Toluene Toxicity

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Practice Essentials

Toluene (methylbenzene, toluol, phenylmethane) is an aromatic hydrocarbon (C7 H8) commonly used as an industrial solvent for the manufacturing of paints, chemicals, pharmaceuticals, and rubber. It is identified as CAS#108-88-3, and the United Nations Department of Transportation's number for toluene is UN#1294.

Toluene is found in gasoline, acrylic paints, varnishes, lacquers, paint thinners, adhesives, glues, rubber cement, airplane glue, and shoe polish; and (along with methanol) in carburator cleaner. At room temperature, toluene is a colorless, sweet smelling, and volatile liquid.

Toxicity can occur from unintentional or deliberate inhalation of fumes, ingestion, or transdermal absorption. Toluene abuse or "glue sniffing" is widespread, especially among children or adolescents, because it is readily available and inexpensive. Toluene is commonly abused by saturating or soaking a sock or rag with toluene-contianing product, placing it over the nose and mouth, and inhaling to get a sensation of euphoria, buzz, or high. Slang names for inhalation include huffing (ie, soaking a sock or rag) and bagging (ie, spraying paint into a plastic bag and inhaling). With bagging, exhaled air is rebreathed and resulting hypoxia and hypercarbia may add to the disorienting effects of the solvent.

The Occupational Safety and Health Administration (OSHA) has determined the acceptable level of occupational exposure to toluene for people in the workplace. The Permissible Exposure Limit (PEL) of 200 ppm is considered an acceptable level of exposure as a time-weighted average for an 8-hour workday.[1]  Toluene levels of 500 ppm are considered immediately dangerous to life and health.

Due to genetic polymorphisms, some people may be more sensitive to the effects of inhaled solvents than others.[2] Occupational asthma has occurred in some workers exposed to toluene levels considered safe in the workplace. For such people, protective equipment should be used and provided by employers, even when toluene levels are in the acceptable range.

Workers with a history of asthma induced by solvent exposure should also be warned about and protected from short-term exposure to higher concentrations. The duration of the exposure, not just the level, may also contribute to asthma exacerbations, and should be monitored.

Pathophysiology

Toluene is highly lipophilic, so it readily crosses the blood-brain barrier, which accounts for its primary effects on the central nervous system (CNS). In the brain, toluene selectively affects both voltage-gated and ligand-gated ion channels. For example, toluene significantly inhibits the N-methyl-D-aspartic acid (NMDA) subtype of glutamate-activated ion channels.[3]

In rat studies, acute and repeated toluene exposure markedly reduces metabolic function in the brain, especially the hippocampus, pons and thalamus. Toluene also increases dopamine release and the activity of dopaminergic neurons. Specifically, toluene alters the firing rates of dopamine neurons in the ventral tegmental area (VTA), which project to limbic and cortical structures and are critical elements of the brain’s reward circuitry.

Toluene also produces regional brain changes in glutamate, glutamine and monoamine levels and changes NMDA and gamma-aminobenzoic acid–A (GABAA) receptor densities or subunit composition. Repeated exposure can lead to white matter damage (solvent vapor/toluene leukoencephalopathy), which may involve axonal damage rather than demyelination.[3]

Central nervous system

Acute intoxication from inhalation is characterized by rapid onset of CNS symptoms including euphoria, hallucinations, delusions, tinnitus, dizziness, confusion, headache, vertigo, seizures, ataxia, stupor, and coma.

Chronic CNS sequelae, termed chronic solvent-induced encephalopathy (CSE), include neuropsychosis and cerebral and cerebellar degeneration with the following[3] : 

Cardiopulmonary

Toluene has direct negative effects on cardiac automaticity and conduction and can sensitize the myocardium to circulating catecholamines. "Sudden sniffing death" secondary to cardiac dysrhythmias has been reported. Pulmonary effects include bronchospasm, asphyxia, acute lung injury (ALI), and aspiration pneumonitis.

Gastrointestinal

GI symptoms from inhalation and ingestion may result in abdominal pain, nausea, vomiting, and hematemesis. Hepatotoxicity manifests with ascites, jaundice, hepatomegaly, and liver failure. A rare form of hepatitis—hepatic reticuloendothelial failure (HREF)—has been reported with toluene exposure.[4] With the widespread abuse of volatile substances in young adults today, hepatitis secondary to toluene toxicity, not just infectious causes, should be considered in the differential diagnosis in the younger patient population who present with concerning findings.

