eMedicine Specialties > Emergency Medicine > Toxicology

Toxicity, Alcohols

Author: Michael D Levine, MD, Physician, Department of Medical Toxicology, Banner Good Samaritan Medical Center
Coauthor(s): Tobias D Barker, MD, Attending Physician, Department of Emergency Medicine, Research Director, STRATUS Center of Medical Stimulation, Brigham and Women's Hospital
Contributor Information and Disclosures

Updated: Aug 27, 2008

Introduction

Background

Although any alcohol can be toxic if ingested in large enough quantities, the term toxic alcohol has traditionally referred to isopropanol, methanol, and ethylene glycol. Prompt recognition and treatment of patients intoxicated with these substances can reduce the morbidity and mortality associated with these alcohols.

This article discusses not only the 3 toxic alcohols but also ethanol. Ethanol withdrawal is a serious and potentially life-threatening problem, which is discussed in Withdrawal Syndromes.

Pathophysiology

Ethanol

Ethyl alcohol (ethanol; CH₃ -CH₂ -OH) is a low molecular weight hydrocarbon, which is derived from the fermentation of sugars and cereals. It is widely available both as a beverage and as an ingredient in food extracts, cough and cold medications, and mouthwashes.  
 
Ethanol is rapidly absorbed across both the gastric mucosa and the small intestines, reaching a peak concentration 20-60 minutes after ingestion. Once absorbed, it is converted to acetaldehyde. This conversion involves 3 discrete enzymes: the microsomal cytochrome P450 isoenzyme CYP2E1, the cytosol-based enzyme alcohol dehydrogenase (ADH), and the peroxisome catalase system. Acetaldehyde is then converted to acetate, which is converted to acetyl Co A, and ultimately carbon dioxide and water.
 
Genetic factors, the amount of alcohol consumed, and the frequency at which ethanol is consumed all affect the speed of metabolism. Chronic alcoholics and those with severe liver disease have increased rates of metabolism. However, as a general rule, ethanol is metabolized at a rate of 20-25 mg/dL in the nonalcoholic but at an increased rate in chronic alcoholics.
  
Isopropanol

Isopropyl alcohol (isopropanol; CH₃ -CHOH-CH₃) is a low molecular weight hydrocarbon. It is commonly found as both a solvent as well as a disinfectant. It can be found in many mouthwashes, skin lotions, and rubbing alcohol. Because of its widespread availability, lack of purchasing restrictions, and profound intoxicating properties, it is commonly used as an ethanol substitute. 
 
Isopropanol is rapidly absorbed across the gastric mucosa and reaches a peak concentration approximately 30-120 minutes after ingestion. Isopropanol is primarily metabolized via alcohol dehydrogenase to acetone. A small portion of isopropanol is excreted unchanged in the urine. The peak concentration of acetone is not present until approximately 4 hours after ingestion. Both the CNS depressant effects and the fruity odor on the patient's breath are due to acetone.  
 
Methanol

Methyl alcohol (methanol; CH₃ OH) is widely used as an industrial and marine solvent and paint remover. It is also used in photocopying fluid, shellacs, and windshield-washing fluids. Although toxicity primarily occurs from ingestion, it can also occur from prolonged inhalation or skin absorption. Methanol is rapidly absorbed from the gastric mucosa, and achieves a maximal concentration 30-90 minutes after ingestion. 
 
Methanol is primarily metabolized in the liver via alcohol dehydrogenase into formaldehyde. Formaldehyde is subsequently metabolized via aldehyde dehydrogenase into formic acid, which ultimately is metabolized to folic acid, folinic acid, carbon dioxide, and water. A small portion is excreted unchanged by the lungs. Formic acid is responsible for the majority of the toxicity associated with methanol. Without competition for alcohol dehydrogenase, methanol undergoes zero-order metabolism, and is thus is excreted at a rate of 8.5 mg/dL/h  to 20 mg/dL/h. Once methanol experiences competitive inhibition, from either ethanol or fomepizole, the metabolism changes to first order. In this later scenario, the excretion half-life ranges from 22-87 hours.  
 
Ethylene glycol

Ethylene glycol (CH₂ OH-CH₂ OH) is an odorless, colorless, sweet-tasting liquid, which is used in many manufacturing processes. Around the house, it is probably most commonly encountered in antifreeze. It is absorbed somewhat rapidly from the gastrointestinal tract, and peak concentrations are observed 1-4 hours after ingestion. 
 
Ethylene glycol itself is nontoxic, but it does get metabolized into toxic compounds. Ethylene glycol is oxidized via alcohol dehydrogenase into glycoaldehyde. Glycoaldehyde subsequently undergoes metabolism via aldehyde dehydrogenase into glycolic acid. The conversion to glycolic acid is somewhat rapid. In contrast, the conversion of glycolic acid to glyoxylic acid is slower and is the rate-limiting step in the metabolism of ethylene glycol.  

