Veterinary Clinical Pathology Clerkship Program

Clinical Pathology of Ethylene Glycol Toxicosis

Bryan T. Torres, DVM; Kenneth S. Latimer, DVM, PhD; Perry J. Bain, DVM, PhD; Heather L. Tarpley, DVM

Class of 2003 (Torres) and Department of Pathology (Latimer, Bain, Tarpley), College of Veterinary Medicine, University of Georgia, Athens, GA 30602-7388

Ice shards, Shovel Point, Tettegouche State Park. March, 1984 by Craig Blacklock


Ethylene glycol toxicosis is commonly encountered by the small animal practitioner, especially in the colder months. Toxicosis is observed most frequently in dogs, but may affect cats or virtually any animal. Ethylene glycol is sweet, colorless (although commercial automotive antifreeze preparations often contain bright yellow or blue dyes), odorless, and water soluble. It is used in the cooling systems of automobiles due to its ability to lower the freezing point and raise the boiling point of water.1 The main source of ethylene glycol is automotive radiator coolant or antifreeze solution that contains approximately 95% ethylene glycol. In colder areas of the nation, ethylene glycol toxicosis is observed seasonally, mainly in the fall, winter, and spring.1 Other sources of this chemical may include any source of heat exchange fluids (sometimes used in solar collectors), certain brake and transmissions fluids, diethylene glycol used in color film processing, cleaning supplies, lacquers, cosmetics, and flavoring extracts.2 Novelty "snow globes" also may contain ethylene glycol. Recently, some "low toxicity" automotive antifreeze solutions have been marketed which contain the less toxic compound propylene glycol.

Ethylene glycol has a relatively small lethal dose of 1.4-1.5 ml/kg in cats and 4.4-6.6 ml/kg in dogs.1 Because of its use in the cooling systems of cars, the abundance of this chemical in many households, its palatability, and relatively low lethal dose, ethylene glycol is commonly associated with poisonings in small animals.


Ethylene glycol is absorbed quickly from the gastrointestinal tract and is distributed to body tissues via the blood.1,4 Metabolism of the chemical takes place mainly in the liver and, to a lesser extent, in the kidney. In the liver, the majority of ethylene glycol is metabolized to water or carbon dioxide, unlike the kidney, which excretes unaltered ethylene glycol.1,2

The toxicity of ethylene glycol per se has not yet been established; however, the metabolites formed from the breakdown of this chemical in the body are very toxic. Ethylene glycol metabolites such as aldehyde, glycolic acid, and oxalate are associated with renal toxicity.1,2,4

Ethylene glycol initially is oxidized to glycoaldehyde by alcohol dehydrogenase. Glycoaldehyde subsequently undergoes oxidation by mitochondrial aldehyde oxidase to form glycolic acid. Glycolic acid is oxidized to glyoxide by either glycolic acid oxidase or lactic dehydrogenase. The glyoxide is then oxidized once more to oxalate via aldehyde oxidase or lactic dehydrogenase.1,2 The first two oxidation steps are fairly rapid. However, the oxidation of glycolic acid to glyoxide via glycolic acid oxidase or lactic dehydrogenase is significantly slower.1 Because of this abrupt deceleration in metabolism, the conversion of glycolic acid to glyoxide is considered to be the rate limiting reaction of ethylene glycol metabolism.1

Clinical Staging of Toxicosis

Ethylene glycol poisoning typically progresses in three distinct stages.2 Stage I begins 30 minutes to 12 hours after ethylene glycol ingestion. During this stage, the most common clinical signs are associated with the central nervous system.1 Most animals display signs similar to alcohol intoxication; nausea and vomiting often are present.2 Other neurologic signs may include ataxia, abnormal proprioception, vestibular abnormalities, seizures, and possibly death. Animals also may experience polydypsia leading to expansion of the intravascular volume. Polyuria may occur secondary to the osmotic effect of ethylene glycol because it is not resorbed in the proximal nephron.4 The toxic aldehyde metabolites have been shown to depress the central nervous system, depress the respiratory system, alter serotonin metabolism, and alter amine concentrations in the central nervous system.4 Therefore, affected animals may be sleepy during this first stage of toxicosis and the owners may not notice an impending problem.2

Stage II usually occurs from 12 to 24 hours after ingestion of ethylene glycol. In this stage, cardiopulmonary signs predominate. Tachypnea and tachycardia are the most common findings on physical examination; however, the majority of owners rarely notice these signs of toxicosis.1,2

