Chapter 17 - Metals and Minerals

Question 1

Example of nutrient excess in some metals that can cause a secondary metal deficiency.

Answer 1

Excessive amounts of one metal can cause a secondary metal deficiency by antagonizaing its absorption, transport or retention:

Excessive metal // Resultant deficiency // Affected Species

• Cadmium // Zinc // All
• Molybdenum // Copper // Cattle
• Potassium // Magnesium // Cattle
• Iron // Phosphate // Swine
• Calcium // Zinc // Swine

Question 2

Example of nutrient deficiencies in some metals that can enhance metal toxicity.

Answer 2

Nutrient deficiencies can enchance metal toxicity. E.g. low dietary calcium, zinc and iron enhance the absorption and toxicity of lead.

Question 3

What is chelation?

Answer 3

Chelation is a reversible interaction between a metal and an anionic or netural molecule that has at least one pair of nonbonded electrons.

Question 4

How can the chemical form and oxidation state (valence) of a metal affect the toxicologic effects of As and Hg

Answer 4

Inorganic forms of As and Hg primarily affect the liver, kidney and digestive tract

Organic forms predominantly accumlate in and affect the nervous system.

Question 5

Arsenic Toxicosis:

Sources

Answer 5

1. Environment:
   
   1. Ores (aresnopyrite, loellingite) mined and smelted to produce: elemental arsenic and arsenic trioxide.
   2. Arsenic in the environment exists in teh pentavalent form and may be methylated by microorganisms.
2. Commercial forms:
   
   1. Inorganic:
      
      1. Arsenic trioxide: (former herbicide)
      2. Pentavalent and trivalent forms (Na, K, Ca salts) used as baits
   2. Organic:
      
      1. Trivalent:
         
         1. Monosodium methanearsonate (MSMA) and disodium methanearsonate (DMSA), used as herbicides
         2. Thiacetarsamide: heartworm therapy in dogs
      2. Pentavalent arsenical feed additives (arsanilic acid, sodium arsanilate, 3-nitro 4-hydroxyphenylarsonic acid)

Question 6

Arsenic Toxicosis:

Exposure:

Answer 6

Arsenic poisoning can result from:

• Accidental exposure of livestock to old pesticides improperly disposed of or stored
• Arsenic-contaminated soils or burn piles (licked by animals that crave salt or minerals)
• Contaminated waters in abandoned minig areas
• Ant baits (sodium or potassium arsenate) - attractive to small animals, specially cats
• Use of thiacetarsamide in dogs
• Overdosage or extended use of organic arsenical feed additives in poultry or swine
• Burning of wood products treated with arsenical preservatives.

Question 7

Arsenic Toxicosis:

Toxicokinetics

Answer 7

1. Absorption: soluble arsenicals are readily absorbed from the gastrointestinal tract and through the skin
2. Metabolism: methylation of inorganic arsenicals occurs in vivo and may aid in detoxification.
3. Excretion: Trivalent arsenic is excreted into the intestine via the bile. Pentavalent arsenic is excreted by the kidneys. Excretion is rapid and nearly complete within a few days.

Question 8

Arsenic Toxicosis:

Mechanisms of Toxicologic Damage

Answer 8

1. Trivalent arsenicals:
   
   1. Inhibition of cellular respiration (binding to sulfhydryl compounds: lipoic acid and alpha-keto oxidases)
   2. Capillary dilatation and degeneration (unknown mechanism)
2. Pentavalent inorganic arsenicals (i.e. arsenates): subsitute for phosphate in oxidative phosphorylation: uncoupling of oxidative phosphoryl. produces cellular energy deficit.
3. Pentavalent organic arsenicals (feed additivies): demyelination and axonal degeneration: interference with B vit.

Question 9

Arsenic Toxicosis:

Toxicity

Answer 9

1. Inorganic arsenicals: Trivalent forms 10x more toxic than pentavalent forms.
   
   1. Acute: single dose lethal toxicity: 1-25 mg/kg. Cats more suscept > horses > cattle and sheep > swine > birds
   2. Subacute: lower dosages over several days
   3. Chronic: generally not described.
2. Organic arsenicals:
   
   1. Pigs: 500ppm dietary arsanilic acid or 250ppm 3-nitro 4-hydroxy phenylarsonic acid for 7-10 days
   2. Poultry: exposure of 2x pigs.

Question 10

Arsenic Toxicosis:

Diagnosis: Clinical signs

Answer 10

1. Inorganic or organic trivalent arsenicals:
   
   1. Acute or peracute poisoning:
      
      1. Vomiting and intense abdominal pain
      2. Weakness, staggering, ataxia, recumbency
      3. Weak, rapid pulse with signs of shock (hypotension, dehydration, hemoconcentration, hypothermia)
      4. Rapid onset of severe, watery diarrhea
      5. Rumen and GI atony
   2. Subacute poisoning: when animals survive acute poisining and live for > 3 days.
      
