What Are the Toxicological Effects of Ethylene Glycol Poisoning?
Course: WB 4342
CE Original Date: March 20, 2020
CE Renewal Date: March 20, 2022
CE Expiration Date: March 20, 2024
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After completing this section, you will be able to describe the toxicological effects of ethylene glycol poisoning.
Ethylene glycol’s toxicity mainly results from the accumulation of its toxic metabolites.
Ethylene glycol is a central nervous system (CNS) depressant that produces acute effects similar to those of ethanol. These CNS effects predominate during the first hours after exposure.
If undetected or untreated, ethylene glycol ingestion can cause serious or fatal toxicity. This section describes the systemic effects associated with significant ethylene glycol exposure.
The main toxicity of ethylene glycol results from hepatic metabolism of ethylene glycol to
- glyoxylate, and
These metabolites inhibit
- oxidative phosphorylation and cellular respiration,
- glucose and serotonin metabolism,
- protein synthesis,
- DNA replication, and
- ribosomal RNA formation.
The effects include CNS depression and cardiopulmonary and renal failure (Bove 1966; Jacobsen and McMartin 1986).
The accumulation of organic acid metabolites, especially glycolic acid, results in an elevated anion gap metabolic acidosis.
- A three-stage theory of ethylene glycol poisoning was introduced in the 1950s (Berman et al. 1957; Kahn and Brotchner 1950). These stages are theoretical descriptions of ethylene glycol poisoning, but the onset and progression of the clinical course is frequently not consistent or predictable. One stage might predominate, whereas another stage might be absent (Jammalamadaka and Raissi 2010).
- The three stages include the following:
- Stage 1 (the neurological stage) occurs within 30 minutes to 12 hours after ingestion.
- Stage 2 (the cardiopulmonary stage) occurs between 12 and 24 hours after ingestion.
- Stage 3 (the renal stage) occurs between 24 and 72 hours after ingestion.
See more details in the section titled “Clinical Assessment—History and Physical.”
The initial phase of ethylene glycol poisoning in humans is characterized by inebriation caused by unmetabolized ethylene glycol. The following effects are common in acute poisoning cases (Buell et al. 1998; Hess et al. 2004; Parry and Wallach 1974):
- Slurred speech
Possible consequences of neurologic effects in severe poisonings (Froberg et al. 2006; Hantson et al. 2002; Walder and Tyler 1994) include the following:
- Myoclonic jerks
Cerebral edema and deposition of calcium oxalate crystals in the walls of small blood vessels in the brain contribute to this CNS toxicity (Bey et al. 2002; Froberg et al. 2006; Jobard et al. 1996; Tobe et al. 2002). Some studies have documented brain dysfunction with corresponding cranial computed tomography (CT) findings after ethylene glycol ingestion, such as low-density areas in the basal ganglia, thalami, midbrain, and upper pons. The neurologic findings reflect dysfunction of all the areas of hypodensity on the cranial CT scan. In one study, magnetic resonance imaging of the brain obtained 24 days after ingestion revealed bilateral putamen necrosis (Chung and Tuso 1989; Morgan et al. 2000; Zeiss et al. 1989).
According to some investigators, effects on cranial nerves appear late (generally 5–20 days after ingestion) and constitute a fourth, late cerebral phase in ethylene glycol intoxication (Chung and Tuso 1989; Gardner et al. 2004; Lewis et al. 1997). The following cranial nerve effects have been reported after acute exposure:
- Facial palsy
- Hearing loss
- Visual disturbances
Such adverse effects are uncommon, but delayed treatment might contribute to their development (Broadley et al. 1997; Lewis et al. 1997; Momont and Dahlberg 1989; Tobe et al. 2002).
Inhaled ethylene glycol can irritate the respiratory tract (Wills et al. 1974).
- Throat and upper respiratory irritation were the most common complaints after prolonged experimental exposures in humans (4 weeks at concentrations of 1–25 parts per million [ppm]).
- Exposure to 60 ppm aerosolized ethylene glycol caused noticeable respiratory irritation.
- Exposure to 80 ppm aerosolized ethylene glycol was “intolerable” because respiratory discomfort developed rapidly.
Pulmonary effects typically occur 12–72 hours after ethylene glycol ingestion. Pulmonary edema, adult respiratory distress syndrome (ARDS), and death have occurred in persons exposed to ethylene glycol (Gordon and Hunter 1982; Haupt et al. 1988; Piagnerelli et al. 1999).
The following respiratory effects often occur 12 hours or more after exposure in victims of severe ethylene glycol poisoning:
- Kussmaul respirations
Such effects most often reflect physiological compensation for severe metabolic acidosis rather than primary lung disease (Friedman et al. 1962; Godolphin et al. 1980; Parry and Wallach 1974). Autopsies [(Vale 1979) of ethylene glycol victims revealed the following:
- Pulmonary edema with diffuse hemorrhagic exudates
- Bronchopneumonia (probably caused by aspiration)
- Deposits of calcium oxalate crystals in lung parenchyma
The following severe cardiovascular effects have been reported in persons 12-24 hours (stage 2) after ingesting ethylene glycol (Friedman et al. 1962; Gordon and Hunter 1982; Parry and Wallach 1974; Vale 1979):
- Hypertension or hypotension
- Dysrhythmias (from electrolyte abnormalities)
- Congestive heart failure with cardiogenic pulmonary edema
- Circulatory collapse
- Cardiac arrest
Ethylene glycol exposure is characterized by an elevated osmolal gap and metabolic acidosis with an elevated anion gap.
