SELENIUM POISONING

SELENIUM POISONING

            Selenium is an essential nutrient for the health of livestock and is necessary for growth, fertility and is important in the proper function of the immune system. However, at high levels selenium can be toxic to animals and humans. Selenium in the soil is absorbed by plants and when animals eat these plants, selenium toxicity can develop. Selenium has a narrow margin of safety, with the difference between adequate and potentially toxic concentrations in the diet being approximately 10- to 20-fold. Feed supplements, resulting in final selenium content of 0.2–0.3 ppm, are added to diets to prevent deficiency and resultant diseases such as white muscle disease in cattle and sheep, exertional myopathy in horses, hepatosis dietetica in pigs, and exudative diathesis in chickens. The maximum tolerable concentrations for selenium in most livestock feed is considered to be 2–5 ppm, although some believe 4–5 ppm can inhibit growth. Selenium is an essential component of >25 selenoenzymes and selenoproteins. The most recognized of these are the glutathione peroxidase enzymes that act as antioxidants in the body.

            Almost all selenium compounds are similar to those of sulphur, but there are not so many. Although the chemistry of selenium is similar to that of sulphur, there are some peculiarities inherent in the chemistry of metalloids and metals close to selenium in the periodic table. Selenium compounds also bear some similarity to compounds of arsenic.

            Aetiology

            All animal species are susceptible to selenium toxicosis. However, poisoning is more common in forage-eating animals such as cattle, sheep, horses, and other herbivores that may graze selenium-containing plants.

            Nearly all plants can accumulate selenium from the soil (Selenium occurs in the soil in various forms. In unweathered rock and some soils in arid regions it may occur in its elemental form or as iron selenide. In both of these forms, selenium has a low availability to plants. Small amounts of organic selenium, derived from decaying plants, may occasionally be available to growing plants. However, the most soluble and most important for insofar as plant availability is concerned, is inorganic selenate.), however some plants require selenium for growth and are called 1. obligate selenium accumulators or indicator plants, as their presence indicates a high level of selenium in the soil.  These plants are unpalatable and are usually only consumed in the spring when lush green plants are rare, or in hay. The common species of these plants include certain Astragalus spp. (milk vetch), Aster spp., Oonopsis (golden weed), Stanleya (prince’s plume), Oxytropis lambertii (purple locoweed), Machaeranthera, and Xylorhiza. Plants may accumulate selenium when the element is found at high concentrations in the soil, but pH and moisture content of the soil play roles in the relative bioavailability of selenium to plants. Generally, selenium is most bioavailable to plants when they grow on more alkaline soils with low rainfall (<50 cm). The alkalinity and low moisture content of the soil tend to allow more of the selenium to be retained as the oxidized form of selenate, which is the most readily available for plant uptake. Because low moisture in the soil decreases the anaerobic environments to greater depths, drought conditions could allow for more/deeper selenium in the soil to be oxidized into plant-available forms, resulting in year-to-year variability in available selenium for plant uptake.

            Selenium poisoning of farm animals (particularly cows, sheep and goats} and wildlife occurs in regions where the soil contains an increased pro­portion of this toxic element. Excess quantities of selenium are absorbed from the soil by plants. Such plants become dangerous to eat. Plants that always accumulate selenium ("Obligate indicator plants/Primary selenium accumulator plants") – require large amounts of selenium for growth and contain high selenium concentrations (often >1,000 to 10,000 ppm). These plants need selenium for their growth and development and grow only in localities where the soil content of selenium is high. Selenium levels in these plants may be very high, amounting to 1000-15000 ppm.

            Plants with facultative accumulation of selenium ("2. Facultative indicator plants / secondary selenium accumulators") absorb and tolerate higher concentrations of soil selenium, with accumulations ranging from trace amounts to a few thousand ppm, but they do not require selenium for growth. Facultative indicators include species of Castilleja, Grindelia, Atriplex, Gatierreaia, and Comandra. Plants of this type may prosper in localities with a minimal soil content of selenium but accumulate the element when growing on a high-selenium soil (e.g. some cereals, savoy cabbages and onions may contain up to 20-60 ppm Se).