      1. Watery diarrhea continues
      2. Oliguria and proteinuria + polyuria and signs of kidney damage.
      3. Dehydration, acidosis, azotemia may cause death.
2. Organic pentavalent arsenical feed additives:
   
   1. 2-4 days: ataxia, incoordination, torticollis, blindness.
   2. Pigs: weak, sitting-dog posture, paralyzed in lateral recumbency
   3. Appetite normal, animals are cognizant, some blindess.

Question 11

Arsenic Toxicosis:

Diagnosis: Lesions

Answer 11

1. Gross lesions:
   
   1. GI irriation: mucosal congestion, submucosal edema, epithelial necrosis, accumulation of fluids in atonic intestine
   2. Subacute: intestinal capillary dilatation, submucosal congestion and edema, intestinal epithelial necrosis, renal tubular necrosis, hepatic fatty degeneration.

Question 12

Arsenic Toxicosis:

Diagnosis: Laboratory diagnosis

Answer 12

1. Packed cell volume increases
2. Blood urea nitrogen (BUN) increases
3. Urinalysis: proteinuria, increased specific gravity, casts.
4. Chemical residues in tissues or body fluids:
   
   1. AM: urine, vomitus, feces, hair. Chronic poisoning: inorgan. As accumulates in epidermis and hair (weeks-months)
   2. PM:
      
      1. Inorgan: acute: liver and kidney, rapidly excreted by animals that survive.
      2. Organ: pentavalent accumulate in nervous tissue (weeks)
5. Analysis of suspected baits, feed, plants or soil

Question 13

Arsenic Toxicosis:

Treatment

Answer 13

Early intervention:

1. Emergency and supportive therapy: correction of shock, acidosis and dehydration.
2. GI detoxification: emetics, activated charcoal, cathartic agents or gastric lavage (recent)
3. Antidotes:
   
   1. Dimercaprol (British antilewisite, BAL): prior to onset of clinical signs.
   2. Thiocitc acid: more effective than 1 in cattle
   3. Mesodimercaptosuccinic acid (MSMA) and dimercaptosuccinic acid (DMSA)

Convalescent animals: bland diets with reduced amounts of protein; vitamin supplementation.

Question 14

Arsenic Toxicosis:

Prognosis

Answer 14

1. Inorgan. trivalent arsenicals: Mortality rate is high among acutely poisoned animals.
2. Organic pentavalent arsenicals: high morbidity rate but low mortality if good nursing and supportive care. Recovery: 2-4 weeks.

Question 15

Copper Toxicosis:

Sources

Answer 15

Sources include:

• copper sulfate foot baths
• fungicides
• algicides

Question 16

Acute Copper Toxicosis:

Mechanisms of toxicologic damage

Answer 16

Copper salts act as direct tissue irritants and oxidants and cause coagulative necrosis of the GI mucosa.

Question 17

Acute Copper Toxicosis:

Toxicity

Answer 17

Single oral toxic dosage is 25-50mg/kg body weight.

Question 18

Acute Copper Toxicosis:

Diagnosis: Clinical signs and Lesions

Answer 18

1. Signs: Rapid onset of salivation, nausea, vomiting, colic, fluid or hemorraghic diarrhea (sometimes green-tinged) with rapid dehydration, shock and death.
2. Lesions: severe gastroenteritis, congestion of the liver, kidneys and spleen.

Question 19

Acute Copper Toxicosis:

Differential Diagnoses:

Answer 19

• Toxicoses:
  
  • Arsenic
  • Mercury
  • Selenium
• Infectious gastroenteritis (acute salmonellosis, canine parvovirus…)

Question 20

Chronic Copper Toxicosis in sheep:

Sources

Answer 20

• Feed additives (copper sulfate, copper oxide, copper chloride)
• Natural copper in soils and plants
• Soils contaminated by mining or smelting
• Soils and plants fertilized with used poultry litter or swine manure

Question 21

Chronic Copper Toxicosis in sheep:

Mechanisms of toxicologic damage

Answer 21

1. Accumulation in hepatic mitochondria and lysosomes (can be seen histol. with rubeanic acid staining) causes cellular degeneration or necrosis.
   
   1. In ruminan. is associated with copper, molybdenum and sulfate imbalances.
   2. Can be secondary to liver damage from xenobiotics or plants: Heliotropium and cause excess accumulation.
2. Acute hemolytic crisis: stress may precipitate sudden loss of stored copper from the liver to the blood.
   
