Toxicology Brief: The toxicity of iron, an essential element - Veterinary Medicine
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Toxicology Brief: The toxicity of iron, an essential element


Second, iron is transferred to ferritin or into circulation bound to transferrin proteins. Transferrin is an alpha1-globulin produced in the liver.1,2,7 Complexed with transferrin, iron is distributed to other iron storage locations in the body. A unique feature of iron metabolism is the almost complete absence of iron excretion. Any iron lost from hemoglobin degradation is rapidly bound to transferrin and transported to the bone marrow for the resynthesis of hemoglobin.2,7 Consequently, little iron is lost in the urine and feces. In addition, iron loss is not notably increased even after iron overdoses.2,4 Most iron loss is through the exfoliation of gastrointestinal mucosal cells in all mammals and through menstrual blood loss.5 While anywhere from 2% to 15% of the iron ingested is absorbed, only about 0.01% of the iron body burden is eliminated every day.1,5

Mechanism of action

When the absorbed iron is not bound to protein, it produces a variety of harmful free radicals. Consequently, the concentration of iron is rigorously controlled in mammalian cells and biological fluids. Acute iron toxicosis causes both a direct corrosive effect on the gastrointestinal tract and cellular damage due to circulating unbound iron.2 Large doses of iron may overcome the rate-limiting absorption step and allow excessive iron to enter the body. When iron-binding proteins become saturated, free iron ions are allowed into the general circulation.2,4-6 Free iron penetrates the cells of the liver, heart, and brain. At the cellular level, free iron increases lipid peroxidation with resulting membrane damage to mitochondria, microsomes, and other cellular organelles.1

Iron exerts its most profound effects on the cardiovascular system. Excessive iron can cause fatty necrosis of the myocardium, postarteriolar dilatation, increased capillary permeability, and reduced cardiac output.2 Free iron stimulates serotonin and histamine release as well as systemic metabolic acidosis caused by lactic acid accumulation. All these mechanisms lead to shock. Excessive iron also interferes with clotting mechanisms, augmenting hemorrhagic processes.1,2,4 Excessive iron also has been reported to cause thrombocytopenia.5

Excessive iron causes metabolic acidosis through several mechanisms. First, lactic acidosis occurs because of hypovolemia and hypotension. Iron disrupts oxidative phosphorylation by interfering in the electron transport chain. Thus, anaerobic metabolism is promoted. As ferrous iron is converted to ferric iron, hydrogen ions are released, adding to the metabolic acidosis. Free iron ions also inhibit the Krebs cycle, and organic acids accumulate.5

The liver accumulates free iron in Kupffer cells and the hepatocytes. The iron localizes in mitochondria of these cells and damages several cell organelles.5 Eventually, hypoglycemia, hyperammonemia, coagulation defects, and hepatic encephalopathy occur.2,5 Free iron inhibits the thrombin-induced conversion of fibrinogen to fibrin. Histopathologic evidence of iron-induced hepatic damage includes cloudy and swollen hepatocytes, portal iron deposition, fatty metamorphosis, and massive periportal necrosis.2,4,5


Since no mechanism exists for excreting iron, toxicity depends on the amount of iron already in the body. Consequently, some animals develop clinical signs of toxicosis even when they receive doses that cause no problems in other animals. Iron is most toxic when given intravenously. Intramuscular injections are less toxic, and iron given orally is the least toxic, probably because the amount of iron absorbed orally is not 100% of the dose ingested.4 When assessing the potential toxicity of an iron overdose, the amount of elemental iron in the products ingested must be determined (Table 1).4 For example, if a 500-mg tablet of ferrous gluconate was ingested, only 60 mg of elemental iron would have been ingested (500 mg X 0.12).

No clinical signs of toxicosis are expected in dogs ingesting less than 20 mg/kg of elemental iron. Dogs ingesting between 20 and 60 mg/kg of elemental iron can develop mild clinical signs. When the amount of elemental iron ingested is greater than 60 mg/kg, serious clinical signs can develop.2 In all animals, oral doses between 100 and 200 mg/kg are potentially lethal.2,4


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