            The majority of plants do not accumulate selenium. 3. Nonaccumulator plants, such as most grasses, passively absorb much lower amounts of selenium from the soil, resulting in trace amounts to a few hundred ppm. Some of them cannot even grow on high-selenium soils.

            Plants transform selenium into organic compounds whose toxicity may be even higher, or of a different nature, than that of its inorganic compounds. Plant fodder containing more than 5 ppm of selenium should be treated as dangerous for ruminants. According to some authors, the danger limit is as low as 1 ppm. Food with 5 ppm and milk with 0.5 ppm Se is dangerous for man.         

            Poisoning of animals by selenium insecticides occurs rarely. There may be exceptional cases of intoxication from over-dosage of the preparation Selevit, containing natrium selenosum  and vitamin E.

            Numerous organic and inorganic chemical forms of selenium are potentially present in plants. Nonaccumulator plants primarily contain selenomethionine, while indicator plants contain more selenate and methylselenocysteine. In comparison, most supplemental dietary sources are in the form of selenite, but selenomethionine supplements are becoming more commonly used in marketed products.

            Acute selenium poisoning in livestock is usually associated with the plants in group 1, while chronic poisonings are associated with groups 2 and 3. Many plants in groups 2 and 3 are good forage plants under normal conditions. The part of the plant eaten is also important in determining selenium content. Seeds usually contain more selenium than leaves, which contain more than stems. Some plants contain volatile selenium compounds that are lost on drying, especially at high temperatures.

            Poisoning may also occur in swine, poultry, and other species consuming grain raised on seleniferous soils or, more commonly, due to errors in feed formulation. Selenium toxicosis after ingestion of selenium-containing shampoos or selenium supplement tablets is rare in small animal pets but can occur. Several factors are known to alter selenium toxicity; however, in general, a single acute oral dose of selenium in the range of 1–10 mg/kg may be lethal in most animals. Parenteral selenium products are also quite toxic, especially to young animals, and have caused deaths in piglets, calves, lambs, and dogs at dosages as low as 1 mg/kg. Younger animals tend to be more susceptible to selenium poisoning, and the chemical forms can result in some differences in relative toxicity.

            Mechanism of action and toxicity

            The mechanism of action of selenium compounds is not fully understood.

            The most realistic explanation will probably come from experimental findings by which selenium is incorporated instead of sulphur in some amino acids, in important pro­teins and possibly in other important compounds containing sulphur. Abnormal selenoprotides, or other selenium compounds, are probably responsible for the development of the clinical and patho-anatomical picture of chronic selenium toxicoses, including the carcinogenic effects. In view of the recent information on alkylation of nucleic acids, the possibility of abnormal methylation of some cellular substances by compounds such as Se-adenosylselenometheonine should also be taken into account.

            In excess, selenium potentially has three general toxic effects:

1. the direct inhibition of cellular oxidation/reduction reactions by depleting glutathione and S-adenosylmethionine reserves,

2. the production of free radicals that cause oxidative tissue damage, and

3. the replacement of sulfur/sulfur-containing amino acids in the body with selenium/seleno-amino acids.

            The inhibition of numerous cellular functions by high concentrations of selenium results in acute generalized cytotoxicity.

            The replacement of sulfur-containing amino acids with seleno-amino acids leads to altered structure and function of cellular components and enzymes due to loss of the disulfide bonds that commonly occur between sulfur-containing amino acids. Loss of these disulfide bonds can alter the three-dimensional configuration of proteins, potentially resulting in loss of or diminished enzyme activity. The most commonly altered sulfur-containing amino acids are methionine and cysteine, which are replaced with selenomethionine and selenocysteine, respectively. Replacement of these amino acids with selenium-containing amino acids also affects cell division and growth. Especially susceptible are the cells that form keratin (keratinocytes) and the sulfur-containing keratin molecule. Selenium therefore weakens the hooves and hair, which tend to fracture when subjected to mechanical stress.

