Glycol Ether Toxicology

Etiology

Glycol ethers are rapidly absorbed via dermal, inhalational, and gastrointestinal routes. Ingestion is the least likely mode of exposure but has the greatest potential to cause toxicity. Intentional ingestion of glycol ethers has been documented.[16][17] EGEs possess a primary alcohol and are metabolized by alcohol dehydrogenase, producing toxic alkoxyacetic acids. Organic acid accumulation is generally responsible for causing EGEs' renal, neurologic, and reproductive side effects. In contrast, PGEs lack a primary alcohol group and thus cannot produce toxic metabolites.[18][19] 

Epidemiology

Limited human epidemiological data regarding the association between reproductive outcomes and glycol ethers is available. Epidemiological studies focus mostly on EGEs, particularly 2-methoxyethanol, 2-ethoxyethanol, and 2-butoxyethanol (see Image. Structure of 2-Butoxyethanol). These studies include case reports, animal research, and limited prospective cohorts.[20][21][22] Furthermore, these investigations are often confounded by exposures to other occupational chemicals.

Animal models first displayed EGEs' toxic reproductive effects in the 1970s, prompting investigations in the United States a decade later. France partially regulated the compound in 1992, but the first complete ban on using glycol ethers in drugs and cosmetics occurred in 1999.

Occupational exposures comprise most cases since glycol ethers have a ubiquitous industrial role. Semiconductor factory workers are the most vulnerable to reproductive toxicity. A 1996 American retrospective cohort study reported an increased relative risk of spontaneous abortions among female workers in semiconductor manufacturing facilities.[23] Similarly, a 1997 European case-controlled study reported that women exposed to glycol ethers had increased odds of having children with congenital disabilities, especially neural tube defects and cleft lips.[24]

Epidemiological studies likewise show that shipyard workers exposed to glycol ethers have a high prevalence of oligospermia and azoospermia.[25][26] Notably, a 2020 French study demonstrated the widespread detection of glycol ether metabolites in 6-year-old children undergoing neurodevelopmental evaluation[27]

The United States Poison Control Centers reported 6,411 ethylene glycol exposures in 2018, with most cases being unintentional (78%). Among these exposures, 469 occurred in children aged 5 years or younger.[88]

Pathophysiology

EGEs are metabolized by the liver enzyme alcohol dehydrogenase into toxic alkoxyacetic acids. These organic acids are primarily responsible for EGEs' renal, neurologic, and reproductive side effects.[11][12]. The most frequently studied EGE compounds include 2-methoxyethanol, 2-ethoxyethanol, 2-butoxyethanol, 2-propoxyethanol, 2-isopropoxyethanol, and 2-phenoxyethanol. 

Neurological Injury

Acute encephalopathy characterized by confusion, agitation, and depressed mental status has been described in serious EGE poisonings.[28][29][30]. The onset of personality changes, memory loss, headaches, dizziness, ataxia, tremors, and lethargy characterizes chronic toxicity by occupational exposure to high EGE levels.[31] Animal models demonstrate EGEs' capacity to cross the blood-brain barrier. In vivo studies show that administering EGE mixtures to rats' frontal cortex and hippocampus leads to reduced antioxidant capacity, heightened lipid peroxidation, and elevated caspase-3 activity, indicating oxidative stress as the mechanism of EGE toxicity.

Renal Damage

Acute kidney injury and proteinuria have been reported following acute EGE ingestion.[32] Alkoxyacetic acid-induced renal tubular degeneration and necrosis have been found in both animal models and autopsies after fatal EGE poisoning.[33][34]

Hepatic Effects

Glycol ethers are predominantly metabolized in the liver. Hepatic injury arises from various mechanisms. The first is through mitochondrial disruption by EGE metabolism-derived reactive oxygen species, impairing cellular metabolism. The second is primarily mediated by hemolysis and iron deposition in the liver. Iron deposition activates Kupffer cells through the Fenton/Haber-Weiss reactions, releasing more reactive oxygen species and inducing TNF-α production.[35] 

