Toluene (methylbenzene, toluol, phenylmethane) is an aromatic hydrocarbon (C7H8) 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, shoe polish, and (along with methanol) carburetor 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-containing 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.
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]
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] :
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.
Reported renal toxicity from toluene exposure includes the following:
Hematologic consequences of exposure may include lymphocytosis, macrocytosis, eosinophilia, hypochromia, basophilic stippling, and, in severe cases, aplastic anemia.
Cutaneous contact with skin may range in severity from dermatitis to extensive chemical burns with coagulation necrosis.
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]
A Scandinavian registry–based case control study found a modest association between maternal exposure to toluene and testicular germ cell tumors in offspring. In women with occupational exposure to toluene in the year of or the year before giving birth to a boy, the odds ratio (OR) for the child developing a testicular germ cell tumor was 1.67.[7]
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:
Solvents including glue are easily accessible and inexpensive, making them a frequently abused substance. Glue sniffing is most often observed in adolescents and young adults in lower economic groups. According to the 2023 National Survey on Drug Use and Health, inhalants had been used to get high in the previous 12 months by 0.9% of persons aged 12 years or older (2.6 million people). A similar percentage of adolescents (aged 12-17 years) and young adults (aged 18-25 years) used inhalants during that time period, at 2.2% and 2.0%, respectively. Among adults aged 26 years or older, the percentage was lower, at 0.6%.[8]
Chronic nonintentional exposure also occurs among people in the painting, gasoline, chemical, and rubber industries.
The 2023 Annual Report of the National Poison Data System® (NPDS) from America’s Poison Centers®: 41st Annual Report recorded 177 single toluene/xylene exposures (adhesives only), only five of which were intentional. Among the total, there was one major outcome and no deaths.[9]
For toluene/xylene exposures, excluding adhesives, the NPDS report recorded 419 single exposures, including five intentional exposures. There were three major outcomes and one death.[9]
In a separate listing for toluene diisocyanate, used in the production of polyurethane foam, paints, and other compounds, the NPDS report recorded 623 single exposures, including 14 intentional exposures. There was one major outcome and no deaths.[9]
The report likely severely underestimates the abuse of toluene.
A study by Hawkins et al found that of 6672 adolescents from England and Wales, aged 13-14 years, 4.9% reported using volatile solvents at some time in their lives.[10]
“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.[11] 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%) and White (81%), with a mean age of 25.6 years.[12]
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.[13]
In Singapore, from 1983-1991, 33 people were found to have toluene in their blood postmortem; 22 were known glue sniffers, and 11 were suspected of solvent abuse. It was determined that 6.1% of deaths were from acute toluene poisoning, and 87.9% were associated with falling, drowning, or jumping, suggesting a correlation between the intoxicating effect of toluene and the high incidence of traumatic death of its users.[14]
From 1983-1991, four deaths attributed to occupational exposures were reported in Singapore.[14] In a 20-year retrospective review of autopsy cases in South Australia, 0.2% were attributed to inhalant exposure, with the majority (92%) being male.[15]
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.[16] 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.
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. Neurologic 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:
The aforementioned study by Hawkins and colleagues found that among adolescents aged 13-14 years in England and Wales, it was significantly more likely that those who used volatile solvents would report a probable depressive, anxiety, or conduct disorder (ORs = 4.59, 3.47, and 7.52, respectively), as well as auditory hallucinations (OR = 5.35).[10]
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.
Patient education includes the following:
Identifying toluene exposure or risk of exposure is important, as well as the route of exposure (whether by 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 two-fold. Cocaine, or any sympathomimetic use, may increase risks of fatal dysrhythmias.
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 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 a 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:
GI manifestations include the following:
Dermatologic manifestations include the following:
Musculoskeletal manifestations include the following:
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.[17] Blood toluene concentrations of 2.5 mg/L correlate with toxicity. Concentrations of 50 mg/L are probably fatal.
Perform toxicologic screens to test for alcohol and cocaine. Alcohol can cause mental status changes similar to those from toluene and can increase serum toluene levels and decrease its metabolism; cocaine may precipitate cardiac dysrhythmias
A chest radiograph may show aspiration pneumonitis or acute lung injury.
In patients with chronic exposure to toluene, a computed tomography (CT) scan of the head may show cerebral cortex and cerebellar atrophy, with brainstem atrophy in severe cases.
In patients with chronic exposure, a magnetic resonance imaging (MRI) scan 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-99m (99mTc) 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 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 electrocardiograms show nonspecific changes to the ST segment and depressed T waves, but patients with QT prolongation are at particular risk for dysrhythmia.[18]
Cardiac monitoring of patients should be continuous during observation so that any dysrhythmias may be detected promptly.
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).
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 intensive care unit (ICU) facilities.
Patients who have no laboratory abnormalities and who demonstrate improved mental status (asymptomatic, back to baseline) may be discharged from the emergency department (ED) after 4-6 hours of observation, with the following instructions:
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 neurologic or cognitive deficits from chronic exposure.
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.
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.
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 with 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.
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. It is also are used for reducing restlessness and disinhibition. Treatment for persistent agitation and aggression in organic brain syndromes.
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 infusion 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.