            Selenium compounds, administered to experimental animals, are quickly absorbed from the digestive tract and get into all tissues and all organs. The highest Se levels were found in the liver, spleen and kidneys and the lowest in the brain and muscles. After long-continued selenium administration the element is concentrated in the hair and hooves of animals. In pregnant females, selenium penetrates the foetal tissues and causes congenital mal­formations. Selenium that has penetrated the eggs of birds reduces hatchability and inhibits the growth of the progeny.

            Selenium is excreted mainly by the way of kidneys, but some is eliminated through the intestines, in the urine, through the lungs in the expired air, and in the milk.

            Selenium is also believed to have carcinogenic effects, as these were elicited in sewer rats given selenium as selenides, selenates or seleniferous grain at doses of 5-10 ppm in their diet for several months.

            Al though toxic in higher doses, selenium is a biogenic element for some plants, microorganisms and animals. Ruminants require about 0.01-0.1 ppm selenium in feed. If the soil and the plants administered as forage contain little selenium diseases will occur as a consequence of selenium deficit (e.g. "white muscle disease" in lambs).

            Toxic and lethal doses

            The minimum oral selenium doses (selenite): horse 3.3 mg per kg b.m., cow 10 mg per kg, pig 17 mg per kg.

            Subcutaneous, intraperitoneal or intravenous administration of sodium selenite is fatal for rabbits at doses of 0.9-1.5 mg per kg b.m. The lethal dose of sodium selenate for rabbits is higher - 2.0-2.5 mg per kg b.m. The lethal subcutaneous, intravenous or intraperitoneal dose for the dog is 2 mg per kg b.m.

            If the feed given to chickens contains 8 ppm Se (as sodium selenite), growth is impeded. A dose of 4 ppm selenite has no such effect. Selenium injected into ferti­lized eggs in amounts not lower than 0.0005 mg per egg causes typical deformation of the embryo. Feed containing selenium-soaked grains reduces hatchability.

            The course of poisoning

            Three forms of selenium toxicity occur in nature:

1. acute toxicity from a very high dose ingested over a short period of time (greater than 500 to 1000 ppm of selenium ingested in a dry ration) 
2. sub-acute toxicity called blind staggers and caused by the accumulation of 2-5 ppm of selenium in dry matter content 
3. chronic toxicity called alkali disease or bobtail disease. The minimum lethal dose of selenium for the horse is 3.3 mg/kg of body weight.

            Severity of clinical signs of selenium toxicosis depends on the quantity and duration of exposure. Poisoning in animals is characterized as acute, subacute ("blind staggering / blind staggers") and chronic ("alkali disease") forms of selenium intoxication.

            Acute poisoning of cows or sheep, induced by ingestion of a large amount of plants that accumulate selenium, usually occurs after a single grazing or feeding. Most deaths usually follow within a few hours to 2 days after an acutely toxic consumption or injection of selenium. Acute oral selenium poisoning due to consumption of plants or mis-mixed diets with concentrations >50 ppm (dosages 1–10 mg/kg or greater, depending on the species, age, and chemical form of selenium) is not common but has caused large losses in cattle, sheep, and pigs. Animals usually avoid plants with high selenium content because of their offensive odor; however, when pasture is limited, accumulator plants may be the only food available. In some cases, plants may not have the profound offensive odor. Young animals are most susceptible to acute parenteral selenium toxicosis with dosages of 0.2–0.5 mg/kg.

            Symp­toms

            The acute form is the least common and is characterized by nervousness and fear initially, followed by depression, decreased appetite, diarrhea, fever, generalized muscular weakness and respiratory distress. Death occurs in several hours to several days. The symptoms may resemble those of rabies. There is no treatment for acute selenium poisoning. The symptoms also include quickened and weak heart beats, dyspnoea, bloating, colicky pains, polyuria, cyanosis, weakness and death from respiratory failure. Clinical signs are different from those of chronic selenosis and are characterized by abnormal behavior, respiratory difficulty, GI upset, and sudden death. Abnormal posture and depression, anorexia, unsteady gait, diarrhea, colic, increased pulse and respiration rates, frothy nasal discharge, moist rales, and cyanosis may be noted. Sheep usually show these signs to a much lesser degree or just become depressed and die suddenly.

