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Toxicology

Tox Hot Topics: Methanol and Ethylene Glycol: Overview and a Reminder to Use Therapeutic Adjuncts

Matin Shah, MD with Jason B. Hack, MD

Methanol and ethylene glycol are toxic alcohols that are prevalent in many commercial and industrial products. Ingestion of these substances can lead to a number of deleterious health effects. This article provides a brief overview of methanol and ethylene glycol toxicity, discusses current treatment options and touches upon therapeutic adjuncts used to treat these ingestions.

Methanol-EthanolMethanol Toxicity
Methanol is found in a number of commercial products, including windshield washer fluid, racing fuel, canned heat, and photocopying fluid. It is also found as an additive or impurity in the illicit distillation of ethanol. Once ingested, methanol is metabolized by alcohol dehydrogenase and aldehyde dehydrogenase to its toxic product, formic acid.  Formic acid causes metabolic acidosis, neurotoxicity and direct damage to the optic nerve, which results in visual impairment or blindness. First line treatment of methanol toxicity is fomepizole, or if unavailable, ethanol.  Both have a higher affinity for alcohol dehydrogenase than methanol. Through their higher affinity, fomepizole and ethanol preferentially bind alcohol dehydrogenase so it is less available to metabolize methanol into its toxic byproduct1.

The Lesser-Known Adjunct: Folic Acid
Formic acid dissociates into its anion, formate, subsequent to its synthesis as described above. A lesser-known therapeutic adjunct, folic acid, serves a useful role in the treatment of methanol toxicity through its role as a cofactor in the breakdown of formate into carbon dioxide and water. In an animal study using monkeys, folic acid administration was associated with a decrease in serum formate concentration and a reversal of methanol toxicity after methanol administration2.  A subsequent study examining the effect of formic acid on rat brain slice cultures found that supplementation of folic acid prevented neuronal death, as compared to controls3. While not well studied in humans, one case report describes enhanced formate clearance in a subject treated with folinic acid (a folic acid derivative).4

Ethylene Glycol Toxicity
Ethylene glycol is commonly used as an automotive antifreeze and engine coolant. Once ingested, ethylene glycol is metabolized by alcohol dehydrogenase and aldehyde dehydrogenase into glycolic acid, a product that bioaccumulates and contributes to the development of a metabolic acidosis. Further enzymatic breakdown creates oxalic acid, which is directly toxic to renal tubules, and complexes with calcium to create calcium oxalate crystals that deposit within renal tubules to physically obstruct renal filtration and further compound nephrotoxicity. Additionally, the binding of ionic calcium into its calcium oxalate salt may contribute to a serum hypocalcemia that can predispose individuals to QTc prolongation and dysrhythmias. As with methanol, the first line treatment of ethylene glycol toxicity is fomepizole, or in its absence, ethanol, through their effect in decreasing the bioavailability of alcohol dehydrogenase to metabolize ethylene glycol into its toxic byproducts5.

The Lesser Known Adjuncts: Thiamine, Pyridoxine, Magnesium
The proposed role of thiamine, pyridoxine and magnesium in reducing the toxicity associated with ethylene glycol toxicity stems from the minor metabolic pathways that are involved in degrading an intermediate product, glyoxylic acid, away from the toxic oxalic acid byproduct. Thiamine is the cofactor in the transformation of glyoxylic acid into alpha-hydroxy-beta ketoadipic acid, while pyridoxine and magnesium are cofactors in the transformation of glyoxylic acid into glycine6. A recent 2013 human study demonstrates that pyridoxine administration reduces oxalic acid accumulation in patients with primary hyperoxaluria, but this effect has not been studied in ethylene glycol intoxication7.

Hemodialysis
Hemodialysis is a definitive treatment for patients presenting with methanol or ethylene glycol toxicity, as it removes the parent compounds and toxic byproducts from circulation. The American Association of Clinical Toxicology recommends hemodialysis under the following circumstances: metabolic acidosis, vision abnormalities, renal failure, electrolyte abnormalities not responsive to standard treatment, hemodynamic instability not responsive to intensive critical care treatment, and serum concentrations greater than  50 mg/dL8,9.

Conclusion
Methanol and ethylene glycol toxicity is well characterized, and the therapeutic effectiveness of fomepizole, ethanol and hemodialysis has been well studied. Treatment with adjunctive therapies should be provided to encourage the metabolism of toxic metabolites to non-toxic end products.  

References

  1. Kruse, JA. Methanol poisoning. Intensive Care Medicine. 1992;18(7): 391-397
  2. Noker PE, Eells JT, Tephly TR. Methanol toxicity: treatment with folic acid and 5-formyl tetrahydrofolic acid. Alcohol Clin Exp Res. 1980;4:378-383
  3. Kapur BM, Vandenbroucke AC, Adamchik Y, Lehotay DC, Carlen PL. Formic acid, a novel metabolite of chronic ethanol abuse, causes neurotoxicity, which is prevented by folic acid. Alcohol Clin Exp Res. 2007; 31(12): 2114-20
  4. Jacobsen D, McMartin KE. Methanol and ethylene glycol poisonings: mechanism of toxicity, clinical course, diagnosis and treatment. Med Toxicol. 1986;1:309-334
  5. Leth PM, Gregersen, M. Ethylene glycol poisoning. Forensic Science International. 2005;155(2-3);179-184
  6. Nath R, Thind SK, Murthy MS, et al. Role of pyridoxine in oxalate metabolism. Ann NY Acad Sci. 1990;585:274-284
  7. Fargue S, Rumsby G, Danpure, CJ. Multiple mechanisms of action of pyridoxine in primary hyperoxaluria type1. Biochimica et Biophysica Acta (BBA). 2013;1832(10):1776-1783
  8. 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;40:415-446
  9. Barceloux DG, Krenzelok EP, Olson K, et al. American Academy of Clinical Toxicology practice guidelines on the treatment of ethylene glycol poisoning. J Toxicol Clin Toxicol. 1999;37:537-560

 

 

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