TOLUENE

Toluene is a clear, colorless liquid with an aromatic odor.
It is a natural constituent of crude oil and is produced from petroleum refining and coke-oven operations. At room temperature, toluene is both volatile and flammable.
The odor threshold for toluene in air is low—about 80 parts per billion (ppb), which is about 500 times lower than the level permitted in the workplace. In water, it can be tasted and smelled at a level of 40 ppb. These levels are well below the concentrations at which adverse effects have been observed for short-term exposure. Because toluene is lipid soluble, it has a moderate tendency to bioaccumulate in the food chain.
Synonyms for toluene include toluol, methylbenzene, phenylmethane, and methacide . It is a mono-substitutedbenzene derivative, i.e., one in which a single hydrogen atom from a group of six atoms from the benzene molecule has been replaced by a univalent group, in this case CH3.
It is an aromatic hydrocarbon that is widely used as an industrial feedstock and as a solvent. Like other solvents, toluene is sometimes also used as an inhalant drug for its intoxicating properties; however, inhaling toluene has potential to cause severe neurological harm. Toluene is an important organic solvent, but is also capable of dissolving a number of notable inorganic chemicals such as sulfur, iodine, bromine, phosphorus, and other non-polar covalent substances.

Toluene Toxicity

History

The compound was first isolated in 1837 by a Polish chemist Filip Walter through a distillation of pine oil who named it retinaptha. This name was replaced shortly after by by a word toluene derived from the older name toluol, which refers to tolu balsam, an aromatic extract from the tropical Colombian tree Myroxylon balsamum, from which it was also isolated later. It was originally named by Jöns Jakob Berzelius.

Uses

The principal source of toluene exposure for the general population is gasoline, which contains 5% to 7% toluene by weight. Toluene is released to the atmosphere during the production, transport, and combustion of gasoline. Not surprisingly, toluene concentrations are highest in areas of heavy traffic, near gasoline filling stations, and near refineries.
Toluene is short-lived in ambient air because of its reactivity with other air pollutants.
Common household products and cigarette smoke are the principal sources of toluene indoors. Indoor air is often several times higher in toluene concentration than outside air. Cigarette smokers absorb about 80 to 100 micrograms (µg) of toluene per cigarette.
Toluene-containing consumer products include household aerosols, paints, paint thinners, varnishes, shellac, rust inhibitors, adhesives and adhesive products, and solvent-based cleaning and sanitizing agents. Toluene is used as a solvent in cosmetic nail polishes at concentrations of up to 50%. In addition to the products mentioned previously, toluene is commonly used in some printing operations, leather tanning, and chemical processes.
Intentional inhalation of toluene makes it one of the most abused hydrocarbon solvents. Glues, paints, and solvent mixtures are the most commonly abused products.

Metabolism

While a significant amount of toluene, 25%-40%, is exhaled unchanged via the lungs, a greater proportion is metabolised and excreted via other pathways.
The primary route of toluene metabolism is by hydroxylation to benzyl alcohol by members of the cytochrome P450 superfamily.
There are five CYPs which are important in toluene metabolism, CYP1A2, CYP2B6, CYP2E1, CYP2C8, and CYP1A1. The first four seem to be involved in the hydroxylation of toluene to benzyl alcohol. CYP2E1 seems to be the primary enzyme in the hydroxylation of toluene, accounting for roughly 44% of toluene metabolism; however, there is a great deal of ethnic variability. CYP2E1 catalyses the formation of benzyl alcohol and p-cresol, while CYP2B6 produces comparatively little p-cresol.
It is believed that in humans, benzyl alcohol is metabolised to benzaldehyde by CYP rather than alcohol dehydrogenase; however, this belief does not appear to be universal.
Benzaldehyde is in turn metabolised to benzoic acid, primarily by mitochondrialaldehyde dehydrogenase-2 (ALDH-2), while only a small percentage is metabolised by cytosolic ALDH-1.
Benzoic acid is metabolised to either benzoyl glucuronide or hippuric acid.
Benzoyl glucuronide is produced by the reaction of benzoic acid with glucuronic acid, which accounts for 10-20% of benzoic acid elimination. Hippuric acid is also known as benzoylglycine and is produced from benzoic acid in two steps: first benzoic acid is converted to benzoyl-CoA by the enzyme benzoyl-CoA synthase; then benzoyl-CoA is converted to hippuric acid by benzoyl-CoA:glycine N-acyltransferase.
Hippuric acid is the primary urinary metabolite of toluene.

Measure of exposure

Hippuric acid has long been used as an indicator of toluene exposure; however, there appears to be some doubt about its validity.
There is significant endogenous hippuric acid production by humans; which shows inter- and intra-individual variation influenced by factors such as diet, medical treatment, alcohol consumption, etc.
This suggests that hippuric acid may be an unreliable indicator of toluene exposure. It has been suggested that urinary hippuric acid, the traditional marker of toluene exposure is simply not sensitive enough to separate the exposed from the non-exposed.
This has led to the investigation of other metabolites as markers for toluene exposure.
Benzylmercapturic acid, a minor metabolite of toluene, is produced from benzaldehyde. In more recent years, studies have suggested the use of urinary benzylmercapturic acidas the best marker for toluene exposure, because: it is not detected in non-exposed subjects; it is more sensitive than hippuric acid at low concentrations; it is not affected by eating or drinking; it can detect toluene exposure down to approximately 15 ppm; and it shows a better quantitative relationship with toluene than hippuric acid or o-cresol.

