Arsenic poisoning in livestock

ARSENIC

A heavy metal which is an irritant and cumulative poison

            Arsenic (As) was used more than 2400 years ago in Greece and Rome as a therapeutic agent and as a poison. Arsenic is found in soil, water and air as a common environmental toxicant. The element usually is not mined as such but is recovered as a by-product from the smelting of copper, lead, zinc, and other ores. The arsenic atom exists in three oxidation forms i.e. elemental (As), trivalent (As ⁺ or arsenite) and pentavalent (As or arsenate) oxidation states. The organic arsenical compounds contain arsenic linked to a carbon atom by a covalent bond, where it exists in the trivalent or pentavalent states. In general, toxicity increases in the sequence of organic arsenicals < As⁵⁺ < As³⁺ < Arsine (AsH₃).

Availability of Arsenic to livestock

o   Arsenic as a drug for control of ectoparasites (lead arsenate as dip), blood parasites (Sodium thiacetarsamide; Sodium-n-phenylglycineamide-p-arsonate: It is a white crystalline powder and contains 25.1 to 25.5 per cent of arsenic. It is used once a week in the treatment of trypanosomiasis), ruminatoric preparations and skin tonics.

o   Arsenical pesticides, i.e. insec­ticides (Copper acetoarsenite or Paris green - It is an insecticide, but used less now due to high toxicity), defoliants/herbicides (sodium or potassium arsenite or arsenate, monosodium methane arsonate, MSMA), rodenticides (Arsenic trioxide or Arsenious oxide (As₂O₃)/Sankhya: It is commonly called as white arsenic or simply arsenic. It is white amorphous, vitreous or crystalline matter, slightly soluble in cold water (1-2 mg/ml) but highly soluble on boiling (0.2-0.3 g/ml). The solution formed is acidic and is called arsenious acid. Arsenious oxide has a property of floating on water as a white film. It is largely used as principal in­gredient of fly papers, rodenticides, anthelmintic, etc.), wood preservatives (arsenic pentoxide), and ant baits (Sodium or Potassium arsenate - Both sodium and potassium arsenates are poisonous and are used for homicidal pur­poses and malicious poisoning of cattle; Potassium arsenite (K₃AsO₃) and sodium arsenite (Na₂AsO₃): These are white powders, soluble in water. Both are poisonous and are used in the manufacturing of fly papers, insecticides, herbicides, sheep dips, rodenticides, etc.).

o   Other organic arsenic compounds: 3-acetylamino-4-hydroxy phenylarsenic acid (stovarsol): It is an or­ganic compound of arsenic known as acetarsol, or acetarsone. It oc­curs as colourless crystals and contains 27% of arsenic.

o   Arsenic-contaminated soils or burn piles.

o   Contaminated drinking water especially well water containing high concentrations of arsenic. Underground water having high arsenic.

o   Organic arsenical feed additives in poultry or swine as growth promoters (arsanilic acid, sodium arsanilate, etc).

o   Burning of wood products treated with arsenical preservatives or coals which have variable concentration of arsenic.

o   Smelting of copper, zinc, lead and other ores can release arsenic as a by-product into the environment.

o   From arsine [highly toxic gas liberated by the action of water on pyritic ores - Hydrogen arsenide (AsH₃ or arsine): It is a colourless gas with garlic odour. It is generated under the effect of hydrogen on arsenic compounds. It is a very strong poison (10 to 20 times as toxic as CO], 10 ppm is toxic within a min. It has MAC of 0.05 ppm. and arsenic trioxide used in the manufacture of most computer chips using silicon-based technology.

o   Pastures and crops near smelters contaminated with arsenic.

Toxicodynamics of Arsenic

§  As is a general tissue poison.

§  Toxic effects – due to their combining with and inactivating the –SH groups in tissue enzymes.

§  As³⁺ are most toxic.

§  All  tissues are affected – deposition and toxic effects are greatest in those tissues which are rich in these oxidation systems viz., alimentary tract wall, liver, kidney, spleen and lung.

§  As³⁺ primarily binds to -SH compounds especially lipoic (thioctic) acid and alpha-keto oxidases.