Stage III is characterized by oliguric renal failure. This stage occurs 24-72 hours after ingestion of ethylene glycol.1 Affected animals exhibit typical signs of acute renal failure such as anorexia, vomiting, azotemia or uremia, and isosthenuria.1,4 Renal tubular damage due to the presence of toxic metabolites of ethylene glycol is primarily responsible for renal failure at this stage of toxicosis.1 The presence of oxalate leads to crystal formation within the renal tubules. Once oxalate is formed by the metabolism of ethylene glycol, it combines with calcium in the blood to form calcium oxalate. As the kidney attempts to filter the newly formed calcium oxalate from the blood, the pH of the renal tubule is decreased thereby causing the precipitation of calcium oxalate crystals.1 The formation of these crystals contributes to renal impairment, but their overall contribution is small.


Rapid and accurate diagnosis of ethylene glycol toxicosis is necessary if treatment is to be effective. The initial clue to diagnosis may be known ingestion of or exposure to ethylene glycol solutions. Several findings in the biochemical profile may be associated with ethylene glycol toxicosis, including azotemia, hyperphosphatemia, hyperkalemia, severe hypocalcemia, metabolic acidosis, increased anion gap, isosthenuria, and aciduria with or without glucosuria or proteinuria.

Some of the most common laboratory findings are isosthenuria, metabolic acidosis, and increased anion gap. Metabolic acidosis may occur within three hours of ingestion of the toxin. The toxic metabolites of ethylene glycol, along with lactic acid accumulation, lead to acidosis. Glycolate is the major contributor to the metabolic acidosis.4 The first three oxidative steps of ethylene glycol metabolism lead to a reduction in the NADH:NAD ratio.4 This subsequently leads to an increase in lactic acid concentration. Lactic acid and other unmeasured anions will increase the anion gap. An anion gap that is greater than 40-50 mEq/L is considered to be highly suggestive of ethylene glycol toxicosis. A decrease in urine pH also may be observed with the onset of acidosis as hydrogen ion excretion increases.4,3

Calcium oxalate monohydrate crystalluria may be detected by urine sediment examination approximately 3-5 hours after ingestion of ethylene glycol.2 The metabolism of ethylene glycol produces oxalic acid, which then combines with calcium to produce calcium oxalate; the most prevalent form of which is calcium oxalate monohydrate.6 These crystals vary in shape and size. Most crystals, however are clear, six-sided prisms that resemble a doubly pointed picket from a wooden fence (Figure 1). Greater than 99% of the crystals in the urine sediment will have this morphology.6 However, calcium oxalate monohydrate can also present as a sheaf or hempseed shape.5 Although these shapes are less common than the six-sided prism, it is important to be aware of these possibilities as early and prompt diagnosis of toxicosis is the key to successful treatment.

Figure 1. Calcium oxalate monohydrate crystals in unstained urine sediment from a dog with ethylene glycol toxicosis. The crystals are elongate with pointed ends.

Colorimetric test kits also are available to quantify ethylene glycol concentrations in the blood and assist in the early diagnosis of toxicosis. These test kits only detect ethylene glycol and not its toxic metabolites. Thus, this test has a narrow window of usefulness, specifically within 12 to 24 hours after the ingestion of ethylene glycol (Figure 2).2 In patients that have died of suspected ethylene glycol toxicosis, a presumptive diagnosis may be made by the presence of calcium oxalate monohydrate crystals in residual urine or in kidney aspirates or imprints (Fig. 3). Viewing the tissue imprints under polarized light facilitates crystal identification (Fig. 4).

Figure 2. Positive test (purple color) for the presence of ethylene glycol in the blood of a dog within 12 hours of toxin ingestion.

The patient sample is on the left and a positive control sample is on the right.


Figure 3. Blood, calcuium oxalate monohydrate crystals, disrupted renal tubular epithelial cells, and erythrocytes in a renal imprint of a dog that died from ethylene glycol toxicosis. The crystals are present as six-sided prisms and larger arrays. Figure 4. Birefringent calcuium oxalate monohydrate crystals, as viewed through polarized light, in a renal imprint of a dog that died from ethylene glycol toxicosis.


Note: Treatment of animals should only be performed by a licensed veterinarian. Veterinarians should consult the current literature and current pharmacological formularies before initiating any treatment protocol.