            The major lesions are pulmonary edema, pulmonary congestion, pulmonary hemorrhage, hepatic necrosis, myocardial necrosis, myocardial hemorrhage, and potentially renal necrosis. Blood or serum selenium concentration in acute poisoning is often higher than in chronic poisoning. Treatment consists of symptomatic and supportive care. Acetylcysteine to boost systemic glutathione concentrations may be beneficial.

            Subacute and chronic selenium toxicity affects herbivores grazing or feeding on high-selenium plants for a comparatively short time. There are limited areas, including the Rocky Mountains and Great Plains, which have selenium levels high enough in the soil to result in toxicity from the ingestion of many plants growing on these soils. Any soil containing more than 0.5 ppm selenium can cause toxicity. The selenium content in some of these areas is as high as 50 ppm. High selenium soil has been associated with shale and on bare outcroppings and can be confined to small distinct areas (only in a few acres in a pasture). Subacute selenium poisoning is seen predominately in the spring as these plants are among the first to start growing. Animals may be craving green vegetation and consume them even though they are unpalatable. They develop a staggery gait, wander aimlessly, and “head press”, thus the term “blind staggers”. The disease may be expe­rimentally induced by a diet containing 10-20 ppm selenium, given to the experimental animals for 7-8 weeks.

            (Blind staggers is no longer believed to be caused by selenium but by sulfate toxicity due to consumption of high-sulfate alkali water and/or high sulfur-containing forages. Excess sulfate (>1% of diet) leads to polioencephalomalacia and the classical signs of blind staggers. Animals consuming milk vetch (Astragalus bisulcatus) have demonstrated clinical signs similar to those of blind staggers. Although milk vetch contains high levels of selenium, evidence now indicates that the alkaloid swainsonine in milk vetch is responsible for locoism and produces the neurologic clinical signs – Reference: The merck Veterinary Manual- 2014).

            The main symptoms are gradual loss of vision and paralysis. The affected animals lose mass, stray out of the herd, have a stagger­ing gait and poor sight. As the disease advances, the animal starts to move in circles and bumps into obstacles, having lost its sight. There is increased salivation, watery discharge from the eyes, violent abdominal pains, inability to swallow food, paralysis, collapse and death from suffocation.

            Chronic poisoning

            Chronic selenium poisoning (alkali disease or bobtail disease) is the most common form of the disease in our area and is caused by the ingestion of smaller amounts of the element over a longer period of time.  This condition can occur in the spring and summer on pasture or when livestock are on hay containing high selenium plants. Chronic poisoning from selenium salts have also been reported in animals’ drinking water containing 0.5 to 2.0 ppm of selenium. Chronic selenium poisoning usually develops when livestock consume seleniferous forages and grains containing 5–50 ppm of selenium for many weeks or months, although chronic exposure to high concentrations of inorganic selenium can also produce chronic selenosis. Naturally occurring seleno-amino acids in plants are readily absorbed and inserted into proteins in place of their corresponding sulfur-containing amino acids (ie, selenomethionine in place of methionine or selenocysteine in place of cysteine).

            "Alkali disease" is frequent in regions where the plants con­tain about 5-25 ppm Se and are fed to animals over a long period.

            (The name "alkali disease" stems from a time when symptoms of chronic sele­nium poisoning were believed to have been caused by drinking alkaline water).

            Alkali disease has been reported in cattle, sheep, and horses.

            Affected animals are inactive, weak, anorexic, lame, emaciated, anemic, and lack vitality. In addition, the most distinctive lesions are those produced by damage of the keratin of the hair and hooves. The animals lose weight, look stiff, and hobble. A distinct symptom in horses and mules is that they shed the long hairs from the mane and tail. The shedding of these hairs begins after about a month of the animals stay on pasture with high-selenium grass.

