Toxicology Brief managing common poisonings in companion animals PEER-REVIEWED The toxicity of iron, an essential element Jay Albretsen, DVM, PhD, DABT, DABVT TABLE 1 Iron Salts and ron is the most abundant trace min- salts are but is about a fourth as toxic.1,2,4 the Percentage eral in the body and is an essential Product labels do not always indicate if of Elemental Iron* element in most biological sys- the iron is chelated. Most products that I 1,2 tems. It is likely that iron was essential Elemental contain iron have it in a salt form. Table for developing aerobic life on Earth.3 Form of Iron Iron (%) 1 lists several iron salts and the percent- But iron is toxic to cells in excessive Ferric hydroxide 63 age of elemental iron in each. amounts. Acute iron poisoning is com- Ferrous carbonate (anhydrous) 48 mon and potentially lethal in dogs, cats, Ferric phosphate 37 Iron absorption and many other animals. Iron is also a Ferrous sulfate (anhydrous) 37 leading cause of unintentional poisoning Ferric chloride 34 Iron absorption is a two-step process. deaths in children less than 6 years old. Ferrous fumarate 33 First, iron ions are absorbed from the Ferric pyrophosphate 30 intestinal lumen into mucosal cells. Fer- rous iron is better absorbed than ferric Normal iron content and storage Ferrous lactate 24 Ferrous sulfate (hydrate) 20 iron because ferric iron precipitates out About 70% of the iron in mammals is Peptonized iron 17 of solution at around pH 7 or under found in hemoglobin, and about 5% to Ferroglycine sulfate 16 normal physiologic conditions.7 How- 10% is found in myoglobin. When Ferric ammonium citrate 15 ever, both forms can be absorbed if bound to normal hemoglobin and Ferrous gluconate 12 they are ionized.1,2,5 Because iron must myoglobin, iron is in the ferrous (Fe2+) Ferrocholinate 12 be ionized to be absorbed, metallic iron 1,2,4 form. Up to 25% of iron in the body *Source: References 1-3. and iron oxide (rust) are not generally is in the ferric (Fe3+) form and is stored of concern when they are ingested.1,2 in hemosiderin, ferritin, and transferrin available. Many are brightly colored and Most iron absorption occurs in the duo- in the liver, spleen, and bone mar- sugarcoated, making them attractive to denum and upper jejunum, but in ani- row.1,2,5 Ferric iron is used in iron- animals and small children. In addition, mals with iron toxicosis, the iron seems containing enzymes, such as peroxi- several iron supplements are available to be well-absorbed along all parts of dase, catalase, and cytochrome-c. over the counter. Another frequent the intestinal tract.1,2,5,6 A diet high in source of iron overdose in pets is prena- sugar and vitamin C increases iron ab- tal vitamins. Many prescription prenatal sorption, while a high-phosphate diet Sources vitamins contain more than 60 mg of ele- reduces iron absorption.1,2,4,5 But in One reason iron toxicosis is such an mental iron in each pill, so animals can acute overdoses, the iron seems to be important problem is that the general develop severe iron toxicosis even if absorbed in a passive, concentration- public is often unaware of the potential only a few tablets are ingested. dependent fashion, similar to how most toxicity of products that are considered Numerous other products contain other metals are absorbed. natural and necessary for our health.6 iron, including one-time-use heating Second, iron is transferred to ferritin Another reason is that many phar- pads. Iron can also be found in fertilizers or into circulation bound to transferrin 1,2,4 maceutical preparations contain iron. and pesticides and in the soil. proteins. Transferrin is an alpha1- Multivitamins containing iron are readily Iron is also used in injectable prod- globulin produced in the liver.1,2,7 Com- ucts and is bound to proteins in supple- plexed with transferrin, iron is distrib- “Toxicology Brief” was contributed by Jay ments (chelated iron) to treat iron defi- uted to other iron storage locations in Albretsen, DVM, PhD, DABT, DABVT, Covance ciencies in animals. There are several the body. A unique feature of iron me- Laboratories, 3301 Kinsman Blvd., forms of injectable iron (iron dextran, tabolism is the almost complete absence Madison, WI 53704. The department iron dextrin, iron sorbitol, ferric ammo- of iron excretion. Any iron lost from he- editor is Petra A. Volmer, DVM, MS, DABVT, nium citrate) and several chelated forms moglobin degradation is rapidly bound DABT, College of Veterinary Medicine, University of Illinois, Urbana, IL 61802. of iron. Chelated iron is almost as effec- to transferrin and transported to the tive in treating iron deficiencies as other bone marrow for the resynthesis of he- 82 FEBRUARY 2006 Veterinary Medicine Toxicology Brief continued moglobin.2,7 Consequently, little iron is First, lactic acidosis occurs because of lost in the urine and feces. In