§  As³⁺ inhibit many enzymes by reacting with biological ligands containing available -SH groups. The pyruvate dehydrogenase system is especially sensitive because interaction of arsenic with two sulfhydryl groups of lipoic acid results in a stable six-membered ring. (Lipoic acid is an essential cofactor for the enzymatic decarboxylation of keto acids such as pyruvate, ketoglutarate and ketobutyrate. By inactivating lipoic acid, arsenic inhibits formation of acetyl, succinyl, and propionyl coenzymes-A).

§  Other oxidative decarboxylations that use lipoic acid are probably also inhibited.

§  The major effect of lipoic acid inhibition is slowing or inhibition of glycolysis and TCA cycle. Tissues with high oxidative energy requirement e.g. actively dividing cells such as intestinal epithelium, kidneys, liver, skin, lungs etc.) are most affected. Trivalent arsenic affects capillary integrity by an unknown mechanism. The GI tract is most affected. Capillary dilatation is followed by transudation of plasma into the gastrointestinal tract resulting in submucosal congestion and oedema.

§  As⁵⁺: These appear to substitute for phosphate in oxidative phosphorylation. Arsenate (pentavalent) is a well-known uncoupler of mitochondrial oxidative phosphorylation. There is competitive substitution of arsenate for inorganic phosphate in the formation of ATP, with subsequent formation of an unstable arsenate ester that is rapidly hydrolyzed. This process is called as arsenolysis. However, elevated body temperature is not a capillary and vascular dilatation characteristic of arsenate as seen with other oxidative uncouplers (e.g. nitrophenols).

§  Pentavalent organic arsenicals (feed additives): These act by an un­known mechanism. These produce demyelination and axonal degeneration, which may be due to interference with the B vitamins required for maintenance of nervous tissue.

§  Arsine gas (AsH₃): It is a gaseous hydride of trivalent arsenic. It does not cause typical signs of arsenic poisoning. It causes haemolysis and pulmonary oedema by mechanisms which are not clearly understood. Rapid and fatal haemolysis probably results from arsine combining with haemoglobin and then reacting with oxygen to cause haemolysis. Dimercaprol has no effect on the haemolysis.

Factors affecting toxicity

Ø  Species: Herbivores are commonly poisoned due to ingestion of contaminated forages. Cats and dogs are less poisoned while fowl and swine are rarely poisoned due to their limited exposure to arsenic.

Ø  Oxidation state: Inorganic arsenic in the trivalent state is more toxic (upto ten times) than the inorganic pentavalent form (as pentavalent form has less affinity for thiol group) which in turn is more toxic than organic form. Toxicity of pentavalent arsenicals is largely due to then- conversion in vivo to trivalent state.

Ø  Form/solubility: Finely divided soluble arsenic compounds are more toxic than coarse and poorly soluble ones because the latter are poorly absorbed.

Ø  Status/health of animal: Dehydrated, weak, ill and poor condi­tioned animals are more susceptible to toxicity due to slow excre­tion of arsenic.

Ø  Tolerance: Constant exposure to arsenic may confer some degree of tolerance to its toxicity.

Toxicokinetics

ü  Soluble arsenicals (both trivalent and pentavalent) are readily absorbed from GI tract and through the skin.

ü  Percutaneous toxic dose is much lower (probably one-tenth of) than the oral toxic dose.

ü  The absorption is more if the animals are given dip in hot weather, if the fleece is long and if they are crowded too tightly in draining yard.

ü  Absorption of poorly water-soluble ar­senicals such as As₂O₃ greatly depends on the physical state of the compound, be­cause coarsely powdered material is eliminated in faeces before it dissolves.

ü  After absorption, arsenic is distributed throughout the body but tends to reach higher concentration in liver, kidney, heart and lungs. Because of high sulfhydryl con­tent in keratin, high concentrations of ar­senic are found in hair and nails where it stays for months. Because of its chemical similarity to phosphorus, it is deposited in bone and teeth and is retained there for long period.

ü  In domestic animals, arsenic does not stay in tissues very long and is partly methylated (detoxification) in the liver and rapidly excreted in the urine, faeces, bile, milk, saliva and sweat.

ü  Some portion of pentavalent arsenic (arsenate) is reduced to the more toxic trivalent arsenic. In this process, the pentavalent arsenic is coupled to the oxidation of glutathione (GSH) to its disulphide (GSSG) to form a trivalent arsenic (arsenite) which is further methylated to form methyl arsenite and then dimethylarsenite which is readily eliminated from the body.

