidine alkaloid toxicosis depends on a history of exposure to the plants, clinical and pathologic evidence of liver failure, and classic histologic lesions.^60-62 Antemortem diagnosis, in the absence of an appropriate history, can be difficult because of the nonspecific nature of signs and the potential for delayed and progressive effects. Diagnosis in these cases benefits from histologic examination of a surgical liver biopsy. Recent studies suggest that a chemistry test for sulfur-bound pyrrolic metabolites of pyrrolizidine alkaloids in unfixed liver tissue may be useful, but is not yet available for diagnostic use.^63,64

Treatment for pyrrolizidine alkaloid toxicosis centers on treating the liver failure and eliminating additional exposure to the plant. Although not preventive, evidence suggests that ingestion of sulfur-containing amino acids in high levels can influence pyrrolizidine alkaloid toxicity through maintenance of hepatic glutathione levels.⁶⁵ Note that sheep may be fed added molybdenum to delay accumulation of copper on a chronic basis.⁵¹ Prognosis in advanced cases is poor. Very low levels of pyrrolizidine alkaloids are transferred into the milk, but attempts to transfer toxicity in the milk have not resulted in clinical or pathologic evidence of toxicosis.^52,66

LARKSPUR ALKALOIDS

Larkspur (Delphinium) and monkshood (Aconitum) have alternating, palmately divided leaves, which in larkspur may cluster at the base. Racemous flowers have a variety of colors, depending on species, and are characterized by a lower spur (larkspur) or an upper hood (monkshood).⁶⁷ Loss of cattle from larkspur is economically important in the western United States. Unlike many toxic plants that prefer disturbed soil, larkspur is found in undisturbed mountain ranges.⁶⁸ Larkspur species are divided into low and tall varieties based on height (low, <76 cm; tall, >76 cm) and elevations (tall larkspurs are found in high mountain altitudes).⁶⁸ Larkspurs contain a variety of complex, diterpenoid alkaloids, such as methyllycaconitine and deltaline.^69,70 The larkspur alkaloids cause skeletal muscle paralysis by blocking nicotinic, acetylcholine receptors at the neuromuscular junction and in the brain.^69,71,72

Larkspurs are hazardous because they are palatable and appear early in the spring.^68,73 Although dried plants may be toxic, the diterpenoids are highest and most hazardous in the early-spring leaf growth, after flowering racemes are elongated.^72,74,75 During that period, cattle will tend to ingest more larkspur during or just after a summer storm.⁷² All animals may be poisoned by larkspur. Cattle are most sensitive to the plant (17 g/kg of body weight of early plant growth may be lethal), whereas sheep are four times less sensitive.⁷⁶ Calves are often affected when they graze with “nurse” cows on the edges of meadows (likely area for larkspur growth) while dams graze steep hillsides. Clinically, larkspur poisoning results in stiffness and weakness, abdominal pain, collapse (often with forelegs first), and death from aspiration of regurgitated ingesta or respiratory paralysis within 3 to 8 hours after exposure.^{69,73,74,76,77} Death may be sudden (see Chapter 14). Recovery may occur in sublethal cases within 1 to 2 days.⁷⁴

Postmortem, animals with larkspur poisoning bloat rapidly.⁷⁴ Clinicopathologic findings are nonspecific. Diagnosis of larkspur toxicosis depends on a history of sudden death with rapid bloating on rangeland in early spring, evidence of consumption of the plant, and a lack of other diagnostic findings. Chemistry testing is not routinely available for larkspur alkaloids, although testing of urine or serum for the alkaloids may be viable.⁷⁸

Treatment for larkspur poisoning centers on control by pregrazing with sheep (less sensitive), delay of grazing until alkaloid levels drop to less than 3 mg/g in leaves (after seed shatter),⁷⁹ spraying larkspur with nonspecific herbicides such as tebuthiuron,⁸⁰ and attempts to develop in the animals an aversion to grazing the plant.^74,81 Recently, the ability of the larkspur mirid (Hoplomachus affiguratus Uhler) to control larkspur has been suggested as a biocontrol measure.⁸²

NICOTINIC-ACTING ALKALOIDS

The lupines and thermopsis are found in climax and grassy habitats, whereas poison hemlock and the tree tobacco plants are found in disturbed soils. This group has three classes of nicotinic toxins: pyridine alkaloids, quinolizidine alkaloids, and piperadine alkaloids. Nicotinic alkaloids cause toxicity by ganglionic stimulation, followed by blockade and paralysis.^83,84 The teratogenic effects of lupines, tree tobacco, and poison hemlock may result from paralysis of the fetus during the period of joint formation (days 40 to 70 of gestation for cattle; days 30 to 60 for swine and sheep).^85-89 Thermopsis causes myonecrosis by an unknown mechanism.^90,91

The plants are often bitter and are ingested when they are hidden in hay or forage or when animals are forced to do so by drought or hunger. Some lupines may be toxic when incorporated into feed as a supplement, although the toxin and mechanisms remain to be defined.⁹² The plants are toxic when dry except for Conium, which has quite volatile toxins that dissipate with time when plants are dry (fresh hay may be toxic).^84,93 All classes of livestock are affected by the plants, although species variations occur.^83,84,94,95 For example, acute toxicosis is more common in sheep. Conversely, teratogenesis is more likely in cattle.⁹¹ Despite the lower likelihood of acute toxicity, it does occur. For example, deaths occurred in yearling Holstein dairy cattle pastured on lupine (personal observation). Cattle were more sensitive to the acute effects of coniine (poison hemlock) than were horses or sheep.⁹⁵ Acute toxicosis from nicotinic alkaloids is characterized by ataxia, weakness, tremors, initial stimulation of the central nervous system (CNS) followed by lethargy, increased salivation, respiratory distress, bloating, and death from respiratory paralysis.^83,84,96,97 Teratogenic signs include cleft palate (earlier in the susceptible period) and if exposed during joint development, classic arthrogryposis (“crooked calf syndrome”) involving the joints of the legs and spine.^85-89,95,98 Acute T. montana toxicosis in cattle leads to tremors, a stilted gait, and recumbency, followed by respiratory paralysis and death. The animal may be found dead (see Chapter 14).⁹⁰

Clinicopathologic changes are nonspecific for most of the nicotinic plants. Thermopsis may result in elevations of creatine kinase (CK) and AST, suggesting skeletal muscle damage.⁹⁰ Other than bloat and pulmonary edema, acute nicotinic alkaloid toxicosis results in few specific lesions.^93,96 The congenital malformations are usually obvious on postmortem examination. Thermopsis toxicosis is characterized by degeneration and necrosis of skeletal muscles.^90,91

Diagnosis of acute nicotinic alkaloid toxicosis depends on identification of the plant and appropriate signs. Additionally, reliable chemical assays have been developed to detect some of the alkaloids in urine and serum of exposed animals, including those of poison hemlock, tree tobacco, and some lupines.^93,96,99 Diagnosis of the source of crooked calf syndrome requires historical review of plants that may have been grazed during the susceptible period of gestation.

Treatment of acute toxicosis is nonspecific. Exposure should be eliminated. Animals in poor body condition may have higher circulating levels of lupine alkaloids at a given dose, suggesting that disposition of the alkaloids is affected by nutritional condition.¹⁰⁰ Many of the potentially teratogenic alkaloids of these plants, including some from poison hemlock and Lupinus, are passed into milk and muscle tissue.^101,102

STEROIDAL ALKALOIDS

Deathcamas is a slender, perennial herb (up to 50 cm tall) with grasslike basal leaves that grows from an onionlike bulb and has yellow-white flowers.¹⁰³ False hellabore has short, hairy, stout stems with broad, prominently veined leaves.¹⁰⁴ Solanum species range from annual herbs to woody plants. They have four to five lobed, white to purple flowers.¹⁰⁵ The fruit is a berry. The leaves often have two small leaflets at the base or incorporated as small lobes. Deathcamas and Veratrum species, both of which are Liliaceae, are found in moist meadows at upper elevations. Solanum species are found throughout the United States. Deathcamas (alkaloid is zygacine) and false hellabore contain steroidal alkaloids that cause cardiovascular hypotension.¹⁰³ Veratrum alkaloids include the teratogens jervine and cyclopamine.¹⁰⁶ Solanaceous plants such as the nightshades, tomatoes, and potatoes have steroidal alkaloids linked to sugars (glycosides).¹⁰⁷ Those Solanum alkaloids may inhibit cholinesterase, cause gastrointestinal (GI) irritation, and induce constipation. Some solanaceous plants accumulate nitrate (tomato vines)¹⁰⁸ or have other toxic factors such as vitamin D, which causes calcinosis (Solanum malacoxylon, found in South America and Hawaii).

