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Ethylene glycol: an estimate of tolerable levels of exposure based on a review of animal and human data

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Abstract

Upon ingestion ethylene glycol (EG, monoethylene glycol) is rapidly absorbed from the gastrointestinal tract, and depending on the severity of exposure signs of toxicity may progress through three stages. Neurological effects characterize the first step consisting of central nervous depression (intoxication, lethargy, seizures, and coma). The second stage, usually 12–24 h after ingestion, is characterized by metabolic acidosis due to the accumulation of acidic metabolites of EG, primarily glycolic acid (GA), contributing to the ensuing osmolal and anion gaps. Stage 3, generally 24–72 h after ingestion, is determined mainly by oxalic acid excretion, nephropathy, and eventual renal failure. Because the toxicity of EG is mediated principally through its metabolites, adequate analytical methods are essential to provide the information necessary for diagnosis and therapeutic management. The severe metabolic acidosis and multiple organ failure caused by ingestion of high doses of EG is a medical emergency that usually requires immediate measures to support respiration, correct the electrolyte imbalance, and initiate hemodialysis. Since metabolic acidosis is not specific to EG, whenever EG intoxication is suspected, every effort should be made to determine EG as well as its major metabolite GA in plasma to confirm the diagnosis and to institute special treatment without delay. A number of specific and sensitive analytical methods (GC, GC-MS, or HPLC) are available for this purpose. Due to the rapid metabolism of EG, the plasma concentration of GA may be higher than that of EG already upon admission. As toxicity is largely a consequence of metabolism of EG to GA and oxalic acid, the simultaneous quantification of EG and GA is important. Formation of calcium oxalate monohydrate in the urine may be a useful indicator of developing oxalate nephrosis although urine crystals can result without renal injury. The pathways involved in the metabolism of EG are qualitatively similar in humans and laboratory animals, although quantitative differences have been reported. Comparison between species is difficult, however, because the information on humans is derived mainly from acute poisoning cases whereas the effects of repeated exposures have been investigated in animal experiments. Based on published data the minimum human lethal dose of EG has been estimated at approx. 100 ml for a 70-kg adult or 1.6 g/kg body weight (calculation of dose in ml/kg to mg/kg based in EG density=1.11 g/l). However, human data from case reports are generally insufficient for the determination of a clear dose-response relationship and quantification of threshold doses for systemic toxicity, in particular renal effects, is limited. As toxicity is largely a consequence of metabolism of EG to GA, it is important to note that no signs of renal injury have developed at initial plasma glycolate concentrations of up to 10.1 mM (76.7 mg/dl). Plasma EG levels of 3.2 mM (20 mg/dl) are considered the threshold of toxicity for systemic exposure, if therapeutic strategy is based on the EG concentration alone.

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References

  • Aarstad K, Dale O, Aakervik O, Øvrebø S, Zahlsen K (1993) A rapid gas chromatographic method for determination of ethylene glycol in serum and urine. J Anal Toxicol 17:218–221

    CAS  PubMed  Google Scholar 

  • Allen KA, Hamlin CR (1993) Interference in rapid enzymatic method for ethylene glycol. Ann Clin Lab Sci 23:321

    Google Scholar 

  • Bartels MJ (2002) Review of analytical methods for glycolic acid in human plasma. Report prepared for the EO & DER Toxicology Working Group of CEFIC

  • Beasley YR, Buck WB (1980) Acute ethylene glycol toxicosis: a review. Vet Hum Toxicol 22:255–342

    CAS  PubMed  Google Scholar 

  • Blandford DE, Desjardins PR (1994) A rapid method for measurement of ethylene glycol. Clin Biochem 27:25–30

    Article  CAS  PubMed  Google Scholar 

  • Booth ED, Dofferhoff O, Boogaard PJ, Watson WP (2004) Comparison of metabolism of ethylene glycol and glycolic acid in vitro by precision-cut tissue slices from female rat, rabbit and human liver. Xenobiotica 34:31–48

    Article  CAS  PubMed  Google Scholar 

  • Bove KE (1966) Ethylene glycol toxicity. Am J Clin Pathol 45:46–50

    CAS  PubMed  Google Scholar 

  • Brent J, McMartin K, Phillips S, Burkhart KK, Donovan JW, Wells M, Kulig K (1999) Fomepizole for the treatment of ethylene glycol poisoning. N Engl J Med 340:832–838

    Article  CAS  PubMed  Google Scholar 

  • Burns JR, Finlayson B (1980) Changes in calcium oxalate crystal morphology as a function of concentration. Invest Urol 18:174–177

    CAS  PubMed  Google Scholar 

  • Cheng JT, Beysolow TD, Kaul B, Weisman R, Feinfield DA (1987) Clearance of ethylene glycol by kidneys and hemodialysis. J Toxicol Clin Toxicol 25:95–108

