Ethylene Glycol Toxicity

Updated: Dec 05, 2017
  • Author: Daniel C Keyes, MD, MPH; Chief Editor: Sage W Wiener, MD  more...
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Overview

Practice Essentials

Several toxic alcohols are of medical and toxicological importance; the principal ones include ethanol, ethylene glycol (EG), methanol, and isopropanol. See Alcohol Toxicity. This article discusses ethylene glycol, which is extremely toxic. If untreated, ingestion of ethylene glycol can be fatal.

Ethylene glycol is the major ingredient of almost all radiator fluid products in the United States. It is used to increase the boiling point and decrease the freezing point of radiator fluid, which circulates through the automotive radiator. These changes to the boiling and freezing points result from the colligative properties of the solute (ie, they depend on the number of particles in the solution). Hence, ethylene glycol is added to prevent the radiator from overheating or freezing, depending on the season.

Fluorescein dye is often added to radiator fluid to help mechanics identify the source of a radiator leak. The fluorescein in the fluid fluoresces when viewed under ultraviolet light.

Ethylene glycol tastes sweet, which is why some animals are attracted to it. Many veterinarians are familiar with ethylene glycol toxicity because of the frequent cases in dogs and cats that have licked up radiator fluid.

Initially, patients may be asymptomatic, but ethylene glycol is rapidly absorbed (within 1 to 4 hours), and altered mental status and tachypnea then begin to appear as the ethylene glycol is successively metabolized to very toxic compounds. The progression of toxic effects can be roughly divided into the following three stages, although overlap is possible [1] :

  • From 30 minutes to 12 hours after exposure, unmetabolized ethylene glycol produces CNS depression, intoxication, and hyperosmolarity similar to that produced by ethanol.
  • From 12 to 48 hours, ethylene glycol metabolites produce severe anion gap metabolic acidosis with compensatory hyperventilation. The acidosis results primarily from an increase in glycolic acid, although glyoxylic, oxalic, and lactic acids also contribute in small part. Calcium oxalate crystals are deposited in the brain, lungs, kidneys, and heart.
  • From 24 to 72 hours, acute kidney injury.can result from the direct renal toxic effects of the ethylene glycol metabolite calcium oxylate monohydrate.

Initial treatment includes infusion of crystalloids to enhance renal clearance of the toxic metabolites. Ethyl alcohol has traditionally been used for antidotal treatment, but it has largely been supplanted by fomepizole in the United States.

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Pathophysiology

[2] Like the other toxic alcohols mentioned above, ethylene glycol is a parent compound that exerts most of its toxicity by conversion to metabolites. Ethylene glycol itself may cause some alteration of mental status but it is a relatively nontoxic compound before it is metabolized. The metabolites cause the distinctive toxicity associated with this compound.

Knowing the pathway of ethanol metabolism is necessary to understanding ethylene glycol toxicity properly. Ethanol is metabolized by the enzyme alcohol dehydrogenase (ADH), which is located in the liver and gastric mucosa, and by the cytochrome P-450 mixed function oxidase (MFO) system in the liver. The mixed function oxidase component is subject to greater inducibility than alcohol dehydrogenase.

Like ethyl alcohol and methanol, ethylene glycol is metabolized by ADH. In this step it forms glycoaldehyde. Through interaction with aldehyde dehydrogenase, ethylene glycol is then metabolized to glycolic acid (GA), which accumulates and can cause a profound metabolic acidosis. This glycolic acid is eventually converted into glyoxylic acid, and then into the highly toxic oxalate or the safer glutamate or α-ketoadipic acid metabolites.

Calcium oxalate crystals may form and accumulate in blood and other tissues. The precipitation of calcium oxalate in the renal cortex results in decreased glomerular filtration and renal insufficiency. The formation of these crystals consumes circulating calcium, and hypocalcemia may occur, though this is uncommon.

The rate-limiting step of ethylene glycol metabolism is the ADH-catalyzed step. Common ethyl alcohol (ethanol) binds much more easily to ADH than ethylene glycol or methanol does. Because ethanol is the preferred substrate for ADH, the presence of ethanol may essentially block metabolism of ethylene glycol. In addition, this enzyme is blocked by the administration of fomepizole (4-methylpyrazole [4-MP]), which is discussed below (see Emergency Department Care). This is the basis of one therapy used in the United States.

Upon oral ingestion, serum concentrations of ethylene glycol peak within 1-4 hours. The elimination half-life (assuming preserved renal function) is 3 hours. When alcohol dehydrogenase is inhibited by ethanol or fomepizole, the elimination half-life increases to about 16 hours.

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Epidemiology

Frequency

United States

Ethylene glycol is a relatively common cause of overdose in US emergency departments. Single exposures to ethylene glycol in antifreeze and other automotive products reported to the American Association of Poison Control Centers (AAPCC) rose from 5,282 in 2009 to 5,783 in 2016. [3, 4]

Mortality/Morbidity

According to the AAPCC's National Poison Data System, in 2016, 934 had minor outcomes, 448 had moderate outcomes, 124 had severe outcomes, and 7 deaths were documented. [4]

Age

The annual report of the AAAPCC's National Poison Data System in 2016 documented ethylene glycol exposure in 495 children younger than 6 years, 191 in those aged 6-12 years, 489 in those 13-19 years, and 4014 in those 20 years and older. [4]

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