ü  Arsenic probably crosses placental barrier but passage to CNS through blood brain barrier is limited.

ü  Excretion of arsenic in domestic animals is rapid and nearly complete within a few days.

Acute and subacute poisoning

Animals most affected Dogs, cattle (wild birds, all animals).

Etiology

            Accidental ingestion of arsenical agrochemical products (remaining in discarded containers), notably fungicides based on sodium arsenite (used in vines). Available commercially in the form of concentrated suspensions (up to 250 g/l).

            Migrating and other wild birds are frequently killed either during spraying or immediately after application of the chemical to fields and open areas.

            Accidental ingestion of ant killers based on organic salts.

            Several cases of criminal or deliberate poisoning have also been noted.

Toxicity

            A highly toxic, thiol-depriving poison with a general irritant effect.

Oral doses (sodium arsenite):

LD       (all animals)                           5-25 mg/kg

LD       in mg/animal:

            Horses                                                1000-3000

            Cattle                                      1000-4000

            Sheep, goats                           200-500

            Pigs                                         50-100

            Dogs                                       50-150

            Poultry                                   10-100

Clinical features

Acute poisoning

·         Salivation, vomiting;

·         Diarrhoea, severe abdominal pains, intense thirst;

·         Weakness, ataxia, trembling, prostration followed by paralysis during terminal phase of poisoning;

·         Collapse and sudden death.

Subacute poisoning Same clinical features as above but less pronounced with:

·         anorexia;

·         polyuria, then anuria;

·         oedema of the skin, with creasing, skin eruptions and secondary cutaneous infections.

Lesions

·         Haemorrhagic gastroenteritis, with occasional necrosis, perforation of the gastric mucosae and gut wall;

·         Cardiac petechiae and haemorrhages;

·         Renal and hepatic degeneration.

Treatment

Antidotes

·         Dimercaprol (BAL) 2-6 mg/kg by deep i.m. injection, twice a day for 3 days.

Symptomatic

·         Gastrointestinal demulcents;

·         Rehydration therapy;

·         Cardiorespiratory stimulants.

Laboratory investigations

·         Liver and kidney samples;

·         Stomach contents;

·         Intestinal contents (in acute cases).

Chronic poisoning

Animals affected All species.

Etiology

            Ingestion of forage contaminated by industrial pollution (incidence extremely rare). Deliberate or criminal poisoning is often referred to but is rarely seen in veterinary medicine.

Toxicity

            Cumulative poison concentrating particularly in the CNS, the skin and all structures associated with the dermis / epidermis and ectodermis. Toxic doses not well known.

            Sodium arsenite

LD       0.2-0.5 mg/kg per day for several months.

Phenomenon of pseudo-tolerance, due to ‘mithridatism’, or gradual reduction in intestinal absorption.

Clinical features

Cutaneo-mucosal syndrome

·         Alopecia, keratosis;

·         Coryza, cough, laryngitis.

Gastrointestinal effects

·         Salivation, nausea, vomiting;

·         Profuse watery diarrhoea or constipation.

Neurological effects

·         Swelling of the joints, joint pain with stiffness;

·         Paralysis.

Lesions

·         Keratosis;

·         Aplastic anaemia and anaemia;

·         Cirrhosis;

·         Nephritis.

Treatment

Stop further exposure immediately.

Antidotes

·         Dimercaprol (BAL) 2-3 mg/kg by deep i.m. injection, every 4 h for 3-5 days.

·         Monitor renal function as the antidote is nephrotoxic.

Symptomatic

·         Gastrointestinal demulcents;

·         Rehydration therapy;

·         Cardiorespiratory stimulants.

Laboratory investigations

·         Liver and kidney samples;

Diagnosis

• From history, circumstantial evidences, clini­cal signs and lesions.
• A sudden onset of severe colic, bloody or watery diarrhoea containing mucosal shreds, and post-mortem findings of haemorrhagic gastroenteritis and degenerative changes in the liver and kidneys should always be interpreted as possible arsenic poisoning. No other metal or metalloid, with the possible exception of thallium, causes such a speedy onset of severe GI damage. Chemical determination of arsenic in tissues and ingesta provides confirmation. Antemortem samples include urine, vomitus, faeces and hair. After death hepatic, renal and nervous tissues (organic pentavalent toxicosis) may be taken. Analysis of feed, plant, and soil should also be done. Liver and kidney tissues of healthy animal rarely contain > 1 ppm arsenic (wet wt.), whereas toxicity is associated with concentrations > 3 ppm. Urinalysis reveals high ar­senic content for many days, proteinuria, increased specific gravity and casts.

