- Author: Michael D Levine, MD; Chief Editor: Asim Tarabar, MD more...
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 three toxic alcohols but also ethanol. For discussion of the individual agents, see Methanol Toxicity and Ethylene Glycol Toxicity; for discussion of pediatric ethanol ingestion, see Ethanol Toxicity. Ethanol withdrawal is a serious and potentially life-threatening problem, which is discussed in Withdrawal Syndromes.
Ethyl alcohol (ethanol; CH3 -CH2 -OH) is a low molecular weight hydrocarbon that 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 three 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 polymorphisms coding for alcohol dehydrogenase, the amount of alcohol consumed, and the rate 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.
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, rubbing alcohol, and hand sanitizers. 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. The acetone produces CNS depressant effects and a fruity odor on the breath.
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.[5, 6, 7] 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 (CH2 OH-CH2 OH) is an odorless, colorless, sweet-tasting liquid, which is used in many manufacturing processes. Domestically, 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 is metabolized into toxic compounds. Ethylene glycol is oxidized via alcohol dehydrogenase into glycoaldehyde, which then 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.
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.
Acute intoxication with any of the alcohols can result in respiratory depression, aspiration, hypotension, and cardiovascular collapse.
In 2014, 6026 single exposures to ethanol in beverages, with 219 major outcomes and 15 deaths, were reported to US Poison Control Centers. There were 3508 non-beverage exposures, with 13 major outcomes and 4 deaths; ethanol-based hand sanitizers accounted for 18,322 single expsoures, with 11 major outcomes and no deaths, and ethanol-containing mouthwashes accounted for 6,539 single exposures, with 20 major outcomes and two deaths.
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.
Long-term 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 2014, 15,334 single exposures to isopropanol (from sources including rubbing alcohol, cleaning agents, and hand sanitizers) were reported to US Poison Control Centers. Of these, 60 patients were classified as experiencing "major" morbidity, with twoe patient dying.
In the same year, 1,610 single exposures to methanol, including automotive products, and 5,552 exposures to ethylene glycol were reported. Of those intoxicated with methanol, 16 patients were classified as experiencing "major" disability, and 9 additional patients died. For those patients who were intoxicated with ethylene glycol, 141 patients were classified as having "major" disability, with an additional 16 patients dying. 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 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 that the calcium oxalate crystals are deposited not only in the kidneys but in many other organs, including the brain, heart, and lungs.
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.
Jammalamadaka D, Raissi S. Ethylene glycol, methanol and isopropyl alcohol intoxication. Am J Med Sci. 2010 Mar. 339(3):276-81. [Medline].
Hornfeldt CS. A report of acute ethanol poisoning in a child: mouthwash versus cologne, perfume and after-shave. J Toxicol Clin Toxicol. 1992. 30(1):115-21. [Medline].
Martz W. A lethal ingestion of a household cleaner containing pine oil and isopropanol. J Anal Toxicol. 2010 Jan-Feb. 34(1):49-52. [Medline].
Slaughter RJ, Mason RW, Beasley DM, Vale JA, Schep LJ. Isopropanol poisoning. Clin Toxicol (Phila). 2014 Jun. 52(5):470-8. [Medline].
ATSDR. Methanol toxicity. Agency for Toxic Substances and Disease Registry. Am Fam Physician. 1993 Jan. 47(1):163-71. [Medline].
Aufderheide TP, White SM, Brady WJ, et al. Inhalational and percutaneous methanol toxicity in two firefighters. Ann Emerg Med. 1993 Dec. 22(12):1916-8. [Medline].
Coulter CV, Farquhar SE, McSherry CM, Isbister GK, Duffull SB. Methanol and ethylene glycol acute poisonings - predictors of mortality. Clin Toxicol (Phila). 2011 Dec. 49(10):900-6. [Medline].
Cascallana JL, Gordo V, Montes R. Severe necrosis of oesophageal and gastric mucosa in fatal methanol poisoning. Forensic Sci Int. 2012 Mar 5. [Medline].
[Guideline] Caravati EM, Erdman AR, Christianson G, Manoguerra AS, Booze LL, Woolf AD, et al. Ethylene glycol exposure: an evidence-based consensus guideline for out-of-hospital management. Clin Toxicol (Phila). 2005. 43 (5):327-45. [Medline].
Mowry JB, Spyker DA, Brooks DE, McMillan N, Schauben JL. 2014 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 32nd Annual Report. Clin Toxicol (Phila). 2015. 53 (10):962-1147. [Medline]. [Full Text].
Barceloux DG, Bond GR, Krenzelok EP, et al. American Academy of Clinical Toxicology practice guidelines on the treatment of methanol poisoning. J Toxicol Clin Toxicol. 2002. 40(4):415-46. [Medline].
Krahn J, Khajuria A. Osmolality gaps: diagnostic accuracy and long-term variability. Clin Chem. 2006 Apr. 52(4):737-9. [Medline].
Brent J. Fomepizole for ethylene glycol and methanol poisoning. N Engl J Med. 2009 May 21. 360(21):2216-23. [Medline].
Kraut JA, Kurtz I. Toxic alcohol ingestions: clinical features, diagnosis, and management. Clin J Am Soc Nephrol. 2008 Jan. 3(1):208-25. [Medline].
Brent J, McMartin K, Phillips S, et al. Fomepizole for the treatment of ethylene glycol poisoning. Methylpyrazole for Toxic Alcohols Study Group. N Engl J Med. 1999 Mar 18. 340(11):832-8. [Medline].
Brent J, McMartin K, Phillips S, et al. Fomepizole for the treatment of methanol poisoning. N Engl J Med. 2001 Feb 8. 344(6):424-9. [Medline].
Burns MJ, Graudins A, Aaron CK, et al. Treatment of methanol poisoning with intravenous 4-methylpyrazole. Ann Emerg Med. 1997 Dec. 30(6):829-32. [Medline].
Megarbane B, Borron SW, Baud FJ. Current recommendations for treatment of severe toxic alcohol poisonings. Intensive Care Med. 2005 Feb. 31(2):189-95. [Medline].
Lepik KJ, Levy AR, Sobolev BG, Purssell RA, DeWitt CR, Erhardt GD. Adverse drug events associated with the antidotes for methanol and ethylene glycol poisoning: a comparison of ethanol and fomepizole. Ann Emerg Med. 2009 Apr. 53(4):439-450.e10. [Medline].
Thanacoody RH, Gilfillan C, Bradberry SM, Davies J, Jackson G, Vale AJ, et al. Management of poisoning with ethylene glycol and methanol in the UK: a prospective study conducted by the National Poisons Information Service (NPIS). Clin Toxicol (Phila). 2016. 54 (2):134-40. [Medline].
Ghannoum M, Hoffman RS, Mowry JB, Lavergne V. Trends in toxic alcohol exposures in the United States from 2000 to 2013: a focus on the use of antidotes and extracorporeal treatments. Semin Dial. 2014 Jul. 27(4):395-401. [Medline].