Renal and metabolic

Reported renal toxicity from toluene exposure includes the following:

Hematologic

Hematologic consequences of exposure may include lymphocytosis, macrocytosis, eosinophilia, hypochromia, and basophilic stippling, and in severe cases, aplastic anemia.

Dermatologic

Cutaneous contact with skin may range in severity from dermatitis to extensive chemical burns with coagulation necrosis.

Musculoskeletal

Toluene can affect skeletal muscles directly, resulting in rhabdomyolysis and myoglobinemia. Profound hypokalemia, possibly due to RTA, can produce severe muscle weakness mimicking Guillain-Barré syndrome. In animal studies, chronic inhalational exposure to toluene was found to affect bone metabolism, contributing to bone resorption and inhibition of bone formation.[6]

Fetal effects

A Scandinavian registry-based case control study found a modest association between maternal exposure to toluene and testicular germ cell tumors in their offspring. In women with occupational exposure to toluene in the year of or the year before giving birth to a boy, the odds ratio for the child developing a testicular germ cell tumor was 1.67 (95% confidence index, 1.02-2.73).[7]  

Etiology

Inhalation of airborne toluene is the most common cause of exposure. Exposure can occur in several occupations, including paint workers, dye makers, and workers in the chemical and petrochemical industry.

Toluene toxicity can occur from the following:

Toluene is found in the following:

Epidemiology

United States

Solvents including glue are easily accessible and inexpensive, making them a frequently abused substance. Glue sniffing is most frequently observed in adolescents and young adults in lower economic groups. According to the National Survey on Drug Use and Health in 2014, approximately 546,000 people were current inhalant users, representing 0.02 percent of the population. This percentage of the population of current users of inhalants aged 12 or older was similar to the percentages for most years dating back to 2002.[8] Almost 21.7 million people older than 12 years reported trying an inhalant at least once. An estimated 3-4% of American teenagers engage in sniffing on a regular basis, and 7-12% of high school students have tried sniffing at least once.

Chronic nonintentional exposure also occurs among people in the painting, gasoline, chemical, and rubber industries. The 2017 annual report of the American Association of Poison Control Centers' National Poison Data Systems records only 525 single case exposures to toluene/xylene (excluding adhesives), with three major outcomes and one death. In addition, there were 236 single case exposures to  toluene/xylene adhesives with no major outcomes or deaths.[9]  These reports likely severely underestimate the abuse of this agent.

International

Solvent abuse is a popular practice around the world. In the United Kingdom, 3.5-10% of children younger than 13 years have abused volatile substances, and 0.5-1% are long-term users.[8] In Brazil, 6.1% of the population older than 12 years report trying an inhalant at least once.[9] In low-income families in Sao Paulo, Brazil, 24% of children had inhaled a volatile substance at some time and 4.9% had inhaled within the last month.

In Singapore, toluene glue sniffing has reached epidemic proportions.[10] In 1980, 24 cases of solvent abuse were reported. By 1984, this number had increased to 763. From 1987-1991, 1781 glue sniffers were identified.

In 2005, it was reported that street children in India were abusing typewriter eraser fluid, which contains toluene; the patients cited easy access, affordability, and a regular "high" as reasons for usage.[11]

In Australia, 22% of 12-year-olds reported lifetime use of inhalants, decreasing to 15% by age 15 and 11% by age 17.[12]

Mortality/Morbidity

“Sudden sniffing death” is the most serious risk from inhalation of toluene or other volatile substances. Four direct modes of toxicity leading to death from toluene and other inhaled substances are anoxia, respiratory depression, vagal stimulation, and, most importantly, cardiac dysrhythmias. Trauma, aspiration, and asphyxia from plastic bag use are contributing factors to mortality from solvent abuse.

Volatile substance abuse sensitizes the myocardium to circulating catecholamines. Sudden alarm, exercise, sexual activity, or any kind of startling (eg, parents, police) may induce dysrhythmias. In many cases of death associated with solvent abuse, fright and running were the immediate antemortem events.

Prolonged exposure to toluene by inhalation is associated with CNS, heart, liver, kidney, and lung toxicity. Other sequelae include muscle weakness, nasal ulcerations, recurrent epistaxis, chronic rhinitis, neuropsychiatric abnormalities, GI symptoms, and peripheral neuropathies (see Pathophysiology).