The steroidal alkaloids are toxic to all classes of livestock. Sheep are most frequently poisoned by Veratrum and Zigadenus.^103,109 Zigadenus is most hazardous in the early spring because it is among the first plants present.¹⁰³ Veratrum is teratogenic when grazed by ewes around days 14 and 30 of gestation.^110,111 The alkaloids resist drying.¹⁰⁷ Ingestion of as little as 0.6% of body weight of deathcamas can cause ataxia, stiffness, tremors, increased salivation, vomition, and prostration. Death may occur within 1½ to 8 hours of exposure¹⁰³ (see Chapter 14). Solanum species vary in toxicity and effect, causing GI irritation, ileus (in horses), lethargy, increased salivation, dyspnea, tremors, paralysis, diarrhea or constipation, and death.^103,105,107 Pregnant ewes grazing Veratrum during day 14 of gestation produce lambs with craniofacial deformities, including cyclopia, microphthalmia, and cleft palate.^109,110 Gestation may be prolonged in affected ewes.¹⁰³ Limb and bone shortening in the metacarpal and metatarsal joints can occur in lambs when ewes ingest the plant around day 30 of gestation.¹¹¹

Clinical and pathologic findings are nonspecific, except for the teratogenesis from Veratrum. Severe intoxication from Solanum species may lead to congestion of major internal organs.¹⁰⁷ Diagnosis involves accumulated signs with evidence of consumption of the plant. Chemistry testing is not routinely available.

Treatment for poisoning centers on prevention. Deathcamas and false hellabore should be avoided in early spring. The highly variable toxicity of the solanaceous plants makes recommendations about prevention difficult, although feeding large volumes of the plants is ill-advised.

TROPANE ALKALOIDS

Datura and Atropa are also solanaceous plants. Jimsonweeds prefer disturbed soils such as barnyards.¹¹² The plants contain the tropane alkaloids, atropine and scopolamine, which block acetylcholine at muscarinic nerve synapses. Although Datura is bitter and unpalatable, herbicide application or overgrazing may encourage consumption. Grain contaminated with Datura seeds is toxic.¹¹² Datura toxicity results in GI atony, anorexia, rapid heart and respiratory rates, mydriasis, thirst, diarrhea, excess urination, disturbed vision, and delerium.^113-115 Death is uncommon, perhaps because gut atony and anorexia may limit plant intake.¹¹² However, gut atony can be fatal in some species, including the horse.^113,114 Exposure to trace amounts of Datura species, such as in the bedding or feed, may result in urinary residues of tropane alkaloids in the horse’s urine.¹¹³ Lesions are nonspecific. Tropane alkaloids can be identified in urine, ingesta, and plant material.

YEW

Yews are evergreen shrubs and small trees with flattened needles. The plants are found throughout the United States in hedges and yards.¹¹⁶ Yews contain alkaloids called taxines, which depress myocardial conduction by blocking sodium movement through membranes.¹¹⁷ Some yews also contains antimitotic, diterpenoid taxols, which are of medical interest as anticancer agents.¹¹⁸

Yew is extremely toxic; less than 0.1% of body weight of dried leaves may kill a horse.¹¹⁹ Toxicity is retained in dry plants. All species are sensitive to yew toxicity. As with oleander, yew poisoning often results from accidental ingestion of hedge clippings.^116,120 Clinical toxicosis is usually manifested by collapse and sudden death (Chapter 14) related to heart failure, occasionally preceded by tremors and weakness.^116,119-121

Lesions are uncommon, although focal, nonsuppurative myocarditis is possible.¹²⁰ Diagnosis of yew toxicosis requires a history of exposure to yew clippings and sudden death. Finding of leaf parts in the ingesta is diagnostic. The investigator may be confused by needles from Pinus and the coastal redwood (Sequoia sempervirins). Alkaloids have been suggested by mass spectral chemistry in samples from poisoned animals.¹²²

TRYPTAMINE ALKALOIDS

Phalaris species are pasture grasses. Under poorly defined conditions, Phalaris accumulates indole and β-carboline alkaloids.^123,124 Those alkaloids block serotonin in the CNS and may inhibit monoamine oxidases.^124,125 Cattle and sheep are affected, although sheep are more likely to be poisoned by Phalaris.¹²⁶ The alkaloids are bitter, resulting in lowered weight gains if present at levels exceeding 0.2% of plant weight.¹²⁴

Clinically, two syndromes can result from canary grass toxicity. Sudden death with cardiac failure is one possible result of poisoning.^124,126 Chronic lower-level exposures may lead to a staggers syndrome with ataxia, a hopping gait, tremors, excitability, head nodding, convulsions, and eventually paddling and death in sheep and horses.^124,127-129 Onset of signs may be delayed up to 40 days after ending exposure to canary grass.¹³⁰ (See later discussion and Chapter 35 for grass staggers.)

Postmortem examination of sheep with the staggers syndrome reveals characteristic gray to bluish discoloration of the brainstem.^130,131 The kidney and liver also may be pigmented. Pigment in the cytoplasm of the nerves apparently destroys those cells.¹³¹ Clinical signs of sudden death or staggers in sheep that have previously grazed canary grass pasture, along with characteristic discoloration of brain tissue, are used for diagnosis. Treatment of clinically affected animals has not been rewarding; however, supplementation with cobalt may help prevent toxicosis.¹³²

CARDIAC GLYCOSIDES (CARDENOLIDES, GRAYANOTOXINS)

Many families of plants contain cardiotoxic glycosides. Many of the plants, including azaleas, oleander, and Japanese pieris, are evergreen shrubs and small trees.¹³⁵ In addition to plants, cardiac glycosides may be found in animals such as the bufo toad. The toxic cardiac glycosides, including various cardenolides and bufadenolides, are steroid-like in structure and have a lactone ring.¹³⁶ Common cardiac glycosides include digitoxin and digoxin from foxgloves, oleandrin (aglycone = oleandrigenin) from oleander, and grayanotoxins from rhododendron. Cardiac glycosides block cellular sodium-potassium adenosine triphosphatase (ATPase), leading to sodium accumulation in excitable cells such as nervous tissue and myocardium.^136-138 Grayanotoxins block fast sodium inactivation in excitable tissues by binding to sodium channels.¹³⁹ Increased cardiac contraction and altered heart rhythms result from myocardial effects. The plants also are potent GI irritants.

