Page 459 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

426 SECTION | V Metals and Micronutrients

VetBooks.ir excretion. Copper is utilized by essentially every cell in breed differences (Du et al., 1996) but with hemolysis
occurring with less frequency than in sheep.
the body, and there are several important copper-
Chronic copper toxicosis in dogs is primarily seen in
dependent enzymes including cytochrome C oxidase,
superoxide dismutase, lysyl oxidase, and dopamine beta the Bedlington Terrier where genetic studies have shown
hydroxylase (Gaetke et al., 2014). it to be an autosomal recessive disorder (Forman et al.,
In the ruminant, copper has a complex interrelation- 2005). Other breeds including West Highland White
ship with dietary molybdenum and sulfur which, when Terriers, Skye Terriers, and Doberman Pinschers (Speeti
present in excess, will both decrease copper absorption et al., 1998) have breed-related hepatic copper accumula-
and inhibit copper utilization. In the reducing environ- tion, the origin of which is less defined. Chronic copper
ment of the rumen, excess sulfur favors the formation of toxicosis in dogs will also have a period of copper accu-
sulfides, which can inhibit copper absorption from the GI mulation without clinical signs or detectable damage to
tract. Additionally, the formation of tri- and tetrathiomo- the liver. As copper concentrations increase, the animal
lybdates can also inhibit the absorption of copper or, if in develops a chronic active hepatitis with necrosis and
high amounts, can cause systemic effects by holding cop- inflammation. As with sheep, excess free copper damages
per in a nonbiologically available form (NRC, 2005). many cellular components of the liver, including the lipid
peroxidation of mitochondrial membranes. A sudden
release of copper with the resulting hemolytic crisis is
MECHANISM OF ACTION
much less likely to occur in dogs. The disease usually
Acute exposure to excess copper causes GI irritation and appears at 2 6 years of age, with animals often showing
can cause erosions of the mucosa as well as a blue-green no problems before this time.
discoloration of the contents and wall. Normally, the free
copper concentration in cells is kept very low by copper- TOXICITY
binding proteins such as metallothionein, glutathione, and
copper chaperone proteins. An excess of copper can over- There is a paucity of information on the amount of copper
whelm these binding proteins and allow free copper ions needed for acute poisoning in various species, but the
to exist in the cell, which can directly bind proteins and general range is given as 25 50 mg/kg of body weight.
nucleic acids. Additionally, the free copper can form reac- Copper sulfate is most often implicated in clinical cases
tive oxygen species and hydroxyl radicals, causing lipid as the copper source. The toxic dose of copper sulfate in
peroxidation of membranes and damage to nucleic acids cattle is 200 800 mg/kg, with sheep more sensitive at
and cellular proteins (NRC, 2005; Gaetke et al., 2014). In 20 100 mg/kg. Affected animals show clinical signs of
a recent experimental study, Keswani et al. (2013) dem- salivation, gastroenteritis, and abdominal pain, which may
onstrated copper-induced immunotoxicity involving cell rapidly develop to dehydration, shock, and death.
cycle arrest and apoptosis in the liver. Animals that survive longer than 24 48 h develop liver
Chronic copper toxicosis in sheep is caused by the and kidney damage and the animal may have an acute
inability of the sheep to increase the biliary excretion of hemolytic crisis. Postmortem findings include gastroenter-
copper in response to dietary increases. Copper will then itis and a blue-green discoloration to the GI tract and con-
accumulate in the liver but during this accumulation tents. Varying degrees of liver and kidney lesions are
phase there will be little or no evidence of negative present, with milder lesions in acute deaths and more dra-
effects (Bremner, 1998). If accumulation continues, the matic lesions developing after 48 h. Diagnostic testing of
liver can suffer direct damage from the high concentra- the intestinal tract contents shows a high level of copper.
tions of copper. When damage is severe, hepatic necrosis In acute deaths, there are normal levels of copper in the
develops and copper is released into the bloodstream. liver and kidney. If the animal survives over 24 h, ele-
Additionally, stress to the animal can also accentuate this vated copper levels are found in liver and kidney.
mobilization of copper from the liver and into the blood- In sheep, even normal levels of copper in feeds
stream. Increasing copper concentrations in the blood- (10 20 ppm) can cause hepatic copper accumulation
stream will overwhelm the protective transport actions of when the molybdenum level in feed is low (less than
transcuprein and albumin, which can then result in the 1 ppm). As the copper-to-molybdenum ratio (Cu:Mo)
lysis of red blood cells due to the oxidation of the red increases above 6:1, the risk of copper accumulation
blood cell membrane by ionic copper. As copper is mobi- increases, with those diets whose ratio is above 20:1 being
lized from the liver, it can accumulate in the kidney. The very dangerous for sheep. At the higher Cu:Mo ratios,
kidney can be damaged both from the accumulation of toxic accumulation of copper in the liver can occur over a
copper as well as the direct toxic effects of hemoglobin matter of weeks. In affected animals, there may be an
following the hemolytic event. Cattle can also be affected acute hemolytic crisis and the animals show clinical signs
by chronic copper toxicosis, with a strong suspicion of of weakness, anorexia, icterus, dyspnea and pale mucous