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Methanol and ethylene glycol poisonings share many characteristics both clinically and biochemically. Both alcohols are metabolised via alcohol dehydrogenase to their toxic metabolites. Methanol is slowly metabolised to formaldehyde which is rapidly metabolised to formate, the metabolite mainly responsible for methanol toxicity. Formate metabolism depends upon the folate pool which is small in primates compared with other animals. Therefore, formate accumulates in primates during methanol intoxication and is mainly responsible for the metabolic acidosis in the early stage of intoxication. In late stages lactate may also accumulate, mainly due to formate inhibition of the respiratory chain. This tissue hypoxia caused by formate may explain the ocular as well as the general toxicity. Ethylene glycol is metabolised more rapidly than methanol, via alcohol dehydrogenase to glycolaldehyde which is rapidly metabolised to glycolate, the metabolite mainly responsible for the metabolic acidosis in ethylene glycol poisoning. Glycolate is metabolised by various pathways, including one to oxalate which rapidly precipitates with calcium in various tissues and in the urine. Ethylene glycol toxicity is complex and not fully understood, but is mainly due to the severe metabolic acidosis caused by glycolate and to the calcium oxalate precipitation. The clinical course in both poisonings is initially characterised by the development of metabolic acidosis following a latent period, which is more pronounced in methanol poisoning and is the time taken for both alcohols to be metabolised to their toxic metabolites. In methanol poisoning there are usually visual symptoms progressing to visual impairment, whereas ethylene glycol victims develop renal and cardiopulmonary failure. Prognosis is excellent in both poisonings provided that there is early treatment with alkali to combat acidosis, ethanol as an antimetabolite, and haemodialysis to remove the alcohols and their toxic metabolites. Ethanol is also metabolised by alcohol dehydrogenase, but has a much higher affinity for this enzyme than methanol and ethylene glycol. Presence of ethanol will therefore inhibit formation of toxic metabolites from methanol and ethylene glycol. Due to competition for the enzyme, the therapeutic ethanol concentration depends on the concentration of the other two alcohols, but a therapeutic ethanol concentration around 22 mmol/L (100 mg/dl) is generally recommended. Most patients are, however, admitted at a late stage to hospitals not capable of performing analyses of these alcohols or their specific metabolites on a 24-hour basis.(ABSTRACT TRUNCATED AT 400 WORDS)

Ethylene glycol is an infrequent but important cause of toxin-induced acute renal failure. Early detection is crucial so that appropriate therapy can be begun to ameliorate the profound metabolic a...

Six male patients with severe ethylene glycol poisoning were studied with respect to the origin of the metabolic acidosis. The plasma concentrations of ethylene glycol were 4-41 mmol/l and treatment included alkali, ethanol and hemodialysis. Plasma analysis by isotachophoresis and whole blood lactate determinations showed that glycolate (17.0-29.3 mmol/l), lactate (1.4-6.2 mmol/l) and beta-hydroxybutyrate (less than or equal to 1.8 mmol/l) were present in elevated concentrations contributing to the acidosis. Oxalate (less than or equal to 0.33 mmol/l), glyoxylate (less than 0.2 mmol/l) and formate (less than 0.4 mmol/l) concentrations were negligible and did not contribute to any significant degree to the acidosis. The elevated plasma glycolate concentration was highly correlated to the anion gap (r = 0.923) and the glycolate made up for 96.1% (n = 6, range 84.7-108.8) of the increased anion gap. We conclude that glycolate accumulation is the main reason for the metabolic acidosis in ethylene glycol poisoning. The mean dialysator (1.6 m2) clearances of glycolate at a blood flow of 200 ml/min in two patients were 137 ml/min (n = 9, SD +/- 8, range 125-149) and 144 ml/min (n = 11, SD +/- 8, range 133-158). By applying first order kinetics during hemodialysis a volume of distribution of glycolate of 0.55 l/kg was found, assuming that the dialysator clearance equals the total body clearance of glycolate. Thus glycolate, the probable main metabolite of ethylene glycol, is efficiently removed by hemodialysis.