   1. Excess copper oxidases erythrocyte membranes => hemolysis.
   2. Oxidation of hemoglobin to form methemoglobin, no transport of oxygen (aggravate acute hemolytic crisis).

Question 22

Chronic Copper Toxicosis in sheep:

Toxicity

Answer 22

1. Normal feed copper levels (10-20ppm) cause hepatic copper accumulation when molybdenum <1-2ppm or sulfate is not available. (Grains and forages contain <1ppm molybdenum.
2. 2-10 weeks exposure

Question 23

Chronic Copper Toxicosis in sheep:

Diagnosis: clinical signs and Lesions

Answer 23

1. Clinical signs of acute hemolytic crisis: acute anemia. Weakness, anorexia, fever, icterus, pale mucous membranes, dyspnea.
2. Lesions: liver, kidney, spleen.
   
   1. Gross: hepatic icterus; enlarged, pulpy spleen; dark, bluish-black kidneys (gunmetal kidneys)
   2. Micro: swollen, necrotic hepatocytes, vacuolation, periportal fibrosis, renal tubular necrosis, hemogloing casts in renal tubules, excessive fragmented erythrocytes in the spleen.

Question 24

Chronic Copper Toxicosis in sheep:

Diagnosis: laboratory diagnosis

Answer 24

1. Elevated bilirubin, hemoglobinemia, hemoglobinuria.
2. Elevated levels of hepatic enzymes (AST, LDH, SDH, arginase)
3. Elevated serum/blood copper levels (> 1.5ppm)
4. Copper levels in liver > 150ppm and kidneys > 15ppm

Question 25

Chronic Copper Toxicosis in sheep:

Differential diagnoses

Answer 25

1. Infectious diseases: leptospirosis, bacillary hemoglobinuria, babesiosis, anaplasmosis.
2. Plant toxicoses: onions, Brassica, red maple (Acer rubrum)
3. Drug toxicoses: phenothiazine anthelmintic toxicosis.

Question 26

Chronic Copper Toxicosis in sheep:

Prevention

Answer 26

Death within 24-48h of acute hemolytic crisis. Mortality high. Prevention is important!.

1. Feeding rations to ensure maintenance of the maximum copper:molybdenum ratio of 6:1.
2. Copper sulfate added to feed.
3. Addtion of molybdate to rations (2-4ppm)
4. Dosing with 50mg ammonium molybdate and 0.3-1.0 g thiosulfate per day
5. Supplemental zinc (250ppm) reduces hepatic copper accumulation.

Question 27

Chronic Copper Toxicosis in sheep:

Treatment

Answer 27

1. Ammonium tetrathiomolybdate: rapid binding and excretion of copper.
2. D-penicillamine (50 mg/kg orally, 6 days)
3. Subacute cases: molybdenized copper phosphate sprayed on pastures at 4 oz per acre.

Question 28

Chronic Hepatic Copper accumulation in dogs:

Etiology, breeds and ages most affected

Answer 28

Chronic canine hepatic copper accumulation is inherited as an autosomal recessive trait.

Most common in Bedlington terriers, also West Highland white terriers, Doberman pinschers and others.

Usuall appears at 2-6y with no prior signs.

Question 29

Chronic Hepatic Copper accumulation in dogs:

Mechanism of toxicologic damage

Answer 29

Copper accumulates in the lysosomes of hepatocytes until the storage capacity is exceeded. Release the copper to the cytoplasm: necrosis and inflammation.

Question 30

Chronic Hepatic Copper accumulation in dogs:

Diagnosis: clinical signs and Lesions

Answer 30

Clinical signs:

1. Young dogs (<6y): acute with vomiting, anorexia, weakness, dehydration.
2. Older dogs: anorexia, weight loss, icterus, ascites, hepatic encephalopathy.
3. Hemolytic crisis (rare)

Lesions:

1. Gross: Liver: large and necrotic to small and cirrhotic.
2. Micro: focal hepatitis, chronic active hepatitis, cirrhosis. Coper stains (e.g. rubeanic acid) show copper accumulation in hepatocytes.

Question 31

Chronic Hepatic Copper accumulation in dogs:

Laboratory diagnosis

Answer 31

1. Elevated liver enzymes (ALT, AP) and bilirubin.
2. Copper level in liver >1,000ppm (dry-weight basis). Hepatic biopsy confirms presence of copper.
3. Serum copper levels normal
4. Plasma ceruplasmin levels are normal.

[ceruplasmin is a copper-binding protein that is produced in the liver and released to the plasma to bind copper.