Glyoxylic acid is subsequently metabolized into several different products, including oxalic acid (oxalate), glycine, and alpha-hydroxy-beta-ketoadipate. The conversion to glycine requires pyridoxine as a cofactor, while the conversion to alpha-hydroxy-beta-ketoadipate requires thiamine as a cofactor. The oxalic acid combines with calcium to form calcium oxalate crystals. In the presence of normal renal function and no competitive inhibition for alcohol dehydrogenase, the excretion half-life of ethylene glycol is approximately 3 hours. However, in the presence of fomepizole or ethanol, alcohol dehydrogenase undergoes competitive inhibition, and the resulting excretion half-life increases to approximately 17-20 hours.

Frequency

Alcohol intoxication is common in modern society, largely because of its widespread availability. More than 8 million Americans are believed to be dependent on alcohol, and up to 15% of the population is considered at risk. In some studies, more than half of all trauma patients are intoxicated with ethanol at the time of arrival to the trauma center. In addition, ethanol is a common coingestant in suicide attempts.

Mortality/Morbidity

Acute intoxication with any of the alcohols can result in respiratory depression, aspiration, hypotension, and cardiovascular collapse.  
 
Ethanol

Although many patients present with ethanol intoxication as their sole issue, many other patients have ethanol intoxication as part of a larger picture. Thus, the morbidity is often from coingestants or coexisting injuries and illnesses. 
 
Chronic use results in hepatic and gastrointestinal injuries. Coma, stupor, respiratory depression, hypothermia, and death can result from high concentrations of acute ethanol intoxication. Chronic alcoholics, as well as children, are at risk for hypoglycemia.  
 
Isopropanol, methanol, and ethylene glycol

In 2005, 7,394 cases of isopropanol ingestions were reported to the US Poison Control Centers. Of these, 406 patients were classified as experiencing "major" morbidity. Five additional deaths occurred. In the same year, 807 cases of methanol and 5,469 cases of ethylene glycol were reported. Of those intoxicated with methanol, 33 patients were classified as experiencing "major" disability, and 6 additional patients died. For those patients who were intoxicated with ethylene glycol, 176 patients were classified as having "major" disability, with an additional 16 patients dying.¹  It is important to recognize that these numbers likely underestimate the true incidence of exposure, however, because of both a failure to recognize the ingestion as well as a failure to report the suspected or known ingestion to a poison control center.
 
The primary toxicity with isopropanol is CNS depression. These CNS manifestations can include lethargy, ataxia, and coma. In addition, isopropanol is irritating to the GI tract. Therefore, abdominal pain, hemorrhagic gastritis, and vomiting can be observed. Unlike methanol and ethylene glycol, isopropanol does not cause a metabolic acidosis.
 
The toxicity with methanol occurs from both the ensuing metabolic acidosis, as well as the formate anion (formic acid) itself. Although the eye is the primary site of organ toxicity, in the later stages of severe methanol toxicity, specific changes can occur in the basal ganglia as well. Pancreatitis has been reported following methanol ingestion. Hyperventilation will occur as a compensatory mechanism to counteract the acidosis.
 
As previously stated, ethylene glycol by itself is nontoxic. The majority of the metabolic acidosis occurs from glycolic acid. One form of morbidity occurs when oxalate combines with calcium to form calcium oxalate crystals, which accumulate in the proximal renal tubules, thereby inducing renal failure. Hypocalcemia can ensue, and cause coma, seizures, and dysrhythmias. Autopsy studies have confirmed the calcium oxalate crystals are deposited not only in the kidneys but in many organs, including the brain, heart, and lungs. 

Age

Ethanol intoxication is common in older teenagers through adulthood. The toxic dose for an adult is 5 mg/dL, whereas the toxic dose in a child is 3 mg/dL. Children are at higher risks of developing hypoglycemia following a single ingestion than are adults. 
 
Most isopropanol ingestions occur in children younger than 6 years. Most methanol and ethylene glycol ingestions occur in adults older than 19 years. 

Clinical

History

A history of inebriation with associated slurred speech, ataxia, and impaired judgment is common in the initial stages of intoxication of each of these alcohols. Depending on the dose ingested, this may be followed by progressive levels of CNS depression, coma, and premorbid multiorgan failure. The history that is able to be obtained varies with the timing of presentation. The timing of the later stages of toxic alcohol intoxication can also be delayed if ethanol is coingested, prolonging the time it takes to develop metabolic acidosis and other symptoms. The following focuses on symptoms that may be unique to each alcohol.