    CAS  PubMed  Google Scholar 

  • Chou JY, Richardson KE (1978) The effect of pyrazole on ethylene glycol toxicity and metabolism in the rat. Toxicol Appl Pharmacol 43:33–44

    CAS  PubMed  Google Scholar 

  • CICAD (2002) Ethylene glycol: human health aspects. Concise International Chemical Assessment Document 45. World Health Organization, Geneva

    Google Scholar 

  • Clay K, Murphy RC (1977) On the metabolic acidosis of ethylene glycol intoxication. Toxicol Appl Pharmacol 39:39–49

    CAS  PubMed  Google Scholar 

  • Davidson DF (1992) Excess osmolal gap in diabetic ketoacidosis explained. Clin Chem 38:755–757

    CAS  PubMed  Google Scholar 

  • DePass LR, Garman RH, Woodside MD, Giddens WE, Maronpot RR, Weil CS (1986) Chronic toxicity and oncogenicity studies of ethylene glycol in rats and mice. Fundam Appl Toxicol 7:547–565

    CAS  PubMed  Google Scholar 

  • Eder AF, McGrath CM, Dowdy YG, Tomaszewski JE, Rosenberg FM, Wilson RB, Wolf BA, Shaw LM (1998) Ethylene glycol poisoning: toxicological and analytical factors affecting laboratory diagnosis. Clin Chem 444:168–177

    Google Scholar 

  • Ellenhorn MJ, Barceloux DG (1988) Medical toxicology—diagnosis and treatment of human poisoning. Elsevier, New York

  • Frantz SW, Beskitt JL, Grosse CM, Tallant MJ, Dietz FK, Ballantyne B (1996a) Pharmacokinetics of ethylene glycol I. Plasma disposition after single intravenous, peroral, or percutaneous doses in female Sprague-Dawley rats and CD-1 mice. Drug Metab Dispos 24:911–921

    CAS  PubMed  Google Scholar 

  • Frantz SW, Beskitt JL, Grosse CM, Tallant MJ, Dietz FK, Ballantyne B (1996b) Pharmacokinetics of ethylene glycol II. Tissue distribution, dose dependent elimination and identification of metabolites following single intravenous, peroral, or percutaneous doses in female Sprague-Dawley rats and CD-1 mice. Xenobiotica 26:1195–1220

    CAS  PubMed  Google Scholar 

  • Fraser AD, MacNeil W (1993) Colorimetric and gas chromatographic procedures for glycolic acid in serum: the major toxic metabolite of ethylene glycol. Clin Toxicol 31:397–405

    CAS  Google Scholar 

  • Gabow PA, Clay K, Sullivan JB, Lepoff R (1986) Organic acids in ethylene glycol intoxication. Ann Intern Med 105:16–20

    CAS  PubMed  Google Scholar 

  • Gaultier M, Conso F, Rudler M, Leclerc JP, Mellerio F (1976) Intoxication aigüe par l’ethylène glycol. Eur J Toxicol 9:373–379

    CAS  Google Scholar 

  • Gaunt IF, Hardy J, Gangolli SD, Butterworth KR, Lloyd AG (1974) Short-term toxicity of monoethylene glycol in the rat. Research report, BIBRA International, Carshalton

  • Gérin M, Patrice S, Begin D, Goldberg MS, Vyskocil A, Adib G, Drolet D, Viau C (1997) A study of ethylene glycol exposure and kidney function of aircraft-deicing workers. Int Arch Occup Environ Health 69:255–265

    Article  PubMed  Google Scholar 

  • Glasser L, Sternglanz PD, Combie J, Robinson A (1973) Serum osmolality and its applicability to drug overdose. Am J Clin Pathol 60:695–699

    CAS  PubMed  Google Scholar 

  • Hagen L, Walker VR, Sutton RAL (1993) Plasma and urinary oxalate and glycolate in healthy subjects. Clin Chem 39:134–138

    CAS  PubMed  Google Scholar 

  • Hall AH, Rumack BH (eds) (2001) TOMES information system. Micromedex, Englewood

  • Hansson P, Masson P (1989) Simple enzymatic screening assay for ethylene glycol (ethane-1:2-diol) in serum. Clin Chim Acta 182:95–102

    Article  CAS  PubMed  Google Scholar 

  • Harry P, Turcant SA, Bouachour G, Houze P, Alquier P, Allain P (1994) Efficacy of 4-methylpyrazole in ethylene glycol poisoning: clinical and toxicokinetic aspects. Hum Exp Toxicol 13:61–64