Studies also show that diethylene glycol monomethyl ether (DiEGME) and ethylene glycol monomethyl (EGME) increase microsomal protein concentrations and induce hepatic enzymes. Specifically, DiEGME increases cytochrome P-450 but not cytochrome b5 or NADPH-cytochrome c reductase.[36] EGME, on the other hand, has the opposite effect. The reason for the specificity of certain EGEs toward particular hepatic enzymes remains unclear, as does the correlation between the hepatotoxic effects of glycol ethers and the concentration of glycolic acid. These biochemical changes may manifest as hepatic steatosis and aminotransferase derangements due to toxic metabolite accumulation in the liver. Some studies conclude that patients with underlying liver disease would have less functional alcohol dehydrogenase to produce toxic metabolites, creating a less severe clinical presentation.[37]

Reproductive Toxicity

Certain EGEs are associated with reproductive toxicity and neurodevelopmental disorders.[38][39] Numerous animal studies demonstrate testicular weight changes, edema, and tubular atrophy. Routine EGE exposure has been shown to reduce sperm maturation steps.

Daily 2-methoxyethanol administration to pregnant mice delays neurogenesis and morphogenesis, specifically neural tube closure and limb and digit formation.[40] Researchers have determined that glycol ether metabolism to acetic acid is the primary driver of teratogenicity. The compound 2-methoxyacetic acid gets incorporated into the metabolic pathways during embryogenesis. Coenzyme A converts 2-methoxyacetic acid to a thioester, similar to acetic acid's transformation into the Krebs cycle intermediate acetyl CoA.

Researchers found that carbon-labeled CO2 was excreted in embryonic cultures exposed to carbon-labeled 2-methoxyacetic acid. However, competitive inhibitors such as acetate and serine could inhibit 2-methoxyacetic acid incorporation into the metabolic pathways. Serine was likewise found to counteract the decline in sperm production and micromorphological changes caused by toxicity related to 2-methoxyethanol.

Hematologic Manifestations

Butoxyethanol has been specifically identified as potentially toxic to the bone marrow. Studies show that animal exposure leads to hemolysis, hemoglobinuria, leukopenia, and decreased bone marrow cellularity. Further investigation reveals that β-aminolevulinic acid production is a critical factor in hemolysis induction.[41][42]

In vitro animal studies likewise demonstrate EGEs' time- and concentration-dependent hemolytic effect, preceded by a decrease in adenosine triphosphate levels and erythrocyte swelling. The underlying mechanisms behind this phenomenon remain poorly understood, but the erythrocyte membrane appears to be the damage site. Another possibility is that reactive oxygen species generated by the parent glycol ethers cause lipid peroxidation.

Lymphatic Damage

Early animal studies investigated male rat immune reactions after a 4-day EGME dermal exposure at doses of 150 to 1200 mg/kg/day. Thymus and spleen weights were found to decline across all amounts at higher doses. Additionally, lymphoproliferative responses were enhanced at 1200 mg/kg/day. However, 4 days of oral EGME administration impaired antibody response at 300 and 600 mg/kg/day. This immunosuppressive response was blocked with the administration of fomepizole, suggesting that 2-methoxyacetic acid is primarily responsible for mediating the process.[43] A follow-up study showed that different rodent species exhibit sensitivity differences toward EGE.[44] Research on the lymphogenic response to glycol ethers is limited and requires further investigation to elucidate its effects fully.

Dermatologic Injury

Glycol ethers are easily absorbed through the skin. Molecular weight is a significant determinant of these compounds' absorption rates. Smaller glycol ethers more easily penetrate the skin than larger molecules, with a lag time of 1.5 to 2 hours observed in human experiments.[45] 

Other compounds can impact glycol ethers' dermal absorption. A study showed that an aqueous mixture of butoxyethanol was absorbed 6 times more efficiently than a pure glycol ether solvent, with the apparent permeability coefficient increasing as the glycol ether concentration in water decreased.[46] This absorption mechanism is thought to arise from glycol ethers' ability to induce stratum corneum lipid bilayer changes. Glycol ethers undergo cellular metabolism by cytosolic aldehyde dehydrogenase and alcohol dehydrogenase after absorption. These enzymes' concentrations vary in different body sites. Additional research is required to understand the dermatological toxicity of glycol ethers.