Summary Although an uncommon cause of death in Great Britain, ethylene glycol poisoning is potentially serious in that renal and cardiopulmonary failure and central nervous system dysfunction can occur when doses of the order of 100 ml or more are ingested. A case is described in which a child who swallowed approximately 100 ml of ethylene glycol was treated by prolonged peritoneal dialysis. In addition, measures were taken to correct a marked acidosis. Substantial amounts of ethylene glycol were removed by the dialysis fluid and the child made a complete physical and mental recovery.

We report a case of ethylene glycol poisoning in a 54-year-old man found comatose on the street. No history was available. The diagnosis was based on the findings of a high anion gap metabolic acidosis, a high osmolal gap, and the presence of oxalate and hippurate crystals in the urine. The diagnosis was confirmed later by an ethylene glycol level of 775 mg/dl. This case illustrates how these parameters can be used in the emergency department for rapid diagnosis and management.

4-Methylpyrazole in a dose producing an inhibition of alcohol dehydrogenase of about 60% was given alone or in combination with ethanol (10%) as sole drinking fluid to growing rats in periods up to 38 weeks. No effects were observed on the weight curves. Hematologic analyses showed normal values for blood and bone marrow. Studies of liver function with transaminase, bilirubin and albumin did not reveal any functional changes. Kidney function was normal as judged by creatinine and normal electrolytes. Electronmicroscopy of liver, kidney, and heart did not reveal any changes related to treatment. Combined treatment of ethanol and 4-methylpyrazole caused an increase of the microsomal drug-metabolizing activity. Chronic administration of ethanol and 4-methylpyrazole indicated that there is a mutual interaction in the metabolism of ethanol and 4-methylpyrazole, leading to a higher concentration of both ethanol and 4-methylpyrazole in the blood. Acute experiments, where alcohol dehydrogenase is saturated with ethanol, indicated a much slower elimination of 4-methylpyrazole. Administration of ethanol and 4-methylpyrazole in acute experiments showed a lower concentration of 4-hydroxymethylpyrazole in the blood indicating that ethanol interferes with the 4-methylpyrazole- and/or 4-hydroxymethyl-pyrazole-metabolizing enzymes. The present investigation has shown that the acute and chronic toxicity of 4-methylpyrazole alone or in combination with ethanol is minimal at doses that are effective in blocking ethanol metabolism in the rat. Because of its low toxicity and powerful inhibitory capacity, 4-methylpyrazole should be a potential tool for experimental clinical investigation of alcohol metabolism and its effects. 4-Methylpyrazole is also a potential therapeutic agent in methanol or ethylene glycol poisoning.

Administration of ethylene glycol to pigtail monkeys (Macaca nemestrina) or to dogs produced a severe metabolic acidosis. An assay for glycolic acid was developed and used to show that the decrease in blood bicarbonate concentrations was matched by increased blood glycolate concentrations. Treatment of the monkeys with 4-methylpyrazole prior to administration of ethylene glycol prevented metabolic acidosis. Treatment with 4-methylpyrazole after an acidosis had been produced with ethylene glycol resulted in restoration of normal acid-base balance as blood glycolate concentrations decreased. The contribution of other possible ethylene glycol metabolites to the metabolic acidosis was determined to be negligible.