Toluene toxicity(toxicology)

THE IMPORTANCE OF THIS SUBSTANCE

Volatile organic solvents such as toluene are voluntarily inhaled for their intoxicating effects.
Solvent use is especially prevalent among adolescents, and is associated with deficits in a wide range of cognitive tasks including attention, behavioral control, and risk assessment.
These deficits could reflect impairment in the function of the prefrontal cortex, as this region has a crucial role in assessing and integrating risk into expected value signals.
The misuse of volatile substances needs to be recognized as a public health problem that requires tailored interventions.
The intentional inhalation of volatile solvents for intoxicating purposes is a serious health problem, especially among adolescents. According to the most recent Monitoring the Future Survey (2010) the lifetime prevalence of inhalant use among eighth graders is 14.9%, higher than all illicit drugs at this age group except marijuana (15.7%). Furthermore, only 34.1% of eighth graders believe that trying inhalants once or twice poses a great risk, physically or otherwise, and this number has decreased throughout the decade. Among the 2.9 million new users of illicit drugs in 2008, 9.7% reported that inhalants were their first drug, the third highest percentage for all illicit drugs, behind marijuana (56.6%) and prescription pain relievers (22.5%). The staggering numbers of inhalant users may be in part because of the ease of access; volatile solvents such as toluene are contained in many common household products such as spray paints, paint thinners, lacquers, and glues.
Nevertheless, inhaling high concentrations of volatile solvents such as toluene can produce neurological and cognitive defects and can induce ‘sudden sniffing death', due to cardiac arrhythmia and arrest produced by hypersensitivity of the myocardium to epinephrine.
Moreover recent studies demonstrated that the brain solvent concentration accurately predicts acute changes in behavior and neurophysiological function.
Abused solvents such as toluene share a pharmacological profile with other abused depressant drugs including ethanol, barbiturates and benzodiazepines.
Clinically, toluene intoxication resembles alcohol intoxication , and in animal studies abused solvents act as central nervous system depressants.
For instance, toluene produces motor impairment at moderate to high concentrations , has anticonvulsant, antianxiety drug-like effects and shares discriminative stimulus effects with barbiturates and ethanol. This has led to the hypothesis that some abused inhalants may share common mechanisms of action with other abused depressant drugs.
Diagnosis of a sniffing syndrome can be difficult; the differential diagnosis includes alcoholic intoxication, cerebral disease, gastroenteritis, infectious hepatitis, renal failure, and various psychiatric disturbances, and the syndrome should be considered in any obscure and unexplained illness in teenagers.

The Abused Inhalant Toluene Differentially Modulates Excitatory and Inhibitory Synaptic Transmission in Deep-Layer Neurons of the Medial Prefrontal Cortex, 2011
Clinical, socio-demographic, neurophysiological and neuropsychiatric evaluation of children with volatile substance addiction., 2005.

Acute effects

Some effects are irritation of respiratory airways, impaired judgment, tremors, unsteady gait, blurred vision, and memory impairment. Headaches, lightheadedness, auditory buzzing, and muscle weakness are also frequent.
Very high concentrations can produce anesthesia, unconsciousness, and even death. Nausea and vomiting can occur at any stage.
Low concentrations produce an initial euphoria and excitation caused by suppressing inhibitory brain functions.
With higher concentrations, a general nervous system inhibition becomes more evident through dizziness, lack of motor coordination, and slurred speech.
Acute exposure to various solvents can result in anxiolytic-, antidepressant-, and anticonvulsant-like effects, as well as other actions similar to those produced by CNS depressants. At high concentrations, solvents can produce hallucinations. This effect has been associated by volatile substance misusers with toluene-based solvents and glues, chrome spray paints, and butane gas. The desire to have this experience can be a powerful reason to misuse volatile substances.
The acute effects on the heart are potentially fatal. Sudden sniffing death is a risk during any use, including initial experimentation. Solvents and other inhalants sensitize the heart to adrenaline and noradrenaline, the hormones that prepare the organism to react to dangerous situations with a fight-or-flee reaction. Therefore, it is important to avoid frightening any individual who is under the influence of inhalants. Solvents, like other misused drugs, have reinforcing effects. These produce a wide range of actions at different levels, but particularly affect the central and peripheral nervous systems. Using different research procedures, such as drug self-administration and conditioned-place preference, researchers have gathered evidence that animals work to self-administer several solvents, including toluene in ways similar to cocaine, heroin, and nicotine. These findings suggest evidence of the addiction potential of solvents.

Chronic effects

Misused volatile substances primarily affect the CNS, which is vulnerable to long-term toxic effects. In chronic misuse, most of the volatile substances produce memory impairment, loss of smell, and neurological changes. Chronic misusers usually have decreased sensory capacities due to neurological damage.
Several studies have found white matter alterations in