            Horses with chronic selenium toxicosis exhibit weight loss, hair loss (especially obvious in the mane and tail), and lameness in all four limbs. The coronary bands are painful to palpation and the band may separate with excretion of necrotic tissue from the defect. In severe cases the hoof wall may slough off. Provided the hoof wall does not slough the defect will grow down the hoof wall with new growth and eventually leave a normal hoof in 10-12 months. Rotation of the coffin bone (as may occur with founder) is rare and complete recovery is common. The loosening of the mane and tail hairs (which may also occur in cows) is usually accompanied by hobbling caused by damage to the joints and pain in the hooves. Inflammation and swelling start at the coronary corium. In very mild cases no other changes may occur, although the animals still hobble. In severe poisoning the wall of the hoof gradually separates under the coronary corium, from which new horny matter starts to grow. Sometimes the old growth of the hoof is sloughed off, sometimes it is retained, being attached to the new growth until this reaches a normal length. In cattle the old hooves are usually connected to the new growth, giving rise to abnormal grooved, hard and overgrown hooves. The described chan­ges in limb are very painful and sometimes the affected animals are unable even to walk a short distance to drinking water alone, and may thus die of thirst and hunger. Pronounced anaemia is also an important sign of selenium poisoning. For horses, the predominant clinical manifestation is lameness due to founder. The animal has a rough hair coat, and the long hairs of the mane and tail break off, giving a “bob” tail and “roached” mane appearance. Abnormal growth and structure of horns and hooves result in circular ridges and cracking of the hoof wall at the coronary band. Extremely long, deformed hooves that turn upward at the ends also may be seen. Subsequent lameness is compounded by degeneration of joint cartilage and bone. Reduced fertility and reproductive performance occurs, especially in sheep and cattle. Reproductive performance may be impaired with a dietary selenium content lower than that required to produce the other typical signs of alkali disease. Other lesions may include liver cirrhosis, ascites, and myocardial necrosis/scarring.

            In pigs, chronic selenium poisoning is evident by loss of mass, hobbling, hair shedding and painful changes in the feet similar to cows. Young pigs fed grains containing 11-15 ppm Se show symptoms of the disease within 2-3 weeks.

            Pigs fed a diet supplemented with selenium >20–50 ppm for >3 days develop a subchronic selenium toxicosis characterized by neurologic abnormalities. Animals are initially ataxic and uncoordinated, followed by anterior paresis, then quadriplegia. Even though neurologic impairment is occurring, the pigs continue to eat, which would indicate neurologic damage that is not centrally mediated. The hooves show breaks and impaired growth similar to those seen in cattle. Alopecia may also be seen. In sows, conception rate decreases and the number of stillborn pigs increases. Lesions of subchronic toxicosis include focal symmetric poliomyelomalacia, which is most prominent in the cervical and thoracic spinal cord. Death may result from complications of permanent paralysis. Hoof and hair damage is similar to but in most cases less severe than that seen in chronic selenium toxicosis. Treatment is similar to that for chronic toxicosis, but spinal lesions are usually permanent.

            Birds also may be affected with chronic selenium toxicosis. Eggs with >2.5 ppm selenium from birds in high selenium areas have low hatchability and embryos that are usually deformed. Teratologic effects include underdeveloped feet and legs, malformed eyes, crooked beaks, and ropy feathers.

            In selenium-poisoned animals, some alterations in blood chemistries occur. These changes include decreased prothrombin activity, fibrinogen, and glutathione, as well as increased serum alkaline phosphatase, ALT, AST, and succinic dehydrogenase.

            Diagnosis is based on clinical signs, necropsy findings, and laboratory confirmation of the presence of high selenium content in an animal's diet (feed, forage, grains, or water), serum, blood, or tissues (eg, kidney, liver). Selenium in the diet at >5 ppm may produce mild clinical effects after prolonged exposure of ≥30 days. Concentrations of 10–25 ppm would be expected to produce severe clinical signs with prolonged exposure. Environmental exposure potential should be based on forage, feed, or water content, not on soil selenium content, because some chemical forms in soil are not available for uptake by plants and would not result in high exposure potential. Diagnosis of chronic selenium toxicosis can be made from clinical signs alone, however samples of feed, serum, or tissue can be analyzed to confirm the diagnosis. Serum levels of 1 to 5 ppm are consistent with a diagnosis of chronic selenosis, however horses must be consuming the high selenium diet to be diagnostic. A hoof sample containing 5-20 ppm of selenium is considered diagnostic.  Hair analysis is not a reliable test, as it has false negatives.  The concentration of selenium varies according to where the sample is taken from the mane of tail, therefore a high selenium analysis could be positive for chronic selenium poisoning whereas a low reading is inconclusive.