Toxicokinetics

Glycol ethers enter the body by ingestion, inhalation, or dermal exposure.[47][48][49] Ingestion is the most toxic route, while inhalation is the least harmful. Glycol ethers are swiftly absorbed following ingestion and have a large distribution volume. Glycol ethers are metabolized via alcohol dehydrogenase, producing toxic metabolites. 

Similarly, glycol ethers are eliminated through urinary excretion, contrasting with methanol, which undergoes hepatic elimination.[50][51] Human studies indicate that EGME inhalation results in the excretion of unchanged alkoxyacetic acid in urine shortly after exposure. Animal research suggests that elimination occurs via the organic acid transport mechanism. The half-life of glycol ethers typically ranges from 1 to 24 hours, and variations occur between glycol ethers and their respective organic acids. For instance, ethylene glycol monobutyl ether has a half-life of approximately 1 hour, while its resulting organic acid, butoxyacetic acid, has a half-life of about 4 hours.[52][53]

History and Physical

History 

Patients may present to the emergency room reporting accidental or nonaccidental exposure to a glycol ether-containing product. For example, some may disclose having ingested brake fluid or antifreeze. Symptoms vary in severity. Many exposures do not lead to significant illness, leaving most patients asymptomatic. Fatal cases are rare and typically result from significant ingestion. However, chronically exposed individuals may consult in the outpatient setting for insidiously developing symptoms or an incidental abnormal laboratory finding.

Acute glycol ether toxicity may present with gastrointestinal and acute kidney injury symptoms, such as nausea, emesis, decreased urine output, shortness of breath, and abdominal pain. Seizures, headaches, altered sensorium, agitation, weakness, chest pain, and upper gastrointestinal bleeding may also be reported. A history of ingesting large amounts of glycol ether is often elicited.[89] Acute hemolysis may also arise, manifesting as weakness, pallor, or syncope.

Patients initially with oliguria due to kidney damage and dehydration may later develop osmotic diuresis. This paradoxical manifestation may arise due to the accumulation of osmotically active substances in the renal tubules. Consequently, water reabsorption is inhibited and urine output increases despite ongoing renal injury.

A detailed past medical and social history is essential in elucidating glycol ether toxicity. Patients with acute exposures may have recent emotional trauma or belong to a home with safety deficiencies. Inquiring about using commonplace household items such as surface cleaner, all-purpose cleaner, window cleaner, paint, laundry detergents, and cosmetics is also essential. Remember that glycol ether poisoning may resemble toxicity from alcohols such as methanol and exacerbated medical conditions such as diabetic ketoacidosis. Obtaining a psychiatric history is also important because reports of intentional ingestion exist with suicide attempts. Patients with severe presentations may not provide history, highlighting the importance of collateral information from emergency medical services.

Occupational history is crucial in patients with chronic toxicity. Workers in various industries, such as electronics, printing, paint and coating, textiles, adhesives, cleaning, and personal care products may have been inadvertently exposed.[53][54] Additionally, workers in industries that use glycol ether solvents or as product components, such as laboratory technicians, janitorials, and construction workers, may also be at risk.[55][56] 

Physical Examination

The physical examination of a patient who has ingested glycol ethers can vary based on several factors, including the amount consumed, the time since ingestion, and individual patient characteristics. As a result, examination findings can be classified into 3 categories based on disease onset and duration: acute, subacute, or chronic. Some features of these conditions may overlap.

Findings consistent with acute toxicity 

Patients who ingested a large amount may be visibly agitated, confused, or unconscious, with symptoms developing within hours.[57] Metabolic acidosis from acute kidney injury may manifest as tachypnea or hyperventilation.[58] Heart blocks, refractory shock, and various metabolic derangements have been reported in some individuals.[59] Patients may have signs of severe dehydration from vomiting, such as dry oral mucosa, sunken eyeballs, tachycardia, and poor capillary refill.

