Toluene Toxicity

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 (GABA_A) 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] : 

• ​ Ataxia
• Seizures
• Choreoathetosis
• Optic and peripheral neuropathies
• Decreased cognitive ability
• Anosmia
• Optic atrophy and blindness
• Tinnitus and hearing loss

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

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:

• Distal (type I) renal tubular acidosis (RTA; a non-gap metabolic acidosis); however, this has been questioned
• Anion gap metabolic acidosis due to the hippuric acid metabolite ^[5]
• Hypokalemia
• Hypophosphatemia
• Hyperchloremia
• Azotemia
• Sterile pyuria
• Hematuria
• Proteinuria

Hematologic

Hematologic consequences of exposure may include lymphocytosis, macrocytosis, eosinophilia, hypochromia, 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 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:

• Nonintentional or deliberate inhalation of fumes
• Ingestion
• Absorption through the skin

Toluene is found in the following:

• Gasoline
• Acrylic paints
• Varnishes
• Lacquers
• Paint thinners
• Adhesives
• Glues
• Rubber cement
• Airplane glue
• Shoe polish
• Typewriter erasing fluid
• Carburetor cleaner (this product also contains methanol; consequently, methanol toxicity, in addition to toluene toxicity, can occur in patients who intentionally inhale it)

United States

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.

International

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]

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. ^[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:

• CNS complications - Neuropsychosis, cerebellar ataxia, cognitive impairment, dementia, tremors, neuropathies, blindness, and deafness
• Sudden death resulting from cardiac dysrhythmias
• Respiratory depression, hypoxia, bronchospasm, acute lunge injury, and aspiration pneumonitis
• Hepatotoxicity - Hepatic reticuloendothelial failure (HREF), ascites, jaundice, and liver failure
• Renal tubular acidosis, renal stones, hematuria, proteinuria, electrolyte disturbances, and acute kidney injury
• Abdominal pain, hematemesis, and vomiting
• Muscle pain and weakness, rhabdomyolysis, and myoglobinemia
• Contact dermatitis (defatting hydrocarbon dermatitis), chemical burns, and coagulation necrosis
• Epistaxis, nasal ulcerations, and chronic rhinitis

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:

• Inform patients of the consequences of toluene abuse
• Advise patients of opportunities for counseling, therapy, and detoxification
• For patient education information, see Substance Abuse