Cardiac glycosides are found in most parts of the toxic plants.¹⁴⁰ Although plants are bitter, dried leaves (oleander) and flowers are readily ingested by all classes of livestock, causing toxicosis.^10,140,141 Discarded lawn clippings that contain oleander leaves are a common source of livestock poisoning. Some of the plants are extremely toxic, and toxic effects are cumulative. For example, 0.005% to 0.015% of body weight of oleander (equivalent to a handful of leaves) can be lethal in sheep and cattle, and one leaf may kill a human.^125,142 Azaleas may be toxic when livestock ingest 0.2% to 0.6% of body weight of plant material.¹⁴² Clinical signs of toxicosis reflect GI irritation and damage to the heart. The onset of toxicosis may be delayed by several hours after ingestion. Although death may be sudden (see Chapter 14), it usually occurs within 36 hours after ingestion but may take up to 14 days.¹⁴³ Signs include abdominal pain, nausea, weakness, anorexia, muscle tremors, rumen atony, increased salivation, bradycardia (or tachycardia later in the syndrome), heart block, and ventricular arrhythmias (including a gallop rhythm for oleander in cattle).^126,141-147

Animals with acute cardiac glycoside toxicosis may have hypertension, hypoxemia, acidemia, hemoconcentration, hyperkalemia, hyperchloremia, and elevations of serum creatinine and glucose.¹²⁶ Electrocardiogram (ECG) alterations include widening of the QRS complex, ST segment depression, enlarged P waves, and a variety of ventricular arrhythmias. Lesions associated with cardiac glycoside toxicosis are nonspecific and include hemorrhagic gastroenteritis and pale mottling of the heart with congestion, hemorrhage, and histologic evidence of myocardial degeneration and necrosis.^{125,126,143,144}

Diagnosis of cardiac glycoside toxicosis depends on identification of the plant and evidence of its consumption. Two-dimensional thin-layer chromatography (TLC) and liquid chromatography/mass spectrometry (LC/MS) methods have been developed for assay of oleander in ingesta and body fluids from affected animals.^10,145,146 LC/MS can be used to assess grayanotoxin exposure in urine and feces of affected animals.¹⁴⁷ A serum radioimmunoassay (RIA) can be used to assess exposure to Digitalis; this test may cross-react with oleander glycosides for some diagnostic utility.¹⁴⁸

Treatment of cardiac glycoside toxicosis begins with elimination of exposure to the plant and decontamination using cholestyramine resins or activated charcoal (repeated applications suggested).¹²⁷ Fluids with calcium and potassium should be avoided (unless hyperkalemia is absent). Atropine may be useful if bradycardia or heart block is present (use care in horses; it may cause gut stasis). β-Adrenergic blocking agents and antiarrhythmic drugs can be used for cardiac dysrhythmias; otherwise, β-blockers should be avoided.^126,127 Use of anticardiac glycoside Fab antibodies is an experimental treatment for digitalis and oleander toxicoses.^148-150 Stress should be avoided in animals exposed to cardiac glycosides. Prevention of cardiac glycoside toxicosis includes keeping hedge clippings away from animals and avoidance of plants when in full flower. Digitalis glycosides are widely distributed in the body, including in milk and fetal fluids, and the primary elimination pathway is urinary.¹²⁶ Evidence of oleandrin was identified in the milk of poisoned cows using two-dimensional TLC in the author’s laboratory. No oleandrin was found at 5 days after exposure in milk from that dairy.

PHOTOSENSITIZING SAPONINS

These grasses and weeds may contain toxic levels of hepatotoxic, steroidal sapogenins such as disogenin.^151-154 Sapogenins are metabolized in animals to glucuronide conjugates of epismilagenin, which crystallize in bile, leading to biliary blockage, cholangitis, and secondary photosensitization (Chapter 40).^153-155

Plants are most hazardous when grazed during stages of early, rapid growth when sapogenin levels are highest.¹⁵⁵ Feed refusal can occur because the plants can be bitter. Mature plants are often grazed without incident. All herbivores may be affected. Signs of toxicity involve liver damage with anorexia, weight loss, icterus, hepatoencephalopathy, and secondary photosensitization.^{151,152,156-160}

Serum chemistry alterations reflect liver damage.^157,158 Postmortem, affected animals are icteric and have evidence of necrosis and sloughing of skin.¹⁵⁹ Lesions in the liver include bridging and fibrosing hepatocyte necrosis, cholangitis, and occlusion of small bile ducts. Bile ducts may have birefringent crystals, probably related to sapogenin accumulation.^{151,153,158,159} (See Chapter 40 for skin lesions.) Lesions also may be present in the kidneys, heart, and adrenals. Narthecium, as with other lilies, may cause chronic renal failure in ruminants, most likely from a furanone, not a saponin.¹⁶¹ Animals should be removed from offending pastures (at least until the grass matures).

CYANOGENIC GLYCOSIDES

Many grasses, weeds, and cherry bushes contain cyanogenic glycosides. Damage to the plant causes contact between β-glycosidases and the glycosides, releasing free cyanide. Cyanide blocks a variety of metalloenzymes, most notably the terminal oxidase (cytochrome-c oxidase) of oxidative transport.^162,163 The tight affinity of cyanide for ferric (Fe³⁺) iron in the cytochrome prevents electron transfer. Sorghums also can cause peripheral neurologic deficits in laboratory animals and horses (from nitriles or cyanide).^163,164

Many of the listed plants may be grazed safely; however, cyanide is released when plants are damaged from maceration, drought, frost, wilting, and stunting.¹⁶² Toxicity wanes with drying. All animals are sensitive to cyanide toxicosis. Cyanide toxicosis is very rapid in onset, often resulting in sudden death (see Chapter 14). Clinical signs include dyspnea, excitement, tremors, increased salivation, gasping, clonic convulsions, and death.^162,163 Chronic exposure to cyanide in rats can cause paralysis, and cattle, horses, and sheep grazing Sorghum species have developed ataxia, urinary incontinence, and cystitis.^163-166

Blood from animals with cyanide toxicosis is cherry red because hemoglobin cannot release oxygen to tissue. Nonspecific postmortem findings include cardiac hemorrhage associated with acute death. Chronic exposure to cyanide may lead to patchy encephalomalacia and damage to the spinal cord, along with secondary thickening and necrosis in the bladder associated with cystitis.^163,164 Diagnosis of cyanide toxicosis is supported by analytical evidence of cyanide in forage and samples from affected animals. Cyanide levels in excess of 200 ppm in plant material and 1 ppm in liver or blood are significant.¹⁶² Samples for cyanide analysis should be frozen immediately and held frozen until analyzed.

Treatment of cyanide toxicosis is based on removal of the cyanide from affected cytochrome c. Judicious use of sodium nitrite (16 mg/kg intravenously [IV], to form a small amount of methemoglobin, Fe³⁺) can help pull cyanide away from the enzymes. Additional use of sodium thiosulfate (30 to 40 mg/kg IV) will provide substrate for the natural rhodanese enzyme that forms thiocyanate, which is readily excreted in the urine.^162,167

NITROTOXINS

Some common milk vetches in North America contain glucosides of 3-nitropropanol (NPOH) and 3-nitropropanoic acid (NPA).^26,168,169 Miserotoxin is a common glucoside of NPOH. The glucosides are relatively nontoxic until hydrolyzed in the rumen to toxic nitrocompounds and nitrite, which is also toxic.^170-172 NPOH is oxidized to the more toxic NPA in the liver.^170,171 Nevertheless, NPOH may appear more toxic than NPA in ruminants because the NPOH is more thoroughly absorbed from the rumen. Nitrocompound toxicity is distinct from nitrite poisoning (see Nitrates). Less than 33% methemoglobin is usually formed after exposure to nitrocompounds, so nitrite alone does not explain acute nitrocompound toxicity.¹⁷¹ NPA is a powerful inhibitor of succinate dehydrogenase in the Krebs cycle, impairing cellular energy production in the nervous system.¹⁷³

All livestock can be poisoned by nitrocompounds, but cattle and sheep are most at risk. Acute or chronic toxicosis may develop, depending on the amount ingested. Acute nitro-plant toxicosis has a rapid onset of ataxia, distress, dyspnea, cyanosis, weakness, collapse, and death within 4 to 12 hours.¹⁷² Sheep may be found suddenly dead (see Chapter 14). Chronic nitro-plant toxicosis results in respiratory distress, weakness (especially in the pelvic limbs), knuckling of fetlocks, goose stepping, and knocking together of hindfeet when walking (“cracker heels”).¹⁷² Increased salivation, constipation, and diarrhea have all been reported. Animals may linger for months, but severely affected individuals seldom recover. Affected cattle may die suddenly if forced to move quickly.