Differential diagnosis

• Lead poisoning: Lead poisoning, if severe enough, can mimic various aspects of arsenic poisoning but with lead there are nervous and behavioural signs.
• Caustics, irritants, and urea: These also show GI signs like diarrhoea and colic and require careful identification.
• The nervous syndrome in pigs poisoned by organic arsenicals may be confused with organic mercury poisoning, salt poisoning and en­cephalitis, but the mildness of the signs, the lack of effect on appetite and the absence of fever differentiate it from others.

Treatment

Acute and Subacute poisoning

Antidotes

•      Dimercaprol (BAL) 2-6 mg/kg by deep i.m. injection, twice a day for 3 days. Dimercaprol / British Anti-Lewisite (BAL) is a dithiol-containing chelating agent that can form a relatively nontoxic and easily excretable complex with arsenic. However, it is relatively ineffective un­less given prior to a set of clinical signs as enzymes that have been inhibited for a long time are not easily regenerated by BAL. Further, if arsenic is present in large excess, neither BAL nor any other chelator can be expected to work very well to regenerate enzymes activities. BAL also has toxic effects (vomiting, tremors, and convulsions) which limit its dosage and frequency of administration. Dosage and frequency of BAL is highly specific, i.e. if administered too late or in insufficient doses at infrequent intervals, the animals may die of arsenic poisoning; and if administered in excess or at too frequent intervals, the animals may die of BAL poisoning. This is also true for other specific chelating agents used in metals toxicoses. Large animals: 3 mg/kg (5% sol. in a 10% sol. of benzyl benzoate in peanut oil) by I.V. route. The injection should be repeated every 4 hours for the first 2 days, every 6 hours the 3rd day, and twice a day for next 10 days until recovery. Small animals: 2.5 mg/kg (10% sol. in oil). Dose intervals are same as in large animals.

•      Sodium thiosulphate – i.v. 15-30 g in 100-200 ml water (initally) followed by oral dosing of 30-60 g at 6-hour interval. Horses and cattle: 20-30 g, orally in about 300 ml water, plus 8-10 g I.V. in 10-20% solution. Sheep and goat: One fourth of above dose. The sulphur of thiosulphate probably reacts with arsenic and immobilizes it.

•      Thioctic acid: It is considered more effective than dimercaprol for arsenic poisoned cattle, however, it is not available in a commercial dosage form. Thioctic acid is used alone or in combination with BAL. Thioctic acid : 50 mg/kg body wt., I.M. thrice a day as a 20% solution (50g of dl-6,8-thioctic acid dissolved in 100 ml of warm 5 N NaOH, cooled, then adjusted to pH neutrality with 1 N HCl and brought to volume with distilled water).

•      Dimercaptosuccinate is less toxic and more effective.

•      Mesodimercaptosuccinic acid (MDSA) and dimercaptosuccinic acid (DMSA, succimer): These are water soluble derivatives of dimercaprol and said to be superior to dimercaprol, but efficacy is not well tested. MDSA and DMSA: 30 mg/kg have been effective in preventing signs of arsenic toxicosis in rabbits. In higher dosages, these may cause necrotizing lesions at the site of administration. But these are less toxic than dimercaprol.

Symptomatic

•      Gastrointestinal demulcents;

•      Rehydration therapy;

•      Cardiorespiratory stimulants.

•      Stop further exposure immediately.

•      Supportive therapy and maintenance

•      a. Emetics, activated charcoal, or gastric lavage may be employed if ingestion is recent.

•      b. Correction of shock, dehydration and acidosis with extracellular electrolyte solutions may be done. Blood may be transfused, if neces­sary.

•      c. Animal should be kept warm and comfortable.

•      d. Sufficient vitamins, antibiotics, analgesics and other symptomatic care may be instituted.

Chronic poisoning

Antidotes

•      Dimercaprol (BAL) 2-3 mg/kg by deep i.m. injection, every 4 h for 3-5 days.

•      Monitor renal function as the antidote is nephrotoxic.

•      Symptomatic

•      Gastrointestinal demulcents;

•      Rehydration therapy;

•      Cardiorespiratory stimulants.