Toluene Toxicity

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. 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" has become 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 spray paint, 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 (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 include neuropsychosis, cerebral and cerebellar degeneration with ataxia, seizures, choreoathetosis, optic and peripheral neuropathies, decreased cognitive ability, anosmia, optic atrophy, blindness, tinnitus, and hearing loss.^[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 arrhythmias 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:

• Renal tubular acidosis (RTA)
• Hypokalemia
• Hypophosphatemia
• Hyperchloremia
• Azotemia
• Sterile pyuria
• Hematuria
• Proteinuria

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 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.^[5]

Frequency

United States

Solvents including glue are easily accessible and inexpensive, making them a frequently abused substance. Glue sniffing is most frequently observed in teenagers and young adults in lower economic groups. According to the National Survey on Drug Use and Health in 2012, approximately 584,000 people were new inhalant users.^[6] 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 2013 Annual Report of the American Association of Poison Control Centers' National Poison Data Systems records only 311 exposures to toluene and xylene combined.^[7] Of these, only one resulted in a major adverse outcome, and none resulted in death. These reports 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 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 arrhythmias. 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 arrhythmias. 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 damage. 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]

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

Although typically thought of as an activity of young males (most mortalities 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.