Animals exposed to nitro-containing plants can have up to 33% methemoglobin.¹⁷² Although not lethal at this level, methemoglobin probably contributes to respiratory distress. Lesions of nitrocompound toxicosis include pulmonary edema with fibrosis (in longer-standing cases) and nonspecific cerebral hemorrhages. Histologic alterations in nervous tissue include wallerian degeneration of the spinal cord and peripheral (sciatic) nerves, with variable changes reported in the cerebellum.¹⁷² Other neuronal lesions may include white matter vacuolation, glial edema, and bilateral changes of the thalamus and cerebellum.¹⁷¹

Treatment of nitrocompound poisoning centers on prevention. Cattle native to pastures containing timber milkvetch (Astragalus miser) are somewhat tolerant to the plant through rumen microflora adaptation, which may be enhanced by protein supplementation.¹⁷⁴

BRACKEN FERN

Bracken is a perennial fern (up to 2 m high) that arises from a black rhizome and is found in disturbed or cleared uplands. The fronds are coarse, triangular, entire at the apex, and lobed toward the stalk. Bracken fern contains a variety of glycosides, including ptaquiloside (up to 1%), which will alkylate DNA, leading to carcinogenicity and bone marrow suppression in ruminants and laboratory animals.^175-179 Bracken also contains thiaminase activity, which predominates in monogastric animals (horses).^175,178

Grazing of fresh, young fronds when other forage is not yet available early in the grazing season is hazardous for cattle and horses, although plowed rhizomes and hay (20% bracken for 1 month in horses) also may be toxic.^175,180 Signs appear suddenly after animals have grazed approximately their body weight in plant material over several months. Horses develop characteristic thiamine deficiency, with weight loss, ataxia, lethargy, and a braced stance with an arched back, tremors, recumbency (with violent attempts to rise), and death within days to weeks after onset of signs.¹⁸⁰ Cattle with bracken or ptaquiloside toxicosis develop widespread hemorrhages and hematuria (“enzootic hematuria”) resulting from severe bone marrow depression and cancer in the bladder and other organs.^175,178-185 Reduced fertility may occur in chronic cases.

Cattle with bracken toxicosis have a normocytic, normochromic anemia, lymphocytosis, and neutropenia.¹⁸⁶ Severe thrombocytopenia and hemorrhage are also reported, associated with progressive bone marrow failure.^175,178 Urine from affected animals is hemorrhagic, with high levels of calcium and protein.^181,186 Lesions in cattle with bracken toxicosis include the hemorrhages, bone marrow hypoplasia, and a variety of tumors in bladders, including hemangiomas, hemangiosarcomas, transitional cell carcinomas, papillomas, fibromas, and adenomas.^180,181 Other cancers may involve hematopoietic tissues and the GI tract.¹⁸³ Horses with bracken toxicosis have low levels of thiamine.

In addition to prevention, horses that have not reached a terminal state may respond to large doses of parenteral thiamine. No specific treatment is currently recommended for ruminants with bracken poisoning. In terms of safety of food animal products, indirect evidence suggests that bracken ingestion by milking cows may be linked to stomach cancer in people who have chronically ingested that milk.^187,188

PHYTOESTROGENS

Hyperestrogenism caused by feeds and forages (including clover and alfalfa hays) has been reported in cattle, sheep, and swine. A variety of glycosides in those forages interact with estrogen receptors.^189,190 Commonly recognized estrogens include coumestrol, formononetin, biochanin A, daidzein, genistein, equol, and many others.^190,191

Estrogenic compounds vary in potency. Coumestrol from alfalfa and isoflavones from clovers have the most estrogenic activity, followed by genistein, daidzein, biochanin A, and formononetin.¹⁹² Biochanin A and formononetin are not potent in the laboratory, but ruminants metabolize them to the more estrogenic forms of genistein and daidzein, respectively.^190,192 Signs of hyperestrogenism from forages include infertility, hyperestrogenism, and antiestrogenism. Hyperestrogenism includes nymphomania, cystic ovaries, swollen genitalia, and in males development of female characteristics. Antiestrogenic signs include gonadal hypoplasia and anestrus.^189,190 Diagnosis of forage-induced hyperestrogenism is facilitated by demonstration of estrogens in forages and samples of plasma or urine.^193-195 Consumption of highly estrogenic forage types should be limited in breeding animals.

OTHER TOXIC GLYCOSIDES

The sweet clover forages produce the glycoside melilotoside, which contains coumarin. Penicillium species in moldy hay can dimerize the aglycone to dicumarol, which inhibits vitamin K epoxide reductase, leading to failure of vitamin K–dependent clotting factors. Dicumarol can be assayed in feed and animal-related samples. Concentrations of dicumarol in hay as low as 10 ppm may be hazardous to cattle. Moldy sweet clover poisoning in cattle results in widespread, vitamin K–responsive hemorrhage, which is especially hazardous during late-term pregnancy (hemorrhagic abortions).^196,197

Ingestion of young sprouts, burrs, or adult plant in hay of cocklebur can cause massive centrilobular liver necrosis in swine and cattle. Signs of toxicosis include depression, dyspnea, weakness, convulsions with opisthotonos, and death. Severe hypoglycemia may be observed by the clinician.^198-201

Furanocoumarins such as psoralens are primary photosensitizing agents that lead to severe blistering of light-skinned areas of exposed livestock ingesting the plants and poultry exposed to seeds from Bishop’s weed (see Chapter 40).^196,202

These plants contain glycosides of vitamin D (1,25-dihydroxycholecalciferol). Ingestion of the plants causes weight loss, lameness, stiffness, abnormal posturing, and clinicopathologic increases in serum calcium and phosphate in cattle and horses. Lesions include widespread calcification of tissues, including the cardiovascular system, tendons, lungs, and kidney. The vitamin D activity may cross the placenta to affect a developing fetus.^203-206

Plant saponins are bitter, foaming, detergent-like glycosides found in a variety of important forage crops and weeds. Midsummer alfalfa cuttings tend to have the highest saponin contents. Saponin toxicosis is characterized by gastroenteritis with diarrhea, poor weight gain, and ill-thrift in cattle. Broom snakeweed has an abortifacient factor with an effect similar to that in Pinus.²⁰⁷

Horse chestnuts are trees with characteristic palmate leaves and a one- to three-seeded, leathery fruit capsule (large seeds with a scar give the tree its name, buckeye). Young growth, sprouts, and seeds contain toxic levels of the glycoside aesculin. Aesculin causes ataxia, twitching, and excitability or sluggishness in livestock. The alcoholic extract from Aesculus hippocastanum causes incoordination.

Ranunculin is enzymatically converted to the toxic protoanemonin, a potent GI irritant that occurs in bur buttercup, and it becomes nontoxic when the plant is crushed or dried. Thus, bur buttercup in hay is not a hazard. However, grazing of this bitter plant by cattle and sheep, which occurs when animals are forced to do so, results in watery diarrhea, weakness, and dyspnea. Death may occur in severe cases (nonspecific edema and hemorrhage with fluid in the large cavities).^208-210

These plants have a variety of glucosinolates and isothiocyanates that cause GI irritation and, for some chemicals, goitrogenic effects in adults as well as neonates.

Cycads are palmlike plants found in tropical and subtropical climates. They contain a variety of glycosides, including the hepatogastrointestinal toxin (and carcinogen) cycasin, which is metabolized to the highly toxic methylazoxymethanol, and the neurotoxic amino acid β-methylamino-L-alanine. Ruminants with hepato-GI toxicosis from effects of the cycasin develop depression, anorexia, and weight loss. Necropsy findings reveal a cirrhotic liver, ascites, and hemorrhagic gastroenteritis. Ruminants with the neurologic syndrome develop “Zamia staggers,” characterized by weight loss, swaying, weakness, ataxia, and hindlimb ataxia. Postmortem lesions include demyelination and axonal degeneration of the brain, spinal cord, and dorsal root ganglia. In addition, recent research suggests that cycad toxins may also harm pancreatic β-cells, contributing to development of diabetes mellitus.^211-214

GOSSYPOL

Gossypol is a yellow, polyphenolic pigment found in glands of cottonseed (Gossypium). It is present in free (toxic) and bound (to protein, perhaps to the epsilon amino of lysine; not directly toxic) forms.^215,216 Both whole cottonseed and cottonseed meal can be toxic. Extraction of cottonseed using steam and heat will bind gossypol, whereas solvent extraction may leave high levels of free (toxic) pigment. Gossypol binds to cell constituents such as lysine and phospholipids, binds iron, may cause hypokalemia through kidney damage, inhibits a range of dehydrogenases, and uncouples phosphorylation.^215-218 Gossypol also adversely affects male reproduction through a variety of mechanisms, including inhibition of lactate dehydrogenase (LDH) in testicular Leydig cells and inhibition of acrosomal plasminogen activator in the sperm.²¹⁸ Cottonseed meal has limitations in protein quality, poor iron availability, and low concentrations of vitamin A.