An animal model was developed to study the potential toxicity resulting from repeated, topical applications of a polyethylene glycol-based antimicrobial cream. Applications of this cream to open wounds in rabbits produced the same syndrome observed in the burn patients treated with this agent. This syndrome was characterized by (1) elevated total calcium, (2) elevated osmolality gap, (3) high anion gap metabolic acidosis, and (4) renal failure. Ten of twelve treated animals died within one week of therapy. This syndrome appears to result from the absorption of polyethylene glycols and their metabolism to nephrotoxic compounds and to mono- and diacids. We propose that the increased serum osmolality reflects the absorption of glycols and their presence in the circulation, while the acidosis reflects the presence in plasma of mono- and diacid metabolites of the glycols. The diacid metabolities of low-molecular-weight polyethylene glycols are excellent calcium chelators and can account for the hypercalcemia. Finally, we suggest that polyethylene glycol metabolites produce renal destruction via mechanisms similar to those involved in the renal failure associated with ethylene glycol poisoning.

Conditions for isotachophoretic determination of anionic metabolites in blood from ethylene glycol in poisoned humans were established. Leading electrolytes with 5 m M chloride and a pdH between 2.3 and 2.5 gave good separation. Optimal separation was found with leading electrolytes at pH 2.5, and 10 m M acetic acid as terminating electrolyte. Separation and quantification of four out of six metabolites were possible. The four were glycolic acid, glyoxylic acid, oxalic acid and formic acid. Besides these compounds, citric acid, lactic acid, and α- and β-hydroxybutyric acid were separated and quantified. The formation of mixed zones did not give any serious problems, although in samples with high amounts of glycolic acid we had to reduce the maximum injected amount from 3 to 1 μl. This method might be valuable in further studies of the mechanism of ethylene glycol toxicity and as an important supplement in the diagnosis of late stages of ethylene glycol poisoning in which the glycol has been metabolized to glycolic acid.

The Effect of Pyrazole on Ethylene Glycol Toxicity and Metabolism in the Rat. Chou, J. Y., and Richardson, K. E. (1978), Toxicol. Appl. Pharmacol. 43 , 33–44. The toxic effects of ethylene glycol are well known, but the specific mediator of the toxicity has not been identified. The alcohol dehydrogenase inhibitors, pyrazole and 4-methylpyrazole (3 mmol/kg), administered 4 hr before or concurrently with lethal concentrations of ethylene glycol (10 ml/kg) fed by stomach tube, reduced the mortalities from 100 to 0%. The excretion of ethylene glycol in the urine was increased, and the excretion of glycolate, a metabolic intermediate, was decreased. The excretion in the urine of glycolaldehyde, glyoxylate, and oxalate was essentially unchanged. The mortalities observed correlated inversely with the percentage of ethylene glycol, recovered in the urine and directly with the time of pyrazole administration and the concentration of glycolate recovered in the urine. Essentially the same distribution patterns of ethylene glycol metabolic intermediates were found in both rat urine and blood plasma. The protective effects of pyrazole were reduced if the time of administration was delayed beyond 4 hr after ethylene glycol consumption, if the concentration was reduced below 0.5 mmol/kg, or if the ethylene glycol dose was increased to 20 ml/kg. In contrast with the results obtained with ethylene glycol, inhibiting the oxidation of glycolaldehyde, glycolate, and glyoxylate lowered their LD50 values, demonstrating their direct toxicity. The results suggest that glycolate is the specific toxic agent in acute ethylene glycol poisoning.

High doses of 4-methylpyrazole (4-MP) could be administered to monkeys in long- and short-term experiments without yielding any general toxicity or any toxic influence on the retinal photoreceptors, the conduction of impulses through the retina or on the activity in the inner nuclear layer detectable by recording the electroretinogram (ERG). Both series included a low dose (20 mg/kg) and a high dose level (100 mg/kg), the former being a tentative therapeutic dose. In the first series the substance was administered for 6 weeks and the toxicity regarding clinical signs, hematology and blood chemistry, and gross and microscopic pathology evaluated. Furthermore ophthalmoscopy with assessment of the fundus structures and recordings of the ERG were performed. The second series was mainly concerned with revealing of any direct effect of 4-MP on the ERG. Because of the low toxicity of 4-MP and its powerful inhibitory capacity on alcohol dehydrogenase, the substance should prove a potential tool in clinical alcohol research and an effective antidote in clinical situations where inhibition of alcohol dehydrogenase (ADH) is the key to a successful outcome of, for example, methanol and ethylene glycol poisoning.