Findings consistent with subacute toxicity

Neurological signs predominate after 5 to 10 days, including progressive lethargy, bilateral facial paralysis, dysphonia, and nonreactive pupils. Peripheral neuropathies impact specific nerve groups, including the 3rd, 5th, 6th, and 9th through 12th cranial nerves. Focal central nervous system involvement has been described bilaterally in the left partial lobe and occipital and cerebellar regions.[61] Localized skin erythema, dryness, and, in some cases, allergic reactions are possible, depending on the duration and frequency of exposure.[62]

Findings consistent with chronic toxicity

Chronic toxicity, occurring at least 2 weeks after initial exposure, may present with central and peripheral nervous system impairment and can progress to coma. Impaired respiratory function is possible, although the spectrum of long-term neurological injury is variable. Repetitive chronic exposure can also cause weakness, drowsiness, anisocoria (irregular pupils), and hypersomnolence. The resulting pancytopenia can present as a myriad of symptoms related to anemia and immunodeficiency. However, little research exists regarding the long-term sequelae of bone marrow suppression from glycol ether toxicity. Patients may also report a longstanding history of infertility, decreased testicular size, spontaneous abortions, and congenital malformations in the offspring.

Evaluation

Laboratory Tests

Basic laboratory tests, such as a complete metabolic panel and blood count, are recommended to assess for various electrolyte derangements and anemia. Hypocalcemia may be noted in the case of ethylene glycol toxicity. Elevated blood urea nitrogen (BUN), potassium, and creatinine are consistent with renal failure.

Respiratory distress signs like tachypnea warrant an arterial blood gas (ABG) analysis. This test provides information about acid-base balance, oxygenation status, and respiratory function. In cases of glycol ether toxicity, ABG can help assess the severity of metabolic acidosis and respiratory compensation. ABG results can guide treatment decisions, such as the need for respiratory support acid-base imbalance correction.

Metabolic acidosis in the setting of lactic acidosis is often accompanied by a high anion gap, calculated according to the following equation:

Anion Gap = ([Sodium concentration] + [Potassium concentration]) - ([Chloride concentration] + [Bicarbonate concentration])

In glycol ether toxicity cases, an elevated anion gap may be observed due to the accumulation of toxic metabolites, such as glycolic acid or oxalic acid, which are not routinely measured in standard laboratory tests but contribute to the blood's overall anion load.

The osmolality gap is the difference between the measured and calculated serum osmolality. This parameter provides an estimate of unmeasured osmotically active substances in the blood. The calculated serum osmolality is based on the concentrations of sodium, glucose, and BUN. An elevated osmolality gap may indicate the presence of substances not typically measured in standard laboratory tests, such as glycol ethers or their metabolites. Osmotic diuresis is likely accompanied by a high osmolality gap and a low anion gap.[54]

However, recognizing the limitations of utilizing the osmolality gap is important when evaluating glycol ether poisoning. Clinicians should be vigilant of overtly elevated osmolality gaps (ie, >30 mOsl/L) in the presence of altered mental status or other signs suggesting toxic ingestion.

Patients who present early may have a normal anion gap and elevated osmolality gap, as the parent compound has not transformed into its respective organic acid. On the other hand, patients who present late have had time to metabolize the glycol ether, which may produce a high anion gap. Metabolic conversion of the parent compound lowers its quantity, as seen in late-presenting patients. A normal osmolarity gap may be observed in such individuals. 

Lactate levels are measured to assess tissue perfusion and determine lactate's contribution to metabolic acidosis. Elevated lactate levels may indicate tissue hypoperfusion and severe toxicity.

Coingestions of other toxic substances may occur with glycol ether exposure. Screening for common coingestants such as acetaminophen, ethanol, methanol, and salicylates helps identify additional toxicities that may require specific interventions or treatments.