All species can be poisoned by gossypol. Mature ruminants are more resistant to its effects (probably a result of ruminal degradation) than monogastric animals.^215-222 The toxicity of free gossypol depends on the quality of the ration and the amount of stress on the animals. For example, although swine may develop toxicity at free gossypol levels in excess of 0.01% in the total ration,^216,220-223 supplementation of rations with iron and high-quality (lysine) protein will raise the tolerated level to 0.02% to 0.04%.²¹⁶ Although adult ruminants tolerate more than 0.1% to 0.2% of free gossypol in the total ration, some animals may be poisoned at the lower levels if stressed or on a poor ration.^215,219,220 Adult bulls may develop infertility at these levels. Young adult cattle, under conditions of stress and marginal rations, may be sensitive to as little as 0.05% free gossypol in the total ration (perhaps from binding of protein as well as direct toxicity).²¹⁵

Gossypol effects are cumulative. Low levels of gossypol, if in a ration limited in iron or protein, may cause ill-thrift and poor weight gains in swine, baby calves, and young adult cattle (<1 year of age). Acute gossypol toxicosis results in dyspnea, violent labored respirations (“thumping” in swine), weakness, and death (see Chapter 14).^{215,216,220,221,223} Signs may appear suddenly after stress, making gossypol toxicosis resemble acute shipping fever.²¹⁵ Adult ruminants may have decreased milk production, anorexia, dyspnea, weakness, gastroenteritis, decreased humoral immune response, and reproductive failure (impaired spermatogenesis in bulls).^{215,219,224,225} Although the level in feed required to cause clinical reproductive failure in cows is not yet known, laboratory evidence suggests that high levels of gossypol may also impair reproductive performance in females.²²⁶ However, these findings must be balanced with the benefits to lactation and milk quality from feeding a moderate level of cottonseed to dairy cows. Lesions of acute gossypol toxicosis include large amounts of yellow proteinaceous fluid in all body cavities, myocardial degeneration and necrosis (pale streaks in the heart), and liver necrosis (centrilobular pattern).

Analysis of feed for free and bound gossypol levels will support a diagnosis of gossypol poisoning. Sperm morphology is adversely affected in bulls, with high levels of proximal droplets observed.²²⁷ In addition, modern high-performance liquid chromatography (HPLC) methods can detect gossypol in some animal-related samples.

There is no specific treatment for acute gossypol toxicosis. Some evidence suggests that feeding of vitamin E may help control some gossypol effects in young animals, although vitamin E will not prevent toxicosis.²²⁸ The total ration for monogastric animals and swine should contain no more than 0.01% of total gossypol.^{215,216,221,223} Slightly higher levels may be fed successfully to swine if dietary protein and iron are adequate.^215,216,229 Cattle that are less than 1 year of age should have adequate nutrition and minimal stress if being fed more than 0.05% to 0.1% of free gossypol. Adult ruminant cattle should have less than 0.1% to 0.2% of free gossypol in the total ration (avoid cottonseed products in bulls). Lactating dairy cattle should be fed no more than 6 to 8 lb (2.7 to 3.6 kg) of cottonseed per day.^219,220 Infertility in bulls will take 1 to 2 months on feed that has no gossypol to recover.²²⁷

TANNINS

Oaks are trees and brushes that have characteristic multilobed leaves and bear acorns in the autumn. Oaks are common in the United States, especially in Texas and California (60 species in North America).²³⁰ They contain variable amounts of toxic, complex, and hydrolyzable tannins.^231-233 The hydrolyzable tannins are astringents and apparently bind the proteins in plasma and organs, which causes coagulation and necrosis.²³⁴ Acorn calf syndrome, a deformity in calves of cows eating oak, may have a nutritional mechanism and is completely different from the syndrome discussed here.²³⁵

The hazard of oak toxicity parallels the tannin content of plant material.²³⁶ Plants tend to have the highest tannin content in the spring during the budding stage, and acorns may have high tannin levels in the fall.²³¹ All livestock may be poisoned by oak tannins. Signs generally appear after 3 days of initial ingestion of the oak. Losses from oak result from gastroenteritis, renal failure, liver damage, death, and deformities of calves.^{230,234,235,237} Clinical effects in cattle include rumen atony, anorexia, constipation with black feces, lethargy, icterus, hematuria, dehydration, and evidence of renal failure.^230,234 (See Chapter 32 for further discussion of oak toxicosis.)

SOLUBLE OXALATES

Many oxalate-bearing plants grow in disturbed or arid soils.²³⁸ Soluble oxalate in acidic plants such as Oxalis is present as the potassium salt. Sodium salts of oxalate are present in plants such as halogeton that grow at more neutral pH levels.²³⁹ Proposed mechanisms of acute poisoning from soluble oxalates include hypocalcemia, GI irritation, and inhibition of respiratory enzymes. Subacutely, oxalate is deposited as insoluble, birefringent crystals in kidneys, leading to renal failure. Chronic oxalate poisoning resulting from Setaria may lead to calcium deficiency with relative hyperphosphatemia.^239,240 Insoluble calcium salts of oxalate are present in plants such as Dieffenbachia and Philodendron species. Those insoluble calcium oxalates are not absorbed, but they do act as potent local membrane irritants.

Oxalate-bearing plants are bitter and not ingested unless grazing is forced. All species are poisoned by oxalate, although historically sheep have been the most frequent victims.²³⁹ Rumen flora adapt to oxalate in forage if animals are gradually acclimated to oxalate over 4 days.²⁴¹ Poisoning occurs when hungry animals that are unaccustomed to oxalate ingest the plants in large quantities.^236-240242 Soluble oxalate toxicosis results in labored breathing, ataxia, rumen stasis and bloat, depression, weakness, coma, and death.^239,241 Horses chronically grazing setaria develop “bighead,” which is associated with a low calcium/phosphorus ratio.

Soluble oxalate—related changes in serum parameters reflect hypocalcemia or uremia. Postmortem lesions include hemorrhage and edema of the rumen wall and kidneys. Refractile crystals are found in the kidneys and rumen wall. Renal tubular necrosis and rumenitis are the major lesions, along with the presence of crystals.^239,240,242 Analytical tests are available for oxalate in plant and animal-related samples.

Treatment of oxalate toxicosis is for gastroenteritis, shock, and renal failure. Gradual acclimation of ruminants to forages containing soluble oxalates and providing adequate levels of clean water may help prevent clinical disease.

WHITE SNAKEROOT

White snakeroot is a perennial that grows in clumps from clusters of snakelike roots in shady, wooded areas in the midwestern United States. The leaves are opposite and have three characteristic veins on the underside.²⁴³ The plant tends to remain green when other plants have dried. The toxin of white snakeroot has not been identified but is extractable with a ketone and sterol-rich fraction, called collectively tremetol.²⁴³ The toxins may require microsomal activation in animals.²⁴⁴

White snakeroot (fresh or dried) is hazardous to all species studied, although lactating animals are resistant because of rapid excretion of the toxins in milk.^243,245-248 The hazard to grazing animals is highest when other forages have dried during the winter season or conditions force overgrazing. Feeding of 1% and 2% of body weight of the plant to horses resulted in toxicity after 1 to 2 weeks.²⁴⁵ White snakeroot toxicosis causes cardiac and skeletal muscle damage along with ketosis.²⁴³ Clinical signs include weight loss, tremors and stiffness, ataxia, depression, cardiac arrhythmias (especially ST segment depression), recumbency, and death (within hours of recumbency).^{243,245,247-249} Sudden death is possible (see Chapter 14).