addition, hypovolemia and hypotension. Iron iron loss is not notably increased even disrupts oxidative phosphorylation by after iron overdoses.2,4 Most iron loss is interfering in the electron transport through the exfoliation of gastrointesti- chain. Thus, anaerobic metabolism is nal mucosal cells in all mammals and promoted. As ferrous iron is converted through menstrual blood loss.5 While to ferric iron, hydrogen ions are re- anywhere from 2% to 15% of the iron leased, adding to the metabolic acido- ingested is absorbed, only about 0.01% sis. Free iron ions also inhibit the Krebs of the iron body burden is eliminated cycle, and organic acids accumulate.5 every day.1,5 The liver accumulates free iron in Kupffer cells and the hepatocytes. The iron localizes in mitochondria of these Mechanism of action cells and damages several cell orga- When the absorbed iron is not bound nelles.5 Eventually, hypoglycemia, hy- to protein, it produces a variety of perammonemia, coagulation defects, harmful free radicals. Consequently, and hepatic encephalopathy occur.2,5 the concentration of iron is rigorously Free iron inhibits the thrombin-induced controlled in mammalian cells and conversion of fibrinogen to fibrin. His- biological fluids. Acute iron toxicosis topathologic evidence of iron-induced causes both a direct corrosive effect hepatic damage includes cloudy and on the gastrointestinal tract and cellu- swollen hepatocytes, portal iron depo- lar damage due to circulating un- sition, fatty metamorphosis, and mas- bound iron.2 Large doses of iron may sive periportal necrosis.2,4,5 overcome the rate-limiting absorption step and allow excessive iron to enter Toxicity the body. When iron-binding proteins become saturated, free iron ions are Since no mechanism exists for excret- allowed into the general circulation.2,4-6 ing iron, toxicity depends on the Free iron penetrates the cells of the amount of iron already in the body. liver, heart, and brain. At the cellular Consequently, some animals develop level, free iron increases lipid peroxi- clinical signs of toxicosis even when dation with resulting membrane dam- they receive doses that cause no prob- age to mitochondria, microsomes, and lems in other animals. Iron is most toxic other cellular organelles.1 when given intravenously. Intramuscu- Iron exerts its most profound ef- lar injections are less toxic, and iron fects on the cardiovascular system. Ex- given orally is the least toxic, probably cessive iron can cause fatty necrosis of because the amount of iron absorbed the myocardium, postarteriolar dilata- orally is not 100% of the dose ingested.4 tion, increased capillary permeability, When assessing the potential toxicity of and reduced cardiac output.2 Free iron an iron overdose, the amount of ele- stimulates serotonin and histamine re- mental iron in the products ingested lease as well as systemic metabolic must be determined (Table 1).4 For ex- acidosis caused by lactic acid accumu- ample, if a 500-mg tablet of ferrous glu- lation. All these mechanisms lead to conate was ingested, only 60 mg of ele- shock. Excessive iron also interferes mental iron would have been ingested with clotting mechanisms, augmenting (500 mg ϫ 0.12). hemorrhagic processes.1,2,4 Excessive No clinical signs of toxicosis are ex- iron also has been reported to cause pected in dogs ingesting less than 20 thrombocytopenia.5 mg/kg of elemental iron. Dogs ingest- Excessive iron causes metabolic aci- ing between 20 and 60 mg/kg of ele- dosis through several mechanisms. mental iron can develop mild clinical 84 FEBRUARY 2006 Veterinary Medicine Toxicology Brief continued signs. When the amount of elemental factor synthesis.5 In people, the pres- iron dose is unknown or the animal is iron ingested is greater than 60 mg/kg, ence of hyperglycemia and leukocytosis symptomatic. An abdominal radio- serious clinical signs can develop.2 In often indicates a serum iron concentra- graphic examination can be useful to all animals, oral doses between 100 and tion of greater than 30 µg/dl.2 Finally, identify metallic objects since iron 200 mg/kg are potentially lethal.2,4 iron toxicosis results in several central tablets are radiopaque.2,5 nervous system signs. Often these signs result from effects on other cellular Clinical signs Treatment processes. For example, metabolic aci- Iron toxicosis manifests clinically in dosis and hepatotoxicity can lead to A protocol for treating iron toxicosis is four stages. The first stage occurs in the other signs such as lethargy and hepatic described in Figure 1. Animals that six hours after an iron overdose. It is encephalopathy.5 Other central nervous have recently ingested large doses of marked primarily by gastrointestinal ef- system signs that occur are comas, iron will benefit from gastrointestinal fects, such as vomiting, diarrhea, and seizures, and tremors.1,2,5 decontamination.