Urinalysis is performed to assess renal function and detect any abnormalities such as hematuria, proteinuria, or crystalluria that may indicate kidney injury or dysfunction secondary to glycol ether toxicity. Urinalysis findings can also help monitor the progression of renal impairment and guide treatment decisions.

Time-consuming metabolite testing of organic acids is of little utility, especially in the acute setting. Many hospitals do not routinely test for metabolites.[55][56]

Electrocardiography

Electrocardiography is also essential for detecting conduction abnormalities, which can be a byproduct of various electrolyte derangements and acidosis. ECG findings should be interpreted in conjunction with the patient's clinical presentation, laboratory results, and overall clinical context to guide diagnosis and management.

Imaging 

A computed tomography (CT) scan of the head may help rule out other causes of altered mental status. However, this modality may be of low value in assessing neurological damage due to the systemic nature of the primary etiology. Meanwhile, the utility of obtaining magnetic resonance imaging (MRI) is unclear, as evidence of neurologic injury may not be evident in this study.

A case series by Yahi et al reported that initial head CT scans in patients with glycol ether toxicity were without abnormality. Two patients initially had unrevealing MRIs, but a third demonstrated edema and herniation. These initial MRI findings may hold a poor prognosis. Other reports showed regular MRIs in patients with fatal outcomes. Yahi et al also mention brain atrophy in 2 of their surviving cases but with typical MRIs, questioning the true etiology of these findings. Brain imaging to evaluate glycol ether toxicity requires further investigation.

Chest imaging may also be considered to evaluate for pneumonitis from exposure to glycol ether vapor or aspiration in the setting of altered mental status. An abdominal ultrasound may help identify changes in size, texture, and even necrosis in the kidney and liver.

Electroencephalogram and Electromyography

Nerve conduction studies may also be beneficial in evaluating neuropathy. A case study reported that most patients with glycol ether exposure and elevated CSF protein, without pleocytosis, developed a neurological injury. An electroencephalogram may be helpful in patients with repeated seizures, although limited reports of this initial presentation exist.[57]

Treatment / Management

The initial treatment for glycol ether toxicity involves addressing the patient's airway, breathing, circulation, disability, and exposure. After the primary survey, additional therapies depend on the presentation's severity, often determined by which glycol ether was ingested, the route, and the time elapsed since ingestion. Glycol ether exerts toxicity primarily through its alkoxyacetic acid metabolite produced by alcohol dehydrogenase. Treatment aims to inhibit the production of the toxic metabolite and subsequent removal of the parent compound.[58] Fomepizole, an alcohol dehydrogenase inhibitor, is administered, and the parent compound is urgently eliminated via extracorporeal enhanced elimination by hemodialysis.[59] (B3)

Fomepizole monotherapy may be considered if the toxic compound has a short elimination half-life (ie, less than the half-life of fomepizole) in a patient with normal renal function. More importantly, these treatment strategies would benefit most during the early toxicity stages. As such, early suspicion of glycol ether toxicity is paramount. Note that fomepizole carries a half-life of about 12 hours and is therefore started at 15 mg/kg every 12 hours.[60][61] Additional adjustments may be required per hemodialysis and other patient-specific factors, such as a history of chronic kidney disease. The dialysability of a toxin primarily depends on its free plasma concentration, size, weight, and volume of distribution.[62] Small, unbound toxins with a low distribution volume are readily removed by dialysis.[63][64] Therefore, patients with toxicity to glycol ether exposure would benefit from hemodialysis. (A1)

Propylene glycol, a secondary alcohol, is structurally similar to glycol ethers but is generally less toxic. Both alcohols are metabolized by alcohol dehydrogenase and produce toxic metabolites. However, alcohol dehydrogenase does not readily metabolize propylene glycol because this glycol's hydroxyl group is bound to a secondary carbon. Nonetheless, propylene glycol toxicity management follows the same principle for glycol ether toxicity: inhibition of alcohol dehydrogenase with fomepizole and toxic alcohol removal with hemodialysis.[65][66] 

Electrolyte management may also be beneficial, particularly in hyperkalemia and severe metabolic acidosis. Intubation and mechanical ventilation may become necessary if the patient has severe respiratory distress or no longer protecting their airway due to a depressed sensorium. Blood transfusions may also be needed if hemolysis results in severe anemia. 