Clinicopathologic alterations include ketosis (many have breath smelling of acetone) and increased serum activities of CK, LDH, ALP, and AST.^243,245-247 Lesions of white snakeroot toxicosis include pale streaking in the heart with multifocal myocardial degeneration, necrosis, and mineralization.²⁴⁵ Skeletal muscle necrosis also may occur, especially with the Haplopappus species. The liver may have centrilobular degeneration and necrosis. Diagnostically, white snakeroot poisoning should be differentiated from selenium deficiency and ionophore toxicosis. Treatment for white snakeroot toxicosis is supportive. Milk from exposed animals is hazardous and should not be fed or consumed.

OTHER TOXIC ALCOHOLS AND ACIDS

Lush, early growth of many forages, including crested wheatgrass, can contain acid compounds that sequester magnesium. Ingestion of the plants during this lush stage can lead to hypomagnesemia in cattle, including tetany (see Chapter 41).²⁵⁰

Ingestion of pine needles by pregnant cows during late gestation causes abortions or birth of weak calves, with digestive upset and lethargy in cows. The abortions are characterized by retained placentas and metritis. Many cows may die from effects of metritis. The toxins in ponderosa pine include isocupressic acid esters along with a unique class of vasoactive lipids. The major lesion of pine needle abortion is necrosis in the placental trophoblast region, perhaps also resulting from reduced uterine blood flow.^251-258

Water hemlock and some of the more toxic narrow-leafed milkweeds contain convulsant resins. Most of the toxicity of water hemlock lies in the resins of the chambered root. Ingestion of less than 0.2% to 0.5% of an animal’s body weight of either plant may be lethal. Signs of toxicosis (in all species) may appear within 15 minutes of ingestion and include nervousness, excessive salivation, weakness, tremors, violent convulsions, and death. Postmortem lesions include skeletal muscle and myocardial necrosis, perhaps associated with seizures. Administration of sodium pentobarbital at the onset of signs can result in recovery.^259-262

The toxins of St. John’s wort (a weed of disturbed areas) and buckwheat (an off-season cover crop used for forage) are primary photosensitizing toxins (see Chapter 40).²⁶³

Ingestion of horsebrush by sheep, plus black sage (contains a sesquiterpene lactone), at levels of 1% of body weight, can cause hepatogenous photosensitization (see Chapter 40). The tetradymols are bioactivated in the liver to toxic substances that, among other mechanisms, uncouple oxidative phosphorylation.^264,265

NITRATES

Toxic levels of nitrate and nitrite are found in forage, water, and many fertilizers. Sources in water include biologic runoff, industrial effluents (nitrite in water from ponds near oil wells), and fertilizer. Nitrate is reduced to nitrite in the rumen. Nitrite converts hemoglobin (Fe²⁺) to methemoglobin (Fe³⁺), which does not bind or transport oxygen, leading to hypoxia.²⁶⁶

Although many of the listed forages are widely used for animals, environmental conditions such as drought, plant stress, rapid growth spurts, some herbicide uses, low light, and fertilization can lead to nitrate accumulation.²⁶⁷ All animals are sensitive to nitrite. Ruminants are 10 times more sensitive to nitrate than monogastric animals because the rumen reduces nitrate to nitrite.^266,268 Forage containing a nitrate concentration of 1% (dry weight) may be lethal in cattle not acclimated to it.²⁶⁶ Acute toxicosis can result from nitrate in water at levels over 0.12%.²⁶⁶ Levels exceeding 0.5% in forage and 400 ppm in water may be hazardous to pregnant cattle.²⁶⁶ Clinical nitrate toxicosis appears within 4 hours of exposure. Signs include polypnea, dyspnea, weakness, tremors, intolerance to exercise, and terminal convulsions; death is possible within hours (see Chapter 14).^266,268 Mildly affected cattle may recover spontaneously. Abortion may occur in mild, or apparently nonclinical, cases in cattle within 5 days of exposure (half-life of nitrite in fetus is greater than three times that of adults).^268,269 Hypoxic stress in the fetus may aggravate other causes of abortion.

Cattle with nitrate poisoning will have chocolate-brown blood (>30% methemoglobin). Postmortem findings are nonspecific. A diagnosis of nitrate toxicosis is supported by finding greater than 45 ppm of nitrate in ocular fluid or serum, along with identification of a toxic level of nitrate in forage or water.

Clinical cases respond well to administration of methylene blue (5 to 15 mL of a 1% solution) by intravenous injection.²⁶⁶ Prevention of nitrate toxicosis requires proper harvest of forage and gradual acclimation of ruminants to potential high-nitrate—type forages.

SELENIUM (INDICATORS LISTED)

The listed plants are called “selenium indicator plants” because of their requirement for high selenium levels in soil for growth.^26,270 Although these plants are not palatable because of a garlicky odor, they indicate the presence of selenium. In the presence of arid, alkaline soil, selenium also may be accumulated in toxic levels in a variety of common forage plants and consumable weeds (alfalfa, Asteraceae, Castilleja, Atriplex). Selenium, an essential element (see Chapter 40), can cause both peracute toxicosis from oversupplementation in feed or injection^270-273 or chronic toxicosis at lower levels.^26,270,274 The mechanism of acute selenium toxicity is unknown but may involve direct effects of organoselenium compounds on cell energy production.²⁷⁴ The mechanism of chronic selenium poisoning is related to its replacing or interacting with sulfur in structural amino acids needed for cross-linking (cysteine or methionine).^270,274

All species may be affected by selenium toxicosis. Acute toxicosis is caused by oversupplementation of feeds containing selenium, ingestion of indicator plants (10,000 ppm of selenium), or injection of excessive selenium (0.4 mg/kg of body weight was lethal to lambs). Signs include weakness, dyspnea, bloating, abdominal pain with diarrhea, paresis in some species, and shock and death from respiratory failure.^272-276 Animals, especially horses, with chronic alkali disease from selenium in forage (5 to 50 ppm dry weight in forage is toxic) develop ill-thrift, anemia, stiffness, lameness, loss of mane and tail, and deformation and sloughing of hooves.^26,270,274 Cattle with chronic selenosis may also develop hoof lesions, develop immune incompetence, and if pregnant, may give birth to nonviable calves.^277,278 Neurologic diseases often reported, such as “blind staggers,” are probably not caused by selenosis and may have resulted from ingestion of related locoweeds.²⁷⁷

Lesions of selenium toxicosis vary based on dose and duration of disease. Peracute toxicosis leads to widespread organ congestion, cardiac damage, and severe pulmonary edema.^272-274 Chronic selenosis results in articular erosions and deformed, sloughed hooves in horses with loss of longer mane and tail hair.^26,271,274 Selenium in feed should not exceed 1 to 2 ppm dry weight. Selenium in whole blood should range between 0.08 and 1.0 ppm and, in liver, from 0.25 to 1.0 ppm for most normal animals. After exposure to excessive selenium is terminated, tissue levels may return to normal well before clinical signs dissipate, leading to a false-negative finding (hair testing may be beneficial to diagnose chronic selenosis).

No specific treatment is recommended for chronic selenosis. Reportedly, feeding of proteins that are high in sulfur-containing amino acids may be beneficial.²⁷⁰ Food animals poisoned with selenium may require at least 60 days to clear the excess selenium.²⁷⁹

SULFUR-CONTAINING PLANTS

Certain plants, feed mixes, and water can contain high levels of sulfur. In general, the total amount of sulfur intake for a ruminant should contain no more than 0.4% of sulfur overall. High levels of sulfur as sulfate may contribute to copper deficiency (see Chapter 32) and can cause polioencephalomalacia in ruminants, as can other forms of sulfur.

In the ruminant and perhaps the horse, ingestion of excess sulfur in water, feed, or from grazing plants such as turnips that can accumulate sulfur, intestinal microbes (rumen or large bowel) may produce excess sulfide. The excess sulfides can cause polioencephalomalacia as they are rapidly absorbed. Clinical signs of polioencephalomalacia include characteristic CNS disease with blindness (see Chapter 35).