Following ingestion, the metabolites of ethylene glycol are responsible for toxicosis. Therefore, prevention of ethylene glycol toxicosis is accomplished by inhibiting the formation of these toxic metabolites. It is important to initiate treatment within eight hours after ethylene glycol ingestion to ensure the greatest chance of survival. Induction of emesis (if the animal is alert and the gag reflex is present) and the use of activated charcoal may be beneficial if performed within the first 3 hours after ethylene glycol ingestion.2

As previously mentioned, the oxidation of ethylene glycol to glycoaldehyde by alcohol dehydrogenase is the first metabolic step leading to toxicosis. If this reaction is inhibited, then ethylene glycol will be excreted by the kidneys in its native form and without damage to the renal tubules.3 Historically, ethanol has been used as the standard treatment for ethylene glycol toxicosis. Because alcohol dehydrogenase has a higher affinity for ethanol, the administration of ethanol will competitively inhibit ethylene glycol metabolism by alcohol dehydrogenase.3 However, there are noted complications to this method of treatment. Both ethylene glycol and ethanol are central nervous system depressants and act as osmotic agents leading to diuresis.3 Therefore, treatment via ethanol administration is not without risk.

A more modern treatment for ethylene glycol toxicosis is the alcohol dehydrogenase inhibitor 4-Methylpyrazole (4-MP, fomepizole, Antizol®). This drug has been shown to be the most efficient inhibitor of ethylene glycol metabolism while minimizing toxic side effects.3 Dogs presenting in stage I of ethylene glycol toxicosis may recover within 24 hours after treatment with 4-methylpyrazole. Intravenous fluids initially were administered to these animals to correct dehydration; however, once the animals were alert and able to take oral fluids, intravenous fluid administration was discontinued.3 As the amount of time increases between ingestion of ethylene glycol and initiation of treatment, the prognosis becomes more guarded. With delayed treatment, a greater amount of ethylene glycol is converted to toxic metabolites prior to treatment with 4-methylpyrazole. In such instances greater renal tubular damage is present.3,2

In dogs, 4-methylpyrazole treatment requires an initial loading dose of 20 mg/kg IV, followed at 12 and 24 hours with a maintenance dose of 15 mg/kg IV. At hour 36, the dosage should be decreased to 5 mg/kg IV. Subsequently, doses of 5 mg/kg IV can be administered as needed.2 In one study, 4-MP was found to be ineffective for the treatment of ethylene glycol toxicosis in cats.7 A study of in vitro inhibition of feline alcohol dehydrogenase suggested that a significantly higher dosage of 4-MP would be required for effective inhibition of this enzyme in cats.8

Treatment of ethylene glycol toxicosis has improved greatly over the years. However, poisoning with this chemical is still a major problem in small animal medicine because of the prevalence and poor containment of ethylene glycol, leading to easy access by animals. Therefore, preventing exposure to this chemical is the best way to ensure the safety of all animals.


1. Grauer GF, Thrall MA: Ethylene glycol (antifreeze) poisoning in the dog and cat. J Am Anim Hosp Assoc 18:492-497, 1982.

2. Ettinger SJ, Feldman EC (eds): Textbook of Veterinary Internal Medicine: Diseases of the Dog and Cat, 5th ed., vol. 1 & 2. W.B. Saunders Co., Philadelphia, 2000, pp. 361, 1965.

3. Dial SM, Thrall MA, Hamar DW. 4-methylpyrazole as treatment for naturally acquired ethylene glycol intoxication in dogs. J Am Vet Med Assoc 195:73-76, 1989.

4. Grauer GF, Thrall MA, Henre BA, Grauer RM, Hamar DW. Early clinicopathologic findings in dogs ingesting ethylene glycol. Am J Vet Res Am 45:2299-2303,1984.

5. Thrall MA, Dial SM, Winder DR. Identification of calcium oxalate monohydrate crystals by x-ray diffraction in urine of ethylene glycol-intoxicated dogs. Vet. Pathol. 22: 625-628, 1985.

6. Foit FF, Cowell RL, Brobst DF, Moore MP, Tarr BD. X-ray powder diffraction and microscopic analysis of crystalluria in dogs with ethylene glycol poisoning. Am J Vet Res 46:2404-2408, 1985.

7. Dial SM, Thrall MA, Hamar DW. Comparison of ethanol and 4-methylpyrazole as treatments for ethylene glycol intoxication in cats. Am J Vet Res 55:1771-1782, 1994.

8. Connally HE, Hamar DW, Thrall MA. Inhibition of canine and feline alcohol dehydrogenase activity by fomepizole. Am J Vet Res 61:450-455, 2000.

The detail from the photograph "Ice shards, Shovel Point, Tettegouche State Park. March, 1984" by Craig Blacklock is used with permission. Blacklock Gallery and Framing Studio and Blacklock Nature Sanctuary, Moose Lake, MN.


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