Drugs and Human Performance FACT SHEETS

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 to minors.

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.

Effects:

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 several hours.

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 were documented.

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:

ACGIH – American Conference of Government Industrial Hygienists.

Baelum, J. Human Solvent Exposure. Factors Influencing the Pharmacokinetics and Acute Toxicity. Pharmacol Toxicol 1991;68(Suppl 1):1-36.

Balster, R. Neural basis of inhalant abuse.Drug Alc Dep 1998;51(1-2):207-14.

Brugnone F, Gobbi M, Ayyad K, Giuliari C, Cerpelloni M, Perbellini L. Blood toluene as a biological index of environmental toluene exposure in the "normal" population and in occupationally exposed workers immediately after exposure and 16 hours later.Int Arch Occup Environ Health 1995;66(6):421-5.

Byrne A, Kirby B, Zibin T, Ensminger S. Psychiatric and neurological effects of chronic solvent abuse. Can J Psych 1991;36(10):735-8.

Devathasan G, Low D, Teoh PC, Wan SH, Wong PK. Complications of chronic glue (toluene) abuse in adolescents. Aust NZ J Med 1984;14(1):39-43.

Evans E, Balster R. CNS depressant effects of volatile organic solvents.Neurosci Biobehavl Rev 1991;15(2):233-41.

Garriott JC, Foerster E, Juarez L, de la Garza F, Mendiola I, Curoe J. Measurement of toluene in blood and breath in cases of solvent abuse. Clin Toxicol 1981;18(4):471-9.

Gjerde H, Smith-Kielland A, Normann PT, Morland J. Driving under the influence of toluene. Forens Sci Int 1990; 44(1):77-83.

Miyazaki T, Kojima T, Yashiki M, Chikasue F, Tsukue I. Correlation between 'on admission' blood toluene concentrations and the presence or absence of signs and symptoms in solvent abusers. Forens Sci Int 1990;44(2-3):169-77.

OSHA – Occupational Safety and Health Administration.

NIOSH – National Institute for Occupational Safety and Health.

Park SW, Kim N, Yang Y, Seo B, Paeng KJ. Toluene distribution of glue sniffers' biological fluid samples in Korea. J Forens Sci 1998;43(4):888-90.

Rahill AA, Weiss B, Morrow PE, Frampton MW, Cox X, Gibb R, Gelein R, Speers D, Utell MJ. Human performance during exposure to toluene. Aviat Space Environ Med 1996;67(7):640-7.

Tomaszewski C, Kirk M, Bingham E, Cook R, Kulig K. Urine toxicology screens in drivers suspected of driving while impaired from drugs. J Toxicol Clin Toxicol 1996;34(1):37-44.

Waldron H, Cherry N, Johnston JD. The effects of ethanol on blood toluene concentrations. Int Arch Occup Environ Health 1983; 51(4):365-9.

Wallen M, Naslund P, Nordqvist M. The effects of ethanol on the kinetics of toluene in man. Toxicol Appl Pharmacol 1984;76(3):414-9.