Diagnosis of sulfur toxicosis requires testing of all potential sources of sulfur, including feed, pasture, and water, in addition to finding of signs and lesions characteristic for polioencephalomalacia. The differential diagnosis for sulfur toxicosis includes other causes of polio, salt toxicity, water deprivation, lead poisoning, and other infectious causes of neurologic disease in cattle.²⁸⁰

PNEUMOTOXIC PLANTS

Lush forage (“foggage”) and possibly feeds that are high in tryptophan, toxic plants (seed and flowering stage of perilla mint), moldy sweet potatoes (infected with Fusarium solani mold), and moldy green beans (Fusarium semitectum) can cause interstitial pneumonia in animals (see Chapter 31).^281-286 The toxins include the listed pneumotoxic ketones and 3-methyl indole, a rumen metabolite of excessive tryptophan.^284,287,288 Despite some diversity of structure, the toxins are metabolized by the mixed-function oxidases in pulmonary type I pneumocytes and nonciliated bronchiolar epithelial cells (Clara) to highly cytotoxic free radicals, leading to damage to local alveolar and, perhaps most important, endothelial cells.^281-293 These oxidant pneumotoxins also deplete cellular antioxidation factors such as glutathione in the liver and lung.²⁸⁹

Ruminants, especially cattle, are at risk of developing 3-methyl indole toxicosis when moved suddenly from dry feed to a lush pasture.²⁸⁴ Unexplained isolated incidents of interstitial pneumonia also occur in feedlot cattle (perhaps from a change in flora or feed tryptophan). Feeding of moldy sweet potatoes or moldy green beans is also hazardous.^281-283 Perilla mint has pneumotoxic ketones in highest concentrations during the flowering and seed stages.²⁸⁵ Toxicity is retained in dry plant material.²⁸⁵ Clinical effects of these penumotoxins include sudden onset of increased respiration, severe dyspnea with an expiratory grunt, frothing at the mouth with the head down, and open-mouth breathing.^284,285 Animals may be found dead (see Chapter 14).

Affected cattle have wet, heavy lungs with variable amounts of emphysema. Histologically, the lungs have severe interstitial edema. Ultrastructural studies reveal degeneration and necrosis of type I pneumocytes, endothelial cells, and Clara cells, with proliferation of type II pneumocytes in longer-standing cases.^{281,282,284,290-295} Perhaps a result of differential bioactivation rates, the major lesion in the horse is bronchiolitis (not alveolitis).²⁹⁶ The extremely short half-life of 3-methyl indole (14 minutes)²⁸⁸ in cattle has hindered development of diagnostic tests. Specific treatment for toxic interstitial pneumonia is not available.

OTHER NOTABLE TOXIC PLANTS

The onions and brassica plants contain S-methylcysteine sulfoxide, which is metabolized to dimethyl disulfide, which attacks red blood cell (RBC) membranes. Onions and Brassicaceae are toxic to a variety of species, whereas red maple poisoning is reported in horses. Signs in poisoned animals include lethargy, anorexia, dyspnea, coffee-colored urine, icterus, hypoxic abortion, and shock. Death results from respiratory failure secondary to anemia. Affected animals have hemolytic anemia with hemoglobinuria, Heinz bodies, and increased levels of AST, sorbitol dehydrogenase, plasma protein, and bilirubin. Postmortem findings may include icterus, brownish discoloration of blood, centrilobular hepatic degeneration, and hemoglobinemic nephrosis. Note that ruminants such as sheep may adapt to an onion diet because the rumen appears to quickly develop a population of sulfide-reducing bacteria to decrease the hemolytic forms of sulfur.^297-304

In addition to the potential to cause high levels of nitrate when in hay, redroot pigweed also can be toxic to kidneys when grazed fresh in the field. Cattle and swine have developed signs of renal failure, including weakness, tremors, ataxia, recumbency, and death after grazing the plant for 5 to 10 days. Serum potassium, BUN, and creatinine concentrations are increased. Lesions include marked perirenal edema (may be bloody), straw-colored fluid in body cavities, and pale kidneys with histologic evidence of degeneration and necrosis of both proximal and distal tubules. Tubules have proteinaceous, cellular casts.^305-307

These annual shrubs of the southeastern United States contain an unknown myotoxin(s) in all plant parts, but the seeds are most hazardous. Signs of toxicosis may occur in all livestock grazing the plant and include anorexia, ataxia, weakness, intense decrease in weight gain, and recumbency. Clinicopathologic abnormalities may include increased serum levels of CK and AST and myoglobinuria. Postmortem findings include degeneration and necrosis of skeletal and cardiac muscle. Goats and cattle given Cassia roemeriana may also have hepatocellular damage.^308-313

These plants contain sesquiterpene lactones such as the cytotoxic repen, along with aspartic and glutamic acids, all of which are potent neurotoxins. Prolonged ingestion of large amounts (>1.8 kg/100 kg body weight daily) of these plants by horses may result in neurotoxicity. The principal sign of toxicity is dysphagia, characterized by dystonia of the lips and tongue. Lethargy and aimless walking are also reported. Lesions include characteristic foci of necrosis in the globus pallidus and substantia nigra (bilateral) of the brain (nigropallidal encephalomalacia). Yellow star thistle is an aggressively growing plant that is difficult to control. Biologic measures, including introduction of rust and insects, have been considered as control measures. Prevention includes providing adequate alternative feeds.^314-317

These weeds of the Rocky Mountains and southwestern United States are unpalatable but may be ingested by sheep or goats in the winter when other forage is limited. Sesquiterpene lactones bind with sulfhydry groups (cysteine), leading to an extreme irritant effect on the nose, eyes, and GI tract. Affected animals develop severe gastroenteritis (sneezeweed toxicosis is called “spewing sickness” because of vomiting), often with secondary aspiration pneumonia. Affected animals may have increases in serum γ-glutamyltransferase (GGT), AST, creatinine, and BUN. Postmortem lesions include gastroenteritis, congestion of liver and kidney, and aspiration pneumonia. Administration of thiol groups (cysteine, protein, methionine) and antioxidants are protective.^318-322

Horses exposed to fresh black walnut (as little as 5% in shavings used as bedding; possibly also plant) can cause a transient drop in leukocytes, limb edema, and laminitis. The toxin of black walnut is unknown but is not the naphthoquinone juglone, as originally thought. An unknown quinone is suspected. Treatment is removal of offending shavings and traditional therapy for acute laminitis in horses. Rotation of the third phalanx is possible in severe cases.^323-325

Toxicosis with hoary alyssum, a potential weed contaminant of alfalfa hay, is characterized by fever, limb edema, and laminitis in horses.³²⁶ The toxin is unknown.

Coyotillo is a woody shrub from the southwestern United States that may cause toxicosis in cattle, sheep, goats, hogs, and fowl when other forages are scarce. Ingestion of small amounts of the fruit and seeds leads to weakness, incoordination, and eventually paralysis. The onset of signs is delayed for days to weeks after exposure. Lesions include segmental demyelination (wallerian degeneration) of nerve axons. Ingestion of the green parts of the plant may lead to wasting, weakness, and death. Lesions associated with the extraneural syndrome of coyotillo poisoning include necrosis of the myocardium, liver, and kidney, and pulmonary hemorrhage.^327-329

Ingestion by horses of plants such as flatweed, especially in conditions of overgrazing, is suspected as causing outbreaks of Australian stringhalt. Stringhalt is a distal axonopathy characterized in horses by an unusual gait with hyperflexed hock during movement, reluctance to back up, and in some reports a high incidence of roaring. The etiology is unknown for flatweed. Lathyrus neurotoxicity is well described (neurotoxic amino acid derivatives, β-N-oxalylamino-L-alanine).^330-333

Plant matter from avocado trees (primarily the Guatemalan varieties, from most reports) has caused aseptic mastitis, myocardial necrosis, and skeletal muscle lesions with edema. Aseptic mastitis with epithelial necrosis in the mammary gland has been reported in cattle, horses, and goats (an ischemic myotoxin, persin is toxic to the mammary gland). Myocardial necrosis (with widespread edema, including the brisket) has been reported for goats, sheep, horses, and avians including rattites (sudden death with fluid accumulation in avians). Horses develop edema of the lips, tongue, mouth, and neck, along with lethargy and colic. Serum factors increased with avocado toxicosis include CK, AST, and LDH.^334-341