• Ethanol ingestion
  • The history itself can often point to a diagnosis of ethanol intoxication. An associated history of chronic alcoholism alters metabolism, associated comorbidities, and the expected course of recovery. A detailed discussion of this topic is beyond the scope of this article (see Toxicity, Ethanol).
  • Attempting to elicit what has changed recently may reveal the immediate reason for presentation. A history of coingestants may also alter the patient's course.
• Isopropanol ingestion
  • Following an isopropanol ingestion, the patient may not complain of anything specific. Rather, the patient may simply appear intoxicated, as with ethanol intoxication. 
  • A history of abdominal pain, nausea, and sometimes hematemesis may be obtained. 
• Methanol ingestion
  • Following methanol ingestion, a patient is initially inebriated as with the other alcohols. Other symptoms can be delayed for up to 12-24 hours. 
  • The patient may complain of headache, nausea, or anorexia. Occasionally, the patient may complain of shortness of breath related to hyperventilation. 
  • Because one of the primary end-organs involved in methanol is the eye, the patient may complain of difficulty seeing. Specifically, vision is often described as a "snow field," though a variety of visual complaints may be verbalized.
• Ethylene glycol ingestion
  • Ethylene glycol toxicity occurs in 3 stages.
    • The first stage, called the neurologic phase, can occur in less than 1 hour after ingestion and lasts up to 12 hours. During this stage, the patient appears inebriated. The patient may not have any other significant findings during this stage. Occasionally, hypocalcemia can occur at this point and induce muscle spasms and abnormal reflexes. 
    • The second stage, which occurs between 12 and 24 hours after ingestion, is referred to as the cardiopulmonary stage. During this stage, the patient frequently develops mild tachycardia and hypertension. Acute respiratory distress syndrome (ARDS) can also occur. These findings are believed to result from calcium oxalate crystal deposition in the lung parenchyma and myocardium. Significant hypocalcemia can occur at this stage, with QT prolongation and associated arrhythmias. Expect hyperventilation as metabolic acidosis progresses.
    • The third stage, also called the renal stage, typically starts after 24 hours. During this stage, flank pain and acute renal failure can occur. A premorbid patient presenting with ethylene glycol toxicity typically presents comatose, hyperventilating, and in multiorgan failure.

Physical

• Ethanol ingestion
  • The symptoms of ethanol intoxication depend on both the serum concentration as well as the frequency at which an individual ingests ethanol. Thus, a person who consumes large amounts of ethanol on a daily basis may appear sober at the same serum ethanol level at which a novice drinker exhibits cerebellar dysfunction.
  • As a general rule, levels less than 25 mg/dL are associated with a sense of warmth and well-being. Euphoria and decreased judgment occur at levels between 25-50 mg/dL. Incoordination, decreased reaction time/reflexes, and ataxia occur at levels of 50-100 mg/dL. Cerebellar dysfunction (ie, ataxia, slurred speech, nystagmus) are common at levels of 100-250 mg/dL. Coma can occur at levels of greater than 250 mg/dL, whereas respiratory depression, loss of protective reflexes, and death occur at levels greater than 400 mg/dL.
• Isopropanol ingestion
  • As previously stated, the patient who consumes isopropanol may appear inebriated, as with ethanol. Isopropanol concentrations of 50-100 mg/dL typically result in intoxication, which can progress to include symptoms such as dysarthria and ataxia, while lethargy or coma can be seen with levels exceeding 150 mg/dL. Cardiovascular depression can occur with levels exceeding 450 mg/dL. 
  • The presence of acetone may induce a fruity odor on the patient's breath.  
• Methanol ingestion
  • Unlike ethanol or isopropanol, methanol does not cause nearly as much of an inebriated state. If a patient has coingested ethanol, signs or symptoms specific to methanol intoxication are delayed. 
  • The patient may be hyperventilating.
  • If vision is impaired, ocular examination may reveal dilated pupils that are minimally or unreactive to light with hyperemia of the optic disc. Over several days, the red disc becomes pale, and the patient may become blind. Typically, subjective complaints precede physical findings in the eye. 
• Ethylene glycol ingestion
  • The physical findings depend on the stage of the presentation. Thus, the patient may present simply inebriated or progressively more acidotic as renal failure, cardiovascular dysfunction, and coma develop.
  • Examination findings correlate with the symptoms, as previously described. 
  • In patients who survive severe intoxication, calcium oxalate crystal deposition may occur in the brain parenchyma and can induce cranial neuropathies. These findings typically occur as the patient is recovering from the initial intoxication. The cranial nerves most commonly involved include cranial nerve II, V, VII, VIII, IX, X, and XII.

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