Toluene is a colorless, flammable liquid with a sweet pungent odor.
Synonyms: Toluol, methylbenzene, methyl benzol,
Source: Toluene is an aromatic hydrocarbon,
occurring naturally in crude oil and in the tolu tree. It is produced
during the process of making gasoline and other fuels from crude oil,
in making coke from coal, and as a by-product in the manufacture of
styrene. Toluene has numerous commercial and industrial applications
and is a solvent in paints, lacquers, thinners, glues, correction fluid
and nail polish remover, and is used in the printing and leather tanning
processes. Due to its easy accessibility, low cost and ease of concealment,
some U.S. states have placed restrictions on the sale of these products
Drug Class: Volatile solvent, CNS depressant.
Medical and Recreational Uses: No approved
medical use of toluene. It is frequently abused for its intoxicating
effects. Recreational use is most common among younger adolescents primarily
because it is readily available, inexpensive and legal.
Potency, Purity and Dose: Solvents in many
commercial and industrial products are often mixed and the solvent “sniffer” is
often exposed to other solvents in addition to toluene. Acute and chronic
accidental exposure to toluene can also occur, particularly in work
environments. Regulatory Limits: OSHA recommends a maximum of 200 ppm
toluene in workplace air for an 8-hour work day, 40-hour work week;
NIOSH recommends an exposure limit of 100 ppm toluene in workplace air;
and ACGIH recommends an exposure limit of 50 ppm in workplace air.
Route of Administration: Inhalation of vapor.
May be sniffed directly from on open container, or “huffed” from
a rag soaked in the substance and held to the face. Alternatively, the
open container or soaked rag can be placed in a bag where the vapors
can concentrate before being inhaled. Exposure can also occur by ingesting
the liquid or via skin contact.
Pharmacodynamics: Solvents have three proposed
mechanisms of action: they may alter the structure of membrane phospholipid
bi-layers, impairing various ion channels; they may alternatively alter
membrane bound enzymes or receptor-site specificity for endogenous substrates;
or they may produce toxic metabolites modifying the hepatic microsomal
system and possibly adducting RNA and DNA molecules. Toluene depresses
neuronal activity and reversibly enhances GABA A receptor-mediated synaptic
currents and a 1-glycine receptor-activated ion channel function. Toluene
also inhibits glutamatergic neurotransmission via NMDA receptors and
alters dopaminergic transmission.
Pharmacokinetics: Toluene is well-absorbed
following oral ingestion and rapidly absorbed following inhalation.
Toluene is detectable in the arterial blood within
10 seconds of inhalation exposure. It is highly lipid soluble and accumulates
in adipose tissue, tissues with high fat content, and highly vascularized
tissues. Highest concentrations are found in the liver, kidney, brain
and blood. The initial half-life in whole blood averages 4.5 hours,
(range of 3-6 hours), with a terminal phase half-life of 72 hours. The
half-life in adipose tissue ranges from 0.5-2.7 days, increasing with
amounts of body fat. Approximately 80% of a dose is metabolized in the
liver. Side-chain hydroxylation to benzyl alcohol is followed by oxidation
to benzaldehyde by alcohol dehydrogenase, oxidation to benzoic acid
by aldehyde dehydrogenase and conjugation with glycine to hippuric acid
or reaction with glucuronic acid to form benzoyl glucuronide. Ring hydroxylation
to o- and p-cresol is a minor (~1%) metabolic pathway. 4%-20% is excreted
unchanged by the lungs and <0.1% is excreted unchanged in the urine.
60%-70% is excreted in urine as hippuric acid (glycine conjugate), and
10%-20% as benzoic acid glucuronide conjugate.
Molecular Interactions / Receptor Chemistry: Toluene
is metabolized to benzyl alcohol via the cytochrome P450 2E1 isoform,
and to a lesser extent to benzyl alcohol, o-cresol, and p-cresol by
2B6, 2C8, 1A2 and 1A1 isoforms. Potential inhibitors of these isoenzymes
could decrease the rate of toluene elimination if administered concurrently,
while potential inducers could increase the rate of elimination.
Blood to Breath Concentration Ratio: Ranges
from 7 to 15
Interpretation of Blood Concentrations: In
non-exposed individuals, average toluene concentrations have been measured
at 0.47 m g/L (non-smokers) and 1.14 m g/L (smokers). Toluene is detectable
in arterial blood within 10 seconds of inhalation exposure. Exposure
to 38 ppm for 8 hours resulted in blood toluene concentrations of 0.59
mg/L. Similarly, exposure to 34 ppm for 8 hours resulted in blood toluene
concentrations of 0.457 mg/L, decreasing to 0.038 mg/L after 16 hours.
Exposure to 100 ppm for
30 minutes produced 0.4 mg/L of blood toluene in resting individuals
and 1.2 mg/L after exercise. In 136 toluene abusers hospitalized or
arrested while intoxicated, blood toluene concentrations ranged from
0.3-30 mg/L. Three fatalities from acute toluene inhalation had blood
concentrations of 50, 60, and 79 mg/L. In 8 fatal cases of accidental
or intentional acute exposure of toluene, blood concentrations ranged
from 10-48 mg/L (mean 22 mg/L).