In the 1960s, a total of 110 cases of sudden death from solvent abuse were reported in the United States. In a review of death records in Virginia from 1987-1996, 39 deaths related to solvent abuse were identified. Males accounted for 95% of cases with the majority (70%) of deaths occurring at age 22 or younger.[13] One death was reported to be an occupational exposure. In Texas, a 10-year review of death certificates identified 144 people in whom inhalants were a contributing factor. The majority were male (92%), white (81%), with a mean age of 25.6 years.[14]

In 1988, in the United Kingdom, 133 deaths were reported in people aged 11-76 years and from varying social backgrounds; 72% of these deaths occurred in adolescents, and 90% of deaths occurred in males.[8]

In Singapore, from 1983-1991, 33 people were found to have toluene in their blood postmortem; 22 were known glue sniffers; 11 were suspected of solvent abuse; 6.1% of deaths were from acute toluene poisoning; and 87.9% were associated with falling, drowning, or jumping, which suggests a correlation between the intoxicating effect of toluene and the high incidence of traumatic death of its users.[10]

From 1983-1991, four deaths attributed to occupational exposures were reported in Singapore.[10] In a 20-year retrospective review of autopsy cases in Australia, 0.2% were attributed to inhalant use, with the majority (92%) being male.[15]

Race-, Sex-, and Age-related Demographics

No scientific data indicate that outcomes of toluene exposure are based on race.

Although typically thought of as an activity of young males (most deaths occur in young males), epidemiologic studies more than 20 years ago showed more than 50% of chronic solvent abusers were females in their prime childbearing years.[14] A 2006 study in Florida high school students showed higher rates of lifetime and current use in girls than in boys.

Toluene inhalation is found in people of all ages. Most acute cases of toluene toxicity occur in young males aged 11-19 years who participate in glue sniffing as a group activity, but cases have been reported in people in their 50s and 60s.

Prognosis

Patients with toluene toxicity have a good prognosis if they receive appropriate counseling and follow-up and are compliant with recommendations. The prognosis is poor in patients who continue to abuse toluene. Neurological sequelae of chronic toluene abuse may be permanent. Prolonged exposure to toluene by inhalation is associated with CNS, heart, liver, kidney, and lung toxicity. Other sequelae include muscle weakness, nasal ulcerations, recurrent epistaxis, chronic rhinitis, neuropsychiatric abnormalities, GI symptoms, and peripheral neuropathies (see Pathophysiology).

Complications of toluene toxicity are listed below:

Sudden death is the most serious risk from inhalation of toluene or other volatile substances. Four direct modes of toxicity leading to death from toluene and other inhaled substances are anoxia, respiratory depression, vagal stimulation, and, most importantly, cardiac dysrhythmias. Trauma, aspiration, and asphyxia from plastic bag use are contributing factors to mortality from solvent abuse.

Volatile substance abuse sensitizes the myocardium to circulating catecholamines. Sudden alarm, exercise, sexual activity, or any kind of startling (eg, parents, police) may induce dysrhythmias. In many cases of death associated with solvent abuse, fright and running were the immediate antemortem events.

In the 1960s, a total of 110 cases of sudden death from solvent abuse were reported in the United States. In a review of death records in Virginia from 1987-1996, 39 deaths related to solvent abuse were identified. Males accounted for 95% of cases with the majority (70%) of deaths occurring at age 22 or younger.[16]  One death was reported to be an occupational exposure. In Texas, a 10-year review of death certificates identified 144 people in whom inhalants were a contributing factor. The majority were male (92%), white (81%), with a mean age of 25.6 years.[15]

In 1988, in the United Kingdom, 133 deaths were reported in people aged 11-76 years and from varying social backgrounds; 72% of these deaths occurred in adolescents, and 90% of deaths occurred in males.[10]

In Singapore, from 1983-1991, 33 people were found to have toluene in their blood postmortem; 22 were known glue sniffers; 11 were suspected of solvent abuse; 6.1% of deaths were from acute toluene poisoning; and 87.9% were associated with falling, drowning, or jumping, which suggests a correlation between the intoxicating effect of toluene and the high incidence of traumatic death of its users.[12]

From 1983-1991, four deaths attributed to occupational exposures were reported in Singapore.[12]  In a 20-year retrospective review of autopsy cases in Australia, 0.2% were attributed to inhalant use, with the majority (92%) being male.[17]

Patient Education

Patient education includes the following:

History

Identifying toluene exposure or risk of exposure admission is important, as well as the route of exposure, whether inhalation, ingestion, or transdermal absorption. Any history of "huffing" or "bagging" before presentation, or a history of previous abuse of inhalants, should be elicited.