Question 32

Chronic Hepatic Copper accumulation in dogs:

Treatment and prevention

Answer 32

Treatment:

1. Ongoing chelation therapy with D-penicillamine for months, years, lifetime.
2. Adjunctive supportive therapy:
   
   1. Corticosteroids (0.5-1.0 mg/day) [to stablize hepatic lysosomal membranes]
   2. Ascorbid acid (500-1000 mg/day) to enhance excretion.

Prevention: copper intake in diet limited to 5-10ppm.

Question 33

Iron Toxicosis:

Sources

Answer 33

1. Preparations for oral supplementation of iron, including powders, tablets, premixes.
   
   1. Ferrous fumarate (C₄H₂FeO₄)
   2. Ferrous sulfate (FeSO₄·xH₂O)
   3. Ferric phosphate (FePO₄)
   4. Ferrous carbonate (FeCO₃)
2. Injectable iron preparations for prevention of neonatal anemia or use as hematinics
   
   1. Ferric ammonium citrate ((NH₄)₅[Fe(C₆H₄O₇)₂])
   2. Iron-dextran complexes

Question 34

Iron Toxicosis:

Exposure

Answer 34

Iron toxicity most often occurs as teh result of accidental ingestion of oral supplements or overdosage.

Question 35

Iron Toxicosis:

Mechanism of toxicologic damage

Answer 35

1. Normally: levels of iron maintained by selective absorption (energy-dependent carrier)
   
   1. ferrous iron oxidized to ferric iron and bound to transferrin (ß-1 glycoprotein)
   2. used for oxygen transport (hemo-, myoglbin). Excess is stored as hemosiderin or ferritin.
2. Excessive dose: circulates in plasma as free iron
   
   1. direct damage to epithelial cells (e.g. gastric mucosa) - corrosive and strong oxidant
   2. mitochondrial damage: hepatic necrosis
   3. cardiovascular collapse (increased capillary permeability)

Question 36

Iron Toxicosis:

Toxicity (oral preparations)

Answer 36

No mechanism for excreting irong, toxicity depends on the amount of iron already present in the body.

1. Toxicity injectables > orals. Oral:
   
   1. moderately toxic: 20-60 mg/kg bw.
   2. severely toxic: > 60 mg/kg bw
   3. lethal: > 200 mg/kg

Question 37

Iron Toxicosis:

Toxicity: diets with high iron in piglets

Answer 37

Diets > 5,000ppm of iron interfere with phosphate absorption and can lead to retarded growth and rickets in pigles.

Question 38

Iron Toxicosis:

Diagnosis: clinical signs

Answer 38

1. Oral preparations:
   
   1. < 6h: drowsiness, depression, vomiting, hemorrhagic diarrhea
   2. 6-24h: apparent improvement
   3. >24h: diarreha returns, DH, acute liver necrosis, shock acidosis, coma
   4. Ocassionaly: acute hemolytic anemia, icterus, hemoglobinemia, coagulopathy.
2. Injectable preparations: 2 syndromes:
   
   1. severe depression, shock, acidosis from excessive circulating iron.
   2. peracute anaphylactic-like reaction (almost immediately after injection not dosage related) related to histamine release.

Question 39

Iron Toxicosis:

Diagnosis: lesions

Answer 39

1. Oral preparations:
   
   1. mucosal necrosis, ulceration
   2. enteritis, intestinal contents: fluid to hemorrhagic
   3. congestion of spleen, liver, kidneys
   4. liver necrosis, icterus, hemoglobinuria
2. Injectable preparations: yellowish-brown discoloration of tissues and local lymph nodes and edema at or near the injection site

Question 40

Iron Toxicosis:

Diagnosis: laboratory diagnosis

Answer 40

1. Elevated serum iron levels: 1.5x-2x normal (100-300ug/dl)
2. increased saturation of serum total iron-binding capacity (TIBC). No correlation with severity
3. Hemoconcentration (shock and DH)
4. Acidosis
5. increased serum hepatic enzymes and bilirubin
6. Hemoglobinuria
7. Elevated iron in liver
8. Abdominal radiographs: ingestion of iron tablets

Question 41

Iron Toxicosis:

Treatment

Answer 41

1. Decontamination of GI tract <4h (if no vomiting or diarrhea)
   
   1. NO activated charcoal
   2. Milk of magnesia: precipitate iron as insoluble iron hydroxide
2. Supportive to control shock, DH and acidosis
3. Chelation therapy:
   
   1. Deferoxamine parenterally + oral ascorbic acid
   2. urine is reddish-brown
   3. Monitor serum iron levels 2-3 days
4. Convalescent care: residual intestinal scarring and liver damage.