The use of gastric decontamination has not been closely studied. Some authors suggest gastric lavage or nasogastric decontamination, but the benefits of these interventions within the first 1 to 2 hours of ingestion have not been studied. Obtaining an accurate history is another limitation of using gastric lavage. Moreover, as neurotoxicity is a common finding, gastric decontamination may increase the risk of pulmonary aspiration.

Activated charcoal is also not recommended, as the substance has a poor affinity for alcohol.[67] No precise dedicated study suggests using N-acetylcysteine (NAC) to treat glycol ether-induced hepatic injury. However, given that the hepatic injury is mediated by oxidative stress, NAC may provide some utility in theory.[68] Animal studies suggest that NAC prevents genetic damage in testicular germ cells induced by 2-methylacetic acid, an organic acid that also mediates the disease process in glycol ether toxicity.[68](B3)

Differential Diagnosis

The differential diagnosis of glycol ether toxicity includes ingesting similar toxic alcohols such as methanol and isopropyl alcohol. Toxic ingestions of these compounds produce metabolic acidosis similar to glycol ether toxicity. However, the lethal dose and toxicokinetics differ. Drug overdoses may also present with neurological and metabolic derangements.

Toxicity and Adverse Effect Management

Managing glycol ether toxicity depends on factors such as ingested amount, time since exposure, and coingestions. Additionally, underlying comorbid conditions, such as chronic renal failure, should be considered when evaluating treatment options. 

Prognosis

A favorable prognosis is associated with early hospitalization. Respiratory compensation offsetting metabolic acidosis also correlates with a better prognosis. Key findings associated with a poor prognosis include severe neurological damage (eg, coma), respiratory failure, profound metabolic arrangements requiring dialysis, acidosis with a pH of less than 7, and delayed hospital evaluation.[69][70] Ethylene glycol toxicity fatalities have been reported to follow acute renal failure requiring hemodialysis.[71]

Complications

Glycol ether toxicity complications primarily affect the neurologic and renal systems. Seizures and evidence of cranial palsies and structural brain changes have been documented.[72] Clinical case reports and epidemic studies, such as the Panama mass poisoning incident, indicate that patients may experience axonal sensorimotor neuropathy, peripheral neuropathy, cranial nerve neuropathies, and demyelination. Some complications may occur in the acute to subacute stages, while others may develop months after the initial presentation in patients who survive the acute poisoning. However, limited long-term longitudinal studies are available. 

Severe hypocalcemia and acidosis may result in cardiac dysrhythmias and acute renal failure, which may require dialysis. Electrolyte imbalances, pancreatitis, and acidemia are expected acute complications likely related to renal failure, encephalopathy, and peripheral neuropathies. Additionally, a few isolated case reports suggest that significant acute glycol ether ingestion can cause pulmonary edema.[73] However, further research is needed to determine whether the glycol ether or the overall critical presentation causes the respiratory insult.

In patients who survive glycol ether toxicity, the long-term complications can vary widely. For example, mild kidney injury may resolve, but those who require hemodialysis generally remain dialysis-dependent.[74][75][76] Patients may also experience neurological complications, such as neurocognitive changes or quadriplegia, due to oxidative stress and demyelinating injury. A higher risk of developing neurological sequelae has been observed in renal failure patients. The variability of these complications is likely related to the patient's initial presentation.

Oxidative stress caused by glycol ether metabolites can damage the liver, although the long-term hepatic effects have not been studied. Evidence is insufficient to support that glycol toxicity increases malignancy risk. Studies on glycol ether exposure and the risk of developing acute myeloid leukemia do not show statistically significant results. Furthermore, no concrete evidence proves that glycol ether toxicity causes genotoxic changes.[77] Some research indicates that in-utero exposure to glycol ether may reduce telomere length and increase chromatid exchange, but further research is needed to investigate genotoxicity.[78]