The lectins in the listed plants are glycoprotein dimers, joined by a disulfide bond in ricin and abrin. Seeds, cakes, and foliage are poisonous, but not the oil. A portion of the dimer, the haptomer, binds the cell, allowing the other half to enter and block protein synthesis. All classes of livestock are sensitive to the compounds. Ricin and abrin are among the most potent toxins described. Clinical toxicosis reflects primary damage to the GI tract and includes violent gastroenteritis followed by weakness and death from shock and depression of cardiac function. Other poisonous lectins, although less acutely toxic, are found in legume seeds from a variety of unextracted beans. Those factors interfere with intestinal absorption, inhibit growth, and can inhibit the immune system.^342,343

Cattle and horses grazing hairy vetch when it is green may develop a systemic granulomatous disease. Dried seeds may cause convulsions (apparently unrelated to the immunotoxic syndrome discussed here) in cattle. Prior sensitization may be required for development of clinical signs of systemic granulomatous disease in animals exposed to green vetch. Initially, animals are presented for listlessness and welts on the skin, with alopecia and peeling of skin around the nares. Horses may have lymphadenomegaly and dependent edema. Affected animals may develop wasting, diarrhea, and clinicopathologic changes of lymphocytosis and hyperproteinemia. Mortality may be high in affected animals. Postmortem, skin is thickened with scaling and alopecia. Other organs that may be pale or may have gross abnormalities include the heart, kidneys, adrenals, and lymphoid tissues. Microscopically, the skin and other organs, including the liver, have cellular infiltrations of monocytes, lymphocytes, plasma cells, eosinophils, and often, multinucleated giant cells. The mechanism of hairy vetch toxicosis is not known but may involve an immunotoxic lectin.^344-348

Yellow bristlegrass contains sharp, miniature barbs below the seed heads that can cause mucosal trauma, including oral ulcers, in animals ingesting contaminated hay. Horses and young cattle are most frequently affected.

Ingestion of large amounts of lichen growing in the desert during winter has caused paralysis in sheep and Rocky Mountain elk. The paralysis resembles a lower motor neuron failure, but the mechanism of toxicity has not yet been determined. The toxin is not well characterized, although usnic acid has been implicated as causing part of the syndrome.³⁴⁹

BLUE-GREEN ALGAE (FRESHWATER)

Potentially toxic blue-green algae (cyanobacteria) may form on stagnant bodies of water under conditions of heat, eutrophication (high nitrogen and nutrients), low flow rates, oxidative stress, and a concentrating wind.^350-352 The cyclic peptide hepatotoxins cause dissociation of the cytoskeleton of the liver through inhibition of protein phosphatase and induction of apoptosis, leading to disintegration of that organ.^353-355 Anatoxin-a is a bicyclic, secondary amine that causes depolarization of nicotinic receptors, leading to muscle and respiratory paralysis.^351,356 Anatoxin-a(s) is a naturally occurring organophosphorus-like compound that inhibits peripheral cholinesterase.^351,357 Saxitoxin and neosaxitoxin cause paralysis by blocking neural sodium transport.³⁵¹ A variety of cyanophytes cause skin and GI irritation.

All species are sensitive to the listed algae, which, if ingested in sufficient quantities, may cause sudden death (see Chapter 14). Animals exposed to high doses of the cyclic peptide hepatotoxins may die within 1 hour of exposure from hypovolemia and shock secondary to blood loss into the disintegrated liver and embolism of hepatocytes into the lung.^{350,351,353,354} Lower doses lead to characteristic signs of liver failure. Exposure to a toxic dose of anatoxin-a leads to tremor, collapse, exaggerated breathing efforts, convulsions, and death within minutes.^351,356 The paralysis is persistent and not responsive to assisted ventilation.³⁵⁶ Anatoxin-a(s) also can kill in minutes after exposure. Characteristic signs of cholinesterase inhibition in the periphery include diarrhea, tremors, hypersalivation, dyspnea, paresis, opisthotonos, cyanosis, convulsions, and death.^351,357

Animals with hepatotoxic blue-green algae toxicosis may have elevations in liver-associated serum factors including AST, GGT, ALP, and bilirubin, as well as creatinine, BUN, and LDH. Hepatotoxic lesions include enlarged, red- to blue-colored livers with gallbladder edema. Histologic alterations include severe centrilobular hepatocellular dissociation, degeneration, and necrosis. Only a rim of hepatocytes around the periportal triads may remain.^{350,351,353,354} Hepatocyte emboli may be found in the lung.³⁵⁴ Mild renal tubular degeneration may occur. Animals with anatoxin-a(s) toxicosis will have depression of peripheral cholinesterase, although brain cholinesterase may be normal.³⁵¹ Otherwise, pathologic changes in animals with neurotoxicosis reflect hypoxemia and are nonspecific.

If blue-green algae toxicosis is suspected, samples of ingesta and bloom can be mixed with 10% neutral-buffered formalin for visual identification. Samples should be accompanied by at least 2 L of fresh bloom material (refrigerated) for demonstration of the toxin or toxicity. Liquid chromatography of bloom material or ingesta may be useful to help diagnose poisoning from the Microcystis toxins.³⁵⁸

Treatment for blue-green algae poisoning is supportive. Artificial ventilation is required for anatoxin-a toxicosis. Exposed animals might benefit from oral adsorbents such as activated charcoal.³⁵⁰ Exposure of cattle to Microcystis toxins does not appear to cause a food safety risk when tested in liver and blood plasma.³⁵⁹

ERGOT

Classic ergot results from parasitism of developing grass or grain flowers by Claviceps purpurea, leading to formation of a dark sclerotium on the seed heads. Several wild grasses and grains such as rye, triticale, wheat, oats, sorghum, and barley may be affected. Affected grains contain a series of alkaloids, including ergotamine, ergonovine, and ergotaxine (also found in fescue; see earlier). Ergotism in livestock may cause ataxia, convulsions, lameness, dyspnea, diarrhea, dry gangrene of the extremities similar to fescue foot, abortion, neonatal mortality, reduced lactation (ergot alkaloids have been used medicinally for uterotropic effects), poor weight gains, lowered production, and lowered feed intake.^447,448

ZEARALENONE

Zearalenone is an estrogenic mycotoxin produced in corn and other grains by various Fusarium species (especially F. roseum) under similar warm and cold climatic cycles as for trichothecenes (zearalenone is often found with DON; see earlier). Prepubertal swine and dairy cows are the most sensitive animals to zearalenone. Corn contaminated with zearalenone may cause toxicosis at levels as low as 1 ppm, a level well below the toxicity of pure toxin, suggesting the presence of other estrogenic metabolites in field samples. Zearalenone can be metabolized to the more toxic zearalenol. Species-specific sensitivity to the mycotoxin is related to differential metabolism of the zearalenone to zearalenol and to differential detoxification rates in liver. Zearalenone causes chronic hyperestrogenism, with vulvar swelling, prolapsed rectum, enlarged mammary glands, reduced fertility, and feminization of swine and cattle. Although zearalenone may be distributed to milk and meat, medically significant residues would not be expected in products from animals exposed to grain with natural zearalenone contamination.^449-451

SLAFRAMINE

Slaframine is an indolizidine alkaloid mycotoxin produced by black batch mold (Rhizoctonia leguminicola) contamination in moldy red clover forage (including hay, Trifolium repens). Slaframine causes increased salivation, diarrhea, and bloat in affected cattle and horses.^452,453

OCHRATOXIN

Ochratoxin is an isocoumarin derivative of phenylalanine. Feeding of more than 0.2 to 4.0 ppm in grain to livestock can cause nephropathy. Monogastric animals such as swine and horses are more sensitive than ruminants, although young ruminants may be susceptible to levels of ochratoxin above 2 to 40 ppm in the grain. Liver damage, enteritis, reduced growth rates, and abortion also have been reported. Citrinin, another nephrotoxic mycotoxin, might be found along with ochratoxin in a contaminated grain sample.⁴⁴⁹