    CAS  PubMed  Google Scholar 

  • Hewlett TP, Ray AC, Reagor JC (1983) Diagnosis of ethylene glycol (antifreeze) intoxication in dogs by determination of glycolic acid in serum and urine with high pressure liquid chromatography and gas chromatography-mass spectrometry. J Assoc Anal Chem 66:275–283

    Google Scholar 

  • Hewlett TP, McMartin KE, Lauro AJ, Ragan FA Jr (1986) Ethylene glycol poisoning. The value of glycolic acid determination for diagnosis and treatment. Clin Toxicol 24:389–402

    CAS  Google Scholar 

  • Hoffman RS, Smilkstein MJ, Howland MA, Goldfrank LR (1993) Osmol gaps revisited: normal values and limitations. Clin Toxicol 31:81–93

    CAS  PubMed  Google Scholar 

  • Howe R (1995) THRESH: a computer program to compute a reference dose from quantal animal toxicity data using the benchmark dose method. ICF Kaiser Engineers, Ruston

  • Inaba H, Hirasawa H, Mizuguchi T (1987) Serum osmolality gap in postoperative patients in intensive care. Lancet I:1331–1335

    Article  Google Scholar 

  • Jacobsen D, McMartin KE (1986) Methanol and ethylene glycol poisonings. Mechanism of toxicity, clinical course, diagnosis, and treatment. Med Toxicol 1:309–334

    CAS  PubMed  Google Scholar 

  • Jacobsen D, Bredesen JE, Eide I, Ostborg J (1982) Anion and osmolal gaps in the diagnosis of methanol and ethylene glycol poisoning. Acta Med Scand 212:17–20

    CAS  PubMed  Google Scholar 

  • Jacobsen D, Øvrebø S, Østborg J, Sejersted OM (1984) Glycolate causes the acidosis in ethylene glycol poisoning and is effectively removed by hemodialysis. Acta Med Scand 216:409–416

    CAS  PubMed  Google Scholar 

  • Jacobsen D, Hewlett TP, Webb R, Brown ST, Ordinario AT, McMartin KE (1988) Ethylene glycol intoxication: evaluation of kinetics and crystalluria. Am J Med 84:145–152

    Article  CAS  Google Scholar 

  • Jones AW, Nilsson L, Gladh SA, Karlsson K, Beck-Friis J (1991) 2:3-Butanediol in plasma from an alcoholic mistakenly identified as ethylene glycol by gas-chromatographic analysis. Clin Chem 37:1453–1455

    CAS  PubMed  Google Scholar 

  • Kasidas GP, Rose GA (1979) A new enzymatic method for the determination of glycolate in urine and plasma. Clin Chim Acta 96:25–36

    Article  CAS  PubMed  Google Scholar 

  • Kearney J, Rees S, Chiang W (1997) Availability of serum methanol and ethylene glycol levels: a national survey. J Toxicol Clin Toxicol 35:509

    Google Scholar 

  • Litovitz TL, Smilkstein L, Felberg L, Klein-Schwarz W, Berlin R, Morgan JL (1997) 1996 Annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med 15:447–500

    Article  CAS  PubMed  Google Scholar 

  • Malandain H, Cano Y (1995) Interference of glycerol, propylene glycol and other diols in enzymatic assay of ethylene glycol. Clin Chem 41:S120

    Google Scholar 

  • Malmlund H-O, Berg A, Karlman G, Magnusson A, Ullman B (1991) Considerations for the treatment of ethylene glycol poisoning based on the analysis of two cases. Clin Toxicol 29:231–240

    CAS  Google Scholar 

  • Marshall TC (1982) Dose dependent disposition of ethylene glycol in the rat after intravenous administration. J Toxicol Environ Health 10:397–409

    CAS  PubMed  Google Scholar 

  • McChesney EW, Goldberg L, Harris ES (1972) Reappraisal of the toxicity of ethylene glycol. IV. The metabolism of labeled glycolic acid and glyoxylic acids in the Rhesus monkey. Food Cosmet Toxicol 10:655–670

    CAS  PubMed  Google Scholar 

  • Mertens JJWM (2002) A 16-week comparative dietary toxicity study of ethylene glycol in male Wistar and Fischer 344 rats. Study no 186027. WIL Research Laboratories, Ashland

  • Moreau C, Kerns II W, Tomaszewski CA, McMartin KE, Rose SR, Ford MD, Brent J, and the META Study Group (1998) Glycolate kinetics and hemodialysis clearance in ethylene glycol poisoning. Clin Toxicol 36:659–666

    CAS  Google Scholar 

  • Nilsson L, Jones AW (1992) 2:3-Butanediol: a potent interfering substance in the assay of ethylene glycol by an enzymatic method. Clin Chim Acta 208:225–229