Glycolic acid is the ethylene glycol (EG) metabolite that accumulates in the highest concentrations in the blood and may be the major contributing factor to the acute toxicity of EG. Serum and urine levels of glycolic acid have been found to correlate directly with clinical symptoms and mortality in poisoning cases, making it a valuable diagnostic tool. A high pressure liquid chromatographic (HPLC) method for quantitation of glycolic acid in serum was used in several cases of EG ingestion presented to the Louisiana Regional Poison Control Center. The data collected in this study support the value of glycolic acid determination for diagnosis and evaluation of patients poisoned by EG.

Ethylene glycol, a major constituent of antifreeze, is metabolized by alcohol dehydrogenase to glycoaldehyde, glycolate, glyoxylate, and oxalate. The metabolites of ethylene glycol cause severe metabolic acidosis and central nervous system, pulmonary, and renal damage. Ethanol competes with ethylene glycol as an alternate substrate of alcohol dehydrogenase. Two cases of ethylene glycol poisoning associated with serum concentrations of 59 and 150 mg/dl are reported. One patient was protected from the toxic effects of the metabolites because of concomitant ethanol ingestion. In patients with unexplained anion and osmol gaps, early diagnosis and therapy with ethanol and hemodialysis help prevent the toxic manifestations of ethylene glycol poisoning.

A patient poisoned with ethylene glycol exhibited the symptoms of (1) hysteria, (2) metabolic acidosis with both a large anion gap and osmolal gap, and (3) crystalluria. However, the shape of the urinary crystals was prismatic and resembled hippurate rather than the expected dipyramidal calcium oxalate dihydrate. X-ray crystallography positively identified them as calcium oxalate monohydrate.

A new staining technic was used to demonstrate calcium oxalate in tissues from a patient who died after ingesting ethylene glycol. The technic readily demonstrates calcium oxalate as calcium naphthalhydroxamate in a variety of organs, in particular, kidney tubules, intertubular interstitium, hepatic cell nuclei, pulmonary macrophages, dura and leptomeninges. Utilizing this method, calcium oxalate precipitations not associated with ethylene glycol poisoning can also be demonstrated in conditions such as familial hyperoxalosis. Although a positive response to the naphthalhydroxamic acid test appears to be highly characteristic of calcium, other tests to demonstrate calcium should be carried out dealing with an unknown substance.

ETHYLENE GLYCOL has been widely used as a solvent for dyes and drugs and as a constituent of antifreeze mixtures for the cooling systems of automobiles.1Forty to 60 deaths are thought to occur annually from accidental ingestion or from its use as a substitute for beverage alcohol.2The fatal dose in human adults is believed to be about 100 gm.3 Initially, the toxic manifestations of ethylene glycol poisoning relate to central nervous disorder with confusion, convulsions, and coma occurring commonly. Other evidence of neuropathy such as incoordinate movement, ataxia, and ocular palsy may occur. The early symptoms are not unlike those of acute intoxication with ethanol. These symptoms are sometimes associated with signs of cardiopulmonary disease. Tachycardia, tachypnea, cyanosis, and pulmonary edema have been observed early in the course of illness.4Later, however, there is evidence of nephrotoxicity.4,5Blood and protein are found in

Potentially fatal ethylene glycol intoxication in an adult with normal renal function was treated with 4-methylpyrazole administered three hours after the incident occurred. The plasma ethylene glycol concentration was 3.5 g 1-1 on admission. The metabolic acidosis present on admission resolved within four hours, and the subsequent clinical course was uneventful. The apparent plasma half-life of ethylene glycol was 16 h and the mean renal and plasma clearances of ethylene glycol were 24 and 25 ml min-1, respectively. These results support the hypothesis that complete blockade of hepatic metabolism of ethylene glycol is achieved by 4-methylpyrazole. The only side-effect observed as a result of treatment was a transient slight increase in serum transaminase activity.