            Tissue selenium content is the basis for diagnosing selenium poisoning in animals. Organic chemical forms of selenium have greater bioavailability and are retained in the tissues for much longer periods. Thus, timing of the exposure in relation to the collection of tissue, blood, or serum, as well as the chemical form of the selenium exposure, must be taken into account when interpreting the selenium content. In addition, some species variability in regard to concentrations also occurs. In acute toxicosis, the blood and serum selenium concentrations are generally >3–4 ppm, and in chronic toxicosis, it is generally >1–2 ppm. Liver generally contains >3–5 ppm selenium in acute cases, whereas in chronic cases it should be >1.5 ppm. Kidney of selenium-poisoned animals generally contains >1–5 ppm. Hair and hoof wall may have >1.5–5 ppm selenium in chronic poisoning. A “garlicky” odor on the animal's breath may be noted; this finding is more prominent with acute poisoning but can be seen with chronic poisoning as well. The odor is due to elimination pathways producing methylated selenium metabolites that are volatile and expired but may last for only 1–2 days after an acute poisoning incident.

            Post-mortem The characteristic finding in acute selenium poisoning is that of generalized haemorrhage, ascites and atonia of the smooth muscles.

            In subacute poisoning the post-mortem examination reveals chronic degenerative changes in all organs, the liver and spleen being the tissues most damaged. The liver is usually atrophic, necrotic and cirrhotic; the spleen is enlarged, as a rule with haemorrhages. Ascites in among the common findings. Haemorrhagic and oedematous changes in the brain have also been described.

            Post-mortem changes in chronic selenium poisoning. Atrophy and cirrhosis of the liver, atrophy of the cardiac muscle, gastroenteritis and nephritis.

            Material for laboratory examination Suspected feed and changed organs should be examined for the presence and quantity of Se.

            Treatment and Control

            There is no known therapy for acute selenium poisoning. However, subacute and chronic poisoning should be treated by the administration of small amounts of arsenic compounds in drinking water (e.g. water with 5 ppm As in the form of sodium arsenite or water with 25 ppm As in the form of arsenate).  Arsenic should protect the organism against the toxic action of selenium, probably through its non-toxic bond in the liver. Administration of good-quality protein may also be beneficial.

            Treatment is mainly supportive for subacute and chronic poisoning and there is no treatment for acute selenium poisoning. Low doses of arsenic have been advocated however is usually not practical due to the inherent risk. The treatment of chronic selenium toxicity is aimed at reducing intake of selenium and treating the hoof lesions. Animals should be removed from the high selenium feed and provided a balanced, high protein diet. By the time the chronic form is diagnosed the damage is done and the degree of pathology in the hooves dictates the treatment.

            There is no specific treatment for selenium toxicosis. Eliminating the source and exposure, as well as symptomatic and supportive care of the animal, should be started as soon as possible. Addition of substances that antagonize or inhibit the toxic effects of selenium in the diet may help reduce the risk of selenium toxicosis. A high-protein diet, linseed oil meal, sulfur, arsenic, silver, copper, cadmium, and mercury have reduced selenium toxicity in laboratory animals, but their use under field conditions is limited. However, some of the poor reproductive performance associated with selenium poisoning can be decreased by copper supplementation. Addition of arsenic salt at 0.00375% to enhance biliary excretion of selenium or a high-protein diet to bind free selenium has historically been used to reduce incidence of selenium poisoning in cattle. However, this has minimal to poor overall efficacy. Chronically selenium-poisoned animals are less likely to thrive than herdmates, even after exposure has been stopped.

            Forages should be tested regularly in high-selenium areas to evaluate year-to-year risk.