What is toluene?
- Toluene is also known as toluol, methylbenzene, and phenylmethane
- Organic compound
- Volatile liquid
- Non-polar solvent
- Cholinergic antagonist
- Neurotoxin
- Fuel additive
- Clear and colorless
Chemical structure of toluene
Watch this video to learn more about toluene.
Sources of Toluene
- Naturally found in crude oil and the tolu tree
- Can be produced as a byproduct of gasoline or other fuel production, or during the leather tanning process
- Also found in paints, nail polish, adhesives, rubber, and paint thinners
- People working in factories, workshops, and refineries are at risk for occupational exposure
- Voluntary exposure can be due to “huffing, sniffing, cuffing, or bagging” for recreational purposes
- Effects can last from 15-60 minutes
PubChem: Toluene. Review of toluene action: clinical evidence, animal studies and molecular targets.
Biotransformation
Toluene undergoes biotransformation by the cytochrome P450 enzyme CYP2E1, which is a phase 1 enzyme. Interestingly, it has been found that increased exposure to toluene results in increased CYP2E1 mRNA expression.
Toxicokinetics
- Absorption: occurs primarily via the lungs, but can also occur through the skin (dermal) and through the gastrointestinal tract
- Distribution: occurs through organs that are primarily composed of lipids; it is important to note that toluene can readily cross the blood brain barrier and the placenta
- Metabolism: in the liver, where it is converted to benzyl alcohol and benzoic acid; metabolized by CYP2E1
- Ultimately forms hippuric acid
- This dissociates into anions and protons
- Excess hippuric acid formation can result in metabolic acidosis, or too much acid in the body, and hypokalemia, or very low potassium levels; this is extremely dangerous
- Excretion: urine
Review of toluene action: clinical evidence, animal studies and molecular targets.
Watch this video to learn more about inhalants, including toluene.
Carcinogenicity
According to the EPA and IARC, toluene cannot be classified as a human carcinogen because of the insufficient evidence available. Therefore, more studies should be conducted to determine the carcinogenic potential of toluene in humans.
PubChem: Toluene. Agency for Toxic Substances and Disease Registry: Toluene.
Mechanism of Action
Toluene has a variety of effects on the central nervous system. Effects have been shown to be both reversible and irreversible.
- Impacts dopaminergic neurons in the basal ganglia
- This results in changes in sensory-motor functions
- Impacts glutamate and GABA receptor binding
Target organs
Toluene impacts nearly every organ system, including the:
- immune system
- nervous system
- respiratory system
- central nervous system
- eyes
- skin
- liver
- kidneys
Signs and symptoms of toxicity
Please click on the above image to read about the acute and chronic signs and symptoms of toluene exposure.
Genetic Susceptibility
Toluene diisocyanate (TDI) and Occupational Asthma (OA)
- Exposure to toluene diisocyanate is known to cause occupational asthma
- OA is defined as “variable airflow limitation or airway hyperresponsiveness” that is a result of occupational exposure” (Christiani et al).
- Mechanism is unclear, but may be related to an IgE mechanism
- Studies have shown genetic differences in people with TDI-induced OA compared to normal subjects
- The results found a positive association between TDI-induced OA and the HLA-DQB1*0503 gene
- Interestingly, this demonstrates that genetic changes have occurred in people who have been exposed to TDI
Genetic susceptibility to occupational exposures.
Unique Exposures
There have been many epidemiological studies conducted on the effects of toluene exposure. Here are some interesting examples:
- A study in Singapore found that women exposed to toluene while working in an audio speaker factory had higher rates of spontaneous abortion compared to the control group.
- A psychiatric study found that male workers who had over 12 years of toluene exposure were more likely to have intellectual impairments such as problems with concentration, learning, and memory when compared to the non-exposed control group.
- A study in France examined those exposed to toluene while working in a printing plant found that many of the workers exhibited progressive changes in their color vision.
Treatments
- Remove clothing and wash the exposed areas immediately
- Eyes can be flushed with saline
- Do not induce vomiting
- Activated charcoal may be helpful if the patient is alert and has a gag reflex
- Currently, there is no toluene antidote available
- Treatment should focus on respiratory and cardiovascular support
Medical Management Guidelines for Toluene.
Biomarkers
- Levels of toluene in the blood are the most reliable indicator
- Levels of hippuric acid (see image below) in the urine can be used to determine acute toluene exposure
- This is not a reliable indicator of chronic exposure due to the short half-life of hippuric acid
Hippuric Acid
Disclaimer: I do not own any of these images. Each image has been cited with its corresponding link.
References
- PubChem. Toluene. https://pubchem.ncbi.nlm.nih.gov/compound/1140. Accessed June 29, 2019.
- ATSDR – Toxic Substances – Toluene. https://www.atsdr.cdc.gov/substances/toxsubstance.asp?toxid=29. Accessed June 29, 2019.
- Cruz SL, Rivera-García MT, Woodward JJ. Review of toluene action: clinical evidence, animal studies and molecular targets. J Drug Alcohol Res. 2014;3. doi:10.4303/jdar/235840
- Filley CM, Halliday W, Kleinschmidt-Demasters BK. The Effects of Toluene on the Central Nervous System. J Neuropathol Exp Neurol. 2004;63(1):1-12. doi:10.1093/jnen/63.1.1
- Christiani DC, Mehta AJ, Yu C-L. Genetic susceptibility to occupational exposures. Occup Environ Med. 2008;65(6). doi:10.1136/oem.2007.033977
- ATSDR – Medical Management Guidelines (MMGs): Toluene. https://www.atsdr.cdc.gov/mmg/mmg.asp?id=157&tid=29. Accessed June 29, 2019.