In 53 toluene abusers, blood concentrations of less than 1.0 mg/L corresponded
to an odor of “chemical” on the subject’s breath;
some signs of impairment were observed at concentrations of 1.0-2.5
mg/L; 50% of subjects with concentrations of 2.5-10 mg/L were hospitalized
with marked intoxication including hallucinations; and unconsciousness
or death were reported at concentrations of 10 mg/L or greater. In 6
subjects with blood toluene concentrations ranging from 9.8-31 mg/L,
slurred speech, slow movements, and an inability to concentrate were
observed within minutes of cessation of use.
Interpretation of Urine Test Results: In
136 toluene abusers hospitalized or arrested while intoxicated, urine
toluene concentrations ranged from 0-5 mg/L. In 120 glue sniffers, concentrations
of toluene in the urine ranged from 0.1-40.3 mg/L. Urinary o-cresol
and hippuric acid concentrations may have a high correlation with blood
toluene concentrations. Hippuric acid excretion increases during the
first 4 hours of exposure to up to 4 times the background level, then
decreases rapidly to background levels within
6 hours. O-cresol excretion peaks during the last hour of chronic exposure
or in the period immediately after acute exposure. Exercise increases
the rate of both hippuric acid and o-cresol excretion. Hippuric acid
concentrations (not corrected for creatinine) in non-exposed persons
averaged 800 mg/L (range 400-1400); daily exposure to 50 ppm averaged
1920 mg/L (range 1260-2930); 100 ppm ranged from 2800-3500 mg/L; and
200 ppm averaged 5970 mg/L (range 4120-8650). O-cresol is not normally
detected in the urine of non-exposed persons, while exposure to 200
ppm results in concentrations of 1-3 mg/L.
Psychological: Dizziness, euphoria, grandiosity, floating
sensation, drowsiness, reduced ability to concentrate, slowed reaction
time, distorted perception of time and distance, confusion, weakness,
fatigue, memory loss, delusions, and hallucinations.
Physiological: Irritation to the nose, throat, and eyes,
headache, nystagmus, slurred speech, ataxia, staggering, impaired color
vision, vigilance, nausea, vomiting, respiratory depression, convulsions,
severe organ damage, coma, and death.
Mild exposure (100-1500 ppm) dose-dependently results in euphoria,
dizziness, reduced inhibitions, feelings of inebriation similar to alcohol
intoxication, headache, nausea, lethargy, slow thought and speech, impairment
of coordination, loss of memory, slowed reaction time, fatigue, sedation,
confusion, impaired cognition function, impaired visual perception,
staggering gait, muscular fatigue, and insomnia. More severe intoxication
(10,000-30,000 ppm) will lead to tremors, arrhythmias, paralysis, unconsciousness,
coma, and death. Chronic exposure may result in paranoid psychosis,
temporal lobe epilepsy, mental retardation, and visual impairment.
Side Effect Profile: Toluene can cause brain,
liver and kidney damage, hearing loss, memory impairment, and attention
deficits. Death can result from heart failure, asphyxiation or aspiration.
Toluene also owes its pharmacology to a mucosal irritant effect from
an exothermic reaction with water. This results in vomiting, lacrimation
and ocular burning, cough, chest pain, wheezing and possible interstitial
edema, and kidney toxicity with tubular acidosis. Toluene exposure is
also associated with a transient liver injury.
Duration of Effects: Once inhaled, the extensive
capillary surface of the lungs allows rapid absorption of toluene and
blood levels peak rapidly. Entry into the brain is extremely fast and
o nset of effects is almost immediate. Toluene effects generally last
Tolerance, Dependence and Withdrawal Effects: Tolerance
to the effects of toluene has been shown in rats. Toluene has the potential
to produce physical and psychological dependence, and its abuse liability
is significant. Signs of physical dependence are observed on withdrawal.
Drug Interactions: There is a likely synergy
or potentiation of effects with other solvents and CNS depressants.
Acute consumption of ethanol inhibits toluene elimination resulting
in increased blood toluene concentrations and tissue exposure. This
is probably due to competition for alcohol dehydrogenase.
Performance Effects: Most analyses on performance
have been on subjects exposed to 50-200 ppm over a 6-8 hour work period.
Marked impairment in neurological and neuropsychological test performance
have been observed, including impaired working memory and executive
cognitive functions, impairment of visual-vigilance tasks, loss in color
vision and visual perception, inability to concentrate, slow movements,
and decreased response time to simple brief tests.
Effects on Driving: No driving or simulator
studies exist for toluene. Blood toluene concentrations were above ~1.0
mg/L in 114 drivers arrested on suspicion of driving while intoxicated
in Norway between 1983-1987. In 29 of these cases toluene was the only
detected drug, with mean blood concentrations of 10 mg/L (range 1-29.3
mg/L). The authors stated there was no simple relation between blood
toluene concentrations and degree of impairment, however, almost all
drivers with blood toluene concentrations greater than 9.2 mg/L were
considered impaired or highly probably impaired. No driving observations
DEC Category: Inhalant
DEC Profile: Horizontal gaze nystagmus present
in high doses; vertical gaze nystagmus present in high doses; lack of
convergence present; pupil size normal; reaction to light slow; pulse
rate elevated; blood pressure elevated; body temperature normal. Other
characteristic indicators may include strong odor of solvent or chemical
on breath or clothes, residue of substance around nose, mouth or hands,
slurred speech, and general intoxication.
Panel’s Assessment of Driving Risks: Acute
and chronic exposure to toluene can result in severe impairment.
References and Recommended Reading:
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OSHA – Occupational Safety and Health Administration.
NIOSH – National Institute for Occupational Safety and Health.
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