4.6 Metals and Environmental Toxicants

Question 1

Forms of Metals and their basic toxicological properties

Answer 1

• Metallic (elemental forms)
  >As a general rule have low solubility and toxicity
• Inorganic salts (chloride, acetate, sulfate, etc)
  > More water soluble, reactive, bioavailable
  > Some forms more toxic
  » e.g. As3+ >As5+; Fe2+ >Fe3+
• Organic (carbon-bound)
  > Lipid soluble, readily absorbed, neurotoxic

Question 2

dose response to metals

Answer 2

problems if too little or too much > want to be in “sweet spot”
-response shifts due to variety of factors

Question 3

Toxicology of Metals: Mechanisms (4)

Answer 3

1. Association with polar groups
   * Thiol residues, histidine, porphyrins, etc
2. Ionic interactions with charged residues
   * Carboxylic acids
   * Substitution for other ions, e.g. Ca++
3. Generation of free radicals
   * Fe++, Cu++, etc
4. Haptens and immunostimulants
   * e.g. Ni binds to keratohyalin, filaggrin, etc.
   * Aluminum and mercury used as adjuvants

Question 4

most metals are toxic-actors in this way

Answer 4

direct-acting toxicants

Question 5

mechanism of action of nephrotoxic metals

Answer 5

Nephrotoxic metals (Hg, Cd, Pb, U, etc)
1. Bind to metallothionein (MT)
2. Small protein not retained by glomerulus
3. Reabsorbed in proximal tubule (PT)
4. Accumulates to nephrotoxic levels
5. Mitochondrial damage - Tubular necrosis

Question 6

can metals cause problems by binding proteins?

Answer 6

yeah

Question 7

lead major target organs; acute and chronic

Answer 7

Acute: GI tract, brain, kidney
Chronic: Bone marrow, peripheral nerves

Question 8

copper major target organs; acute and chronic

Answer 8

Acute: GI tract, liver
Chronic: Erythrocytes, liver, kidney

Question 9

iron major target organs; acute and chronic

Answer 9

Acute: GI tract, liver
Chronic: Erythrocytes, liver, kidney

Question 10

zinc major target organs; acute and chronic

Answer 10

Acute: GI tract
Chronic: GI tract, hemolysis

Question 11

selenium major target organs; acute and chronic

Answer 11

Acute: CNS, muscle
Chronic: Integument (hoof and hair)

Question 12

aresenic major target organs; inorganic, organic

Answer 12

Inorganic: GI, kidney; Organic: Neuropathy

Question 13

mercury major target organs; inorganic, organic

Answer 13

Inorganic: GI, kidney; Organic: Neuropathy

Question 14

absorption of copper in sheep - mechanism of toxicity

Answer 14

• Sheep are efficient at taking up Cu from the diet
• Tend to accumulate Cu (slow excretion)
• Accumulate more if molybdenum is low
• Store copper in macrophages and hepatocytes (cause some hepatopathy over time)
• Experience some acute period of hepatic necrosis or stress
  > Release copper into blood > Free radical generation causes massive hemolysis and hepatic necrosis

Question 15

treatment and prevention of copper toxicity in sheep

Answer 15

• Sodium molybdate and sodium thiosulfate
• Avoid Cu supplemented feeds intended for other species

Question 16

where do sheep store excess copper? what problems can arise?

Answer 16

Excess copper stored in hepatic macrophages
– seepage/release leads to chronic injury to liver

Question 17

what effect does copper released from liver in sheep have?

Answer 17

hemolytic > hemoglobin casts in kidneys, intravscular hemolysis, icterus, methemoglobin, hemoglobinuria

Question 18

Copper and chronic liver disease - Dogs. what breed? how does it arise?

Answer 18

 Inherited in Bedlington terriers (Cu homeostasis)
 Deletion of COMMD1 (MURR1) gene
 Non-familial and idiopathic in other
breeds
> Doberman, Westie, Dalmatian, Labrador, etc.
 Very high levels of lysosomal Cu in hepatocytes - 500-2000 ppm
 Lysosomes stain with rhodamine in histologic sections

Question 19

what does chronic liver disease look like in PM and clinical signs in a dog?

Answer 19

 Chronic necroinflammatory liver injury
> High liver [Cu] in 34% of dogs with chronic
hepatitis
> Cirrhosis in severe cases
 Gastrointestinal signs, elevated liver values
 Hemolytic crisis is unlikely
 Reduce copper with chelation therapy
> D-penicillamine (long course)
> Triethylene tetramine dihydrochloride (trientine)

Question 20

what problems can excess iron cause? what is an important nutrient to stop this?

Answer 20

-Iron causes free radical formation and lipid peroxidation, OH adducts and DNA breaks
-Vitamin E and Selenium have important antioxidant properties

Question 21

when is iron toxicity most common in piglets? what do we see in PM?

Answer 21

– most common when piglets or sow are vitamin E or selenium deficient!
-acute liver necrosis, myocardial necrosis

Question 22

effects of zinc toxicosis?

Answer 22

GI upset; renal failure Hemolysis; hemoglobinuria

Question 23

spider bite signs

Answer 23

*Cats are the species that most often get
black widow spider bites
* Painful bites, muscle cramps, paralysis

Question 24

blister beetle toxin and signs

Answer 24

• Blister beetles contain cantharidin
  *Necrosis and vesicles – oral, alimentary tract

Question 25

what can some caterpillars cause in mares?

Answer 25

• Placentitis and abortions in mares

Question 26

what do rattlesnake bites contain and cause?

Answer 26

Phospholipases, Coagulation factors, Myotoxic peptides, Other toxins

-Painful wounds with local swelling
-Local necrosis and hemorrhages
-Coagulation problems
-Rhabdomyolysis (muscle necrosis) and myoglobinuria
-Hemolysis and hemoglobinuria sometimes
-Shock and circulatory collapse

Question 27

Environmental Polychlorinated Compounds - whre do we fins them, what problems do they cause?

Answer 27

*Industrial applications (fire retardants, dielectrics, etc)
*Persist in the environment
*Bioaccumulate in animal tissues

*Endocrine disruptors
*Produce tumours in rats and mice

Question 28

what lesions do we see connected with oil spills?

Answer 28

various driller chemicals can cause oxidant RBC injuries