An occupational history should be taken, to identify workers whose occupation may result in nonintentional acute or chronic exposure. Examples of workers who may be at risk include the following:

Hobbies or activities that lead to nonintentional or intentional exposure should be reviewed. Model airplane glues and rubber cements are sources of toluene. Varnishes may affect people refinishing wooden furniture.

Toxicities and risks vary with the route of exposure, as follows:

The history should also identify other drugs that may be in the patient's system, including alcohol, cocaine or other stimulants. Alcohol intoxication and toluene intoxication have a similar presentations. Alcohol inhibits the metabolism of toluene and raises the concentration of toluene in the blood twofold. Cocaine, or any sympathomimetic use, may increase risks of fatal dysrhythmias.

Physical Examination

Physical examination is an important aid in confirming a suspected diagnosis of toluene poisoning. Patients with acute toluene poisoning may present with a range of pulmonary and central nervous system (CNS) symptoms, depending on duration of exposure, route of exposure, and level of toluene in the air or liquid.

Patients with chronic exposure may present with wide variety of complaints.

General /vital sign manifestations include the following:

Head, eyes, ears, nose, and throat (HEENT) manifestations include the following:

Neurologic manifestations are as follows:

Cerebellar signs include the following:

Pulmonary manifestations include the following:

Gastrointestinal manifestations include the following:

Dermatologic manifestations include the following:

Musculoskeletal manifestations include the following:

Laboratory Studies

Indicated laboratory tests and findings in toluene toxicity include the following:

Serum toluene concentrations are available only through specialized laboratories and are not available quickly enough to guide therapy.[18] Blood toluene concentrations of 2.5 mg/L correlate with toxicity. Concentrations of 50 mg/L are probably fatal.

Perform toxicological screens to test for alcohol and cocaine, because alcohol can cause mental status changes similar to those from toluene and can increase serum toluene levels and decrease its metabolism, while cocaine may precipitate cardiac dysrhythmias

Imaging Studies

A chest radiograph may show aspiration pneumonitis or acute lung injury.

In patients with chronic exposure to toluene, a CT scan of the head may show cerebral cortex and cerebellar atrophy with brainstem atrophy in severe cases.

In patients with chronic exposure, an MRI may reveal cerebral cortex, cerebellar, and brainstem atrophy with sulcal widening and ventricular dilation. Increased periventricular white matter and loss of differentiation of gray and white matter may also be observed.

Technetium Tc 99m radionucleotide scan of the liver may show a rare form of hepatotoxicity secondary to toluene exposure. In hepatic reticuloendothelial failure (HREF), a decreased uptake of the radionucleotide suggesting impaired liver function occurs.[4]

Electrocardiography

The ECG is an essential test because toluene-induced dysrhythmias, including torsades de points and ventricular fibrillation, often are responsible for the sudden death associated with poisoning. Most ECG show nonspecific changes to the ST segment and depressed T waves, but patients with QT prolongation are at particular risk for dysrhythmia.[19]

Cardiac monitoring of patients should be continuous during observation so that any dysrhythmias may be detected promptly.

Prehospital Care

Administer supportive care, including supplemental oxygen, as soon as possible at the scene. If a patient is not breathing, administer ventilatory support with a bag valve mask. Avoid mouth-to-mouth breathing because 20% of toluene is expired unchanged, and the rescuer may be overcome by direct inhalation of fumes.

Upon discovery of the patient, remove the patient's clothing because the clothes may have additional solvent on them, which is harmful to the patient and rescue workers. Examine the skin for burns so that irrigation, if needed, can begin immediately.

Remove the patient from the area of contamination because toxic fumes may overcome rescue workers.

Immediate irrigation of the skin, eyes, and mucous membranes at the scene greatly reduces skin damage (eg, coagulation necrosis from prolonged contact).