To the Editor.— We read the recent case reports of massive ethylene glycol ingestion by Stokes and Aueron (1980;243:2065) and by Peterson et al.1Our own experience in a recent ethylene glycol poisoning, where the diagnosis was not evident from the patient's history and made only post mortem, caused us to review the clinical indications and available methods for ethylene glycol determination. A metabolic acidosis value with a high anion gap and a substantial discrepancy between the measured and calculated osmolality is suggestive of ethylene glycol or methyl alcohol intoxication. In either case, one must often start therapy with the infusion of ethyl alcohol, correction of the acidosis with sodium bicarbonate, and preparation for dialysis before there is laboratory confirmation. If a gas chromatograph is available for volatile toxins, a change in the usual screening conditions will include ethylene glycol among the identifiable poisons. As usually performed, volatile screens

Excerpt To the editor: Gabow and coworkers (1), in their recent article, identify glycolate and lactate as the predominant acids causing the metabolic acidosis of ethylene glycol poisoning. They al...

Ethylene glycol intoxication produces a severe metabolic acidosis with an increased anion gap. We examined three patients with this intoxication to identify the organic acids that cause acidemia in humans and to determine how effectively these acids can be removed during dialysis. All patients had markedly elevated glycolic acid levels of more than 7 meq/L and two patients had lactic acidosis, with lactic acid levels of greater than 5.0 meq/L. Hemodialysis clearance of glycolic acid was 105 mL/min, and 159 meq was removed in 3 hours. After hemodialysis using a bicarbonate dialysate, the mean anion gap decreased from 34 to 23 meq/L; the mean serum bicarbonate concentration increased from 5.5 to 20 meq/L. Therefore, glycolic and lactic acids are important in the acidosis caused by ethylene glycol intoxication in humans. Hemodialysis treatment with a bicarbonate dialysate is an efficient method for removing glycolic acid and resolving acidemia.

In the course of phylogenetic evolution, the substrate specificity of alcohol dehydrogenase, the enzyme which detoxicates ethyl alcohol, has apparently broadened. Thus, while the enzyme from yeast oxidizes ethyl alcohol and only a few other alcohols, 1 the enzyme of the horse liver is capable of oxidizing a range of other alcohols. 1,2 The human enzyme has an even wider range, 3 since contrary to the horse enzyme it oxidizes both ethyl alcohol and ethylene glycol. While chemically ethylene glycol is very similar to ethyl alcohol, both these compounds are toxic to man. Detailed studies of the enzymatic oxidation of ethylene glycol demonstrate that ethyl alcohol, the natural substrate, is a potent competitive inhibitor of the oxidation of ethylene glycol. 3 Hence, low concentrations of ethyl alcohol prevent the oxidation of large concentrations of ethylene glycol. These biochemical features of the catalytic behavior of human-liver alcohol dehydrogenase have served as

Ethylene glycol, a major ingredient in radiator antifreeze, is an aliphatic alcohol with prominent toxic effects on central nervous, cardiac, pulmonary, and renal systems. Toxicity results mainly from calcium oxalate and other metabolites rather than ethylene glycol per se. Symptoms resembling those of alcohol intoxication may occur soon after ingestion, and poisonings have resulted when ethylene glycol has been substituted for alcohol. 1 Suicide attempts also account for a substantial number of cases of ethylene glycol poisoning. Death is the usual outcome, 2 but the survival rate has improved with vigorous treatment of metabolic acidosis with hemodialysis 3 and competitive inhibition with alcohol administered parenterally. 4 The present case is unique; despite 50 days of oliguria, during which time the patient had hemodialysis repeatedly, renal function recovered sufficiently so that her only treatment at time of discharge was a modified protein diet. Patient Summary The patient, a 65-year-old woman, was