    Article  CAS  PubMed  Google Scholar 

  • Øvrebø S, Jacobsen D, Sejersted OM (1987) Determination of ionic metabolites from ethylene glycol in human blood by isotachophoresis. J Chromatogr 416:111–117

    Google Scholar 

  • Peterson CD, Collins AJ, Keane WF (1981) Ethanol for ethylene glycol poisoning. N Engl J Med 305:977

    Google Scholar 

  • Petrarulo M, Marangella M, Linari F (1991) High-performance liquid chromatographic determination of plasma glycolic acid in healthy subjects and in cases of hyperoxaluria syndromes. Clin Chim Acta 196:17–26

    Article  CAS  PubMed  Google Scholar 

  • Porter WH, Auansakul A (1982) Gas chromatographic determination of ethylene glycol in serum. Clin Chem 28:75–78

    CAS  PubMed  Google Scholar 

  • Porter WH, Jarrells MC, Sun DH (1994) Improved specificity for ethylene glycol determined as the phenylboronate by capillary column gas chromatography. Clin Chem 40:850–851

    CAS  PubMed  Google Scholar 

  • Porter WH, Rutter PW, Yao HH (1999) Simultaneous determination of ethylene glycol and glycolic acid in serum by gas chromatography-mass spectrometry. J Anal Toxicol 23:591–597

    CAS  PubMed  Google Scholar 

  • Porter WH, Crellin M, Rutter PW, Oelten P (2000) Interference by glycolic acid in the Beckman synchron method for lactate. A useful clue for unsuspected ethylene glycol intoxication. Clin Chem 46:874–875

    CAS  PubMed  Google Scholar 

  • Pottenger LH, Carney EW, Bartels MJ (2001) Dose-dependent non-linear pharmacokinetics of ethylene glycol metabolites in pregnant (GD 10) and nonpregnant Sprague-Dawley rats following oral administration of ethylene glycol. Toxicol Sci 62:10–19

    Article  CAS  PubMed  Google Scholar 

  • Reif G (1950) Selbstversuche Äthylenglykol. Pharmazie 5:276–278

    CAS  Google Scholar 

  • Robinson M, Pond CL, Laurie RD, Bercz JP, Henningsen G, Condie LW (1990) Subacute and subchronic toxicity of ethylene glycol administered in drinking water to Sprague-Dawley rats. Drug Chem Toxicol 13:43–70

    CAS  PubMed  Google Scholar 

  • Schelling JR, Howard RL, Winter SD, Linas SL (1990) Increased osmolal gap in alcoholic ketoacidosis and lactic acidosis. Ann Intern Med 113:580–582

    CAS  PubMed  Google Scholar 

  • Shoemaker JD, Lynch RE, Hoffmann JW, Sly WS (1992) Misidentification of propionic acid as ethylene glycol in a patient with methylmalonic acidemia. J Pediatr 120:417–421

    CAS  PubMed  Google Scholar 

  • Sivilotti ML, Burns MJ, McMartin KE, Brent J for the Methylpyrazole for Toxic Alcohols Study Group (2000) Toxicokinetics of ethylene glycol during fomepizole therapy: implications for management. Ann Emerg Med 36:139–141

    Article  PubMed  Google Scholar 

  • Sklar AH, Linas SL (1983) The osmolal gap in renal failure. Ann Intern Med 98:481–482

    CAS  PubMed  Google Scholar 

  • Terlinski AS, Grochowski J, Geoly KL, Stauch BS, Hefter L (1981) Identification of atypical calcium oxalate crystalluria following ethylene glycol ingestion. Am J Clin Pathol 76:223–226

    PubMed  Google Scholar 

  • Wiley JF (1999) Novel therapies for ethylene glycol intoxication. Curr Opin Pediatr 11:269–273

    Article  PubMed  Google Scholar 

  • Winek CL, Shingleton DP, Shanor SP (1978) Ethylene and diethylene glycol toxicity. Clin Toxicol 13:297–324

    CAS  PubMed  Google Scholar 

  • Wolf BA, Shaw L (1998) Importance of glycolic acid analysis in ethylene glycol poisoning. Clin Chem 44:1769–1770

    CAS  PubMed  Google Scholar 

  • Yao HH, Porter WH (1996) Simultaneous determination of ethylene glycol and its major toxic metabolite, glycolic acid, in serum by gas chromatography. Clin Chem 42:292–297

    CAS  PubMed  Google Scholar 

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Hess, R., Bartels, M.J. & Pottenger, L.H. Ethylene glycol: an estimate of tolerable levels of exposure based on a review of animal and human data. Arch Toxicol 78, 671–680 (2004). https://doi.org/10.1007/s00204-004-0594-8

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