Emergency Department Care

Treatment is supportive, as follows:

Consider admitting patients with toluene exposure or abuse for observation and treatment if they have any of the following:

Patients with continuing respiratory, cardiac, and renal problems may need to be admitted to a critical care unit. Transfer patients to a facility with critical care if they require critical care monitoring and are admitted to a hospital without sufficient ICU facilities.

Patients who have no laboratory abnormalities and who demonstrate improved mental status (asymptomatic, back to baseline) may be discharged from the ED after 4-6 hours of observation, with the following instructions:

Consultations

Consult the regional poison control center or local medical toxicologist (certified through the American Board of Medical Toxicology or the American Board of Emergency Medicine) for additional information and patient care recommendations.

Pursue pulmonary consultation for patients with respiratory compromise or complications from aspiration. Consult cardiology department personnel for patients with ventricular dysrhythmias or cardiac arrest. Consult with ear, nose, and throat (ENT) and/or plastic surgery specialists if significant burns or irritation of the mucous membranes are present on the face or significant dermal burns are observed on the rest of the body. Consult neurology for patients with neurological or cognitive deficits from chronic exposure.

Prevention

Advise workers with occupational exposure not to work in poorly ventilated enclosed rooms.

Inform chronic glue sniffers of the long-term sequelae and consequences associated with abuse.

Medication Summary

No specific antidotal drug therapy for toluene poisoning exists. Toluene is not significantly adsorbed by activated charcoal.

Presently, inhaled beta-agonists and steroid therapy should be considered first-line agents for patients presenting with asthma and respiratory symptoms.

Esmolol

Clinical Context:  Ultra–short-acting agent that selectively blocks beta1-receptors with little or no effect on beta2-receptor types. Particularly useful in patients with elevated arterial pressure, especially if surgery is planned. Shown to reduce episodes of chest pain and clinical cardiac events compared to placebo. Can be discontinued abruptly if necessary. Useful in patients at risk for experiencing complications from beta-blockade; particularly those with reactive airway disease, mild-moderate LV dysfunction, and/or peripheral vascular disease. Short half-life of 8 min allows for titration to desired effect and quick discontinuation if needed.

Propranolol

Clinical Context:  Class II antiarrhythmic, nonselective beta-adrenergic receptor antagonist with membrane-stabilizing activity that decreases automaticity of contractions.

Effective for treating aggression resulting from head injury. They also are used for reducing restlessness and disinhibition. Treatment for persistent agitation and aggression in organic brain syndromes.

Class Summary

These agents may be used to convert an inhalant-induced dysrhythmia.

Sodium bicarbonate (Neut)

Clinical Context:  Neutralizes hydrogen ion concentrations and raises blood and urinary pH. Indicated in patients with renal tubular acidosis due to toluene. In patients with severe non–anion gap acidosis, an iInfusion can be prepared with 3 ampules (133.8 mEq or 150 mEq, depending on whether 7.5% or 8.4% ampules are used) of sodium bicarbonate in 1 L of D5W.

Class Summary

These agents may be used to raise blood and urinary pH.

Author

Nathanael J McKeown, DO, Assistant Professor, Department of Emergency Medicine, Oregon Health and Science University School of Medicine; Medical Toxicologist, Oregon Poison Center; Attending Physician, Emergency Medicine, Portland Veteran Affairs Medical Center

Disclosure: Nothing to disclose.

Specialty Editors

John T VanDeVoort, PharmD, Regional Director of Pharmacy, Sacred Heart and St Joseph's Hospitals

Disclosure: Nothing to disclose.

Fred Harchelroad, MD, FACMT, FAAEM, FACEP, Attending Physician in Emergency Medicine and Medical Toxicology, Excela Health System

Disclosure: Nothing to disclose.

Chief Editor

Sage W Wiener, MD, Assistant Professor, Department of Emergency Medicine, State University of New York Downstate Medical Center; Director of Medical Toxicology, Department of Emergency Medicine, Kings County Hospital Center

Disclosure: Nothing to disclose.

Additional Contributors

Debra Slapper, MD, Physician, Southwest Washington Free Clinic System-Urgent Care; Former FEMA Physician and Military Contractor; Former Associate Professor, University of Miami, Leonard M Miller School of Medicine and University of South Florida Morsani College of Medicine

Disclosure: Nothing to disclose.

Acknowledgements

The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous author, Kevin A Martin, MD, to the development and writing of this article.

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