- Onset occurs within 24 hours after ingestion.
- Acidosis is caused primarily by the accumulation of glycolic and glyoxylic acids. Oxalic acid and lactic acid also contribute.
Ethylene glycol is a small, osmotically active molecule that
- increases plasma osmolality, and
- can cause a large osmolal gap.
Tetany, including muscle twitches, cramps, and contractions, can sometimes result from hypocalcemia, which results from calcium precipitation by the oxalate formed during ethylene glycol metabolism (Parry and Wallach 1974).
Adverse renal effects after ethylene glycol ingestion typically occur during the third stage of ethylene glycol toxicity, 24–72 hours after acute exposure (Davis et al. 1997; Hess et al. 2004).
- Kidney damage manifests as acute oliguric renal failure.
- The most common physical finding is costovertebral angle tenderness (Friedman et al. 1962).
- The most characteristic abnormality is the presence of large numbers of “tent-shaped” (octahedral) or needle-shaped oxalate crystals in the urine (Froberg et al. 2006; Hantson et al. 2002; Huhn and Rosenberg 1995; Leth and Gregersen 2005; McMartin K 2009; Olivero 1993; Takayesu et al. 2006).
- Absence of oxalate crystals does not rule out an ethylene glycol poisoning diagnosis (Baum et al. 2000; Boyer et al. 2001; Curtin et al. 1992; Hantson et al. 2002; Haupt et al. 1988).
Other typical urinalysis abnormalities include the following:
- Low specific gravity
Renal dysfunction might be mild and short-lived or severe and persistent. Although uncommon, permanent renal insufficiency does occur (Berman et al. 1957; Buell et al. 1998; Friedman et al. 1962; Hantson et al. 1998; Parry and Wallach 1974; Takayesu et al. 2006).
The toxicity of ethylene glycol is linked with all four metabolites.
- Glycolic acid contributes to the metabolic acidosis.
- Oxalic acid is poorly soluble in the presence of calcium.
- Calcium oxalate crystals in the urine are supportive of the diagnosis.
- The precipitation of oxalate crystals in the tubular lumen leads to luminal blockage and compression-induced loss of glomerular filtration (renal failure).
- In transformed kidney cells, the oxalate ion induces cytotoxic damage (McMartin KE and Cenac 2000).
- Glycoaldehyde and glyoxylate might be responsible for ethylene glycol nephrotoxicity (Poldelski et al. 2001).
Studies in humans and animals have not shown any associations between ethylene glycol exposure and the incidence of any cancer (ATSDR 2014).
No known human studies have evaluated a link between ethylene glycol exposure and reproductive or developmental hazards in humans (ATSDR 2014).
- Ethylene glycol exposure was teratogenic to mice and rats, resulting in craniofacial and neural tube closure defects and skeletal dysplasia [Lamb et al. 1985; Marr et al. 1992; Price et al. 1985; Tyl et al. 1995].
- Large oral doses of ethylene glycol (>500 mg kg-1 in mice and >1,000 mg kg-1 in rats) might cause developmental toxicity in those animals, including
- axial skeletal malformations,
- reduced body weights,
- external malformations, and
- increased post-implantation loss [IPCS 2002; NTP-CERHR 2004].
Nausea, vomiting (with or without blood), and abdominal pain often occur soon after ethylene glycol ingestion (Davis et al. 1997; Johnson et al. 1999; Moossavi et al. 2003; Singh et al. 2001; Verrilli et al. 1987). Ethylene glycol is only a minor skin and mucous membrane irritant, although a few patients have had allergic contact dermatitis (Clayton GD & Clayton FE 1994). Reported effects on the blood have included (Hantson et al. 1998; Rasic et al. 1999; Verrilli et al. 1987)
- methemoglobinemia (rare), and
- bone marrow arrest.
Reported musculoskeletal effects have included
- muscle tenderness and
- elevation of creatine kinase (Friedman et al. 1962; Parry and Wallach 1974; Verrilli et al. 1987).
- After ethylene glycol ingestion, signs of inebriation are among the first manifestations.
- Unmetabolized ethylene glycol causes CNS depression. Delays in initiating treatment can result in more severe adverse effects.
- The most common cause of tachypnea is uncompensated metabolic acidosis.
- Ethylene glycol poisoning through ingestion can cause noncardiogenic pulmonary edema and ARDS.
- Ethylene glycol poisoning can cause dysrhythmias and heart failure.
- Ethylene glycol toxicity is characterized by an osmolal gap and metabolic acidosis with an elevated anion gap.
- Nephrotoxicity after ethylene glycol ingestion typically occurs 24-72 hours after acute exposure.
- No studies were located that link ethylene glycol exposure to cancer or reproductive or developmental hazards in humans.
Quiz 07:To review relevant content, see “Mechanism of Toxicity” in this section.
Quiz 08: To review relevant content, see “Neurologic Effects” in this section.
Quiz 09: To review relevant content, see “Respiratory Effects” in this section.
Quiz 10: To review relevant content, see “Metabolic Effects” in this section.
Quiz 11: To review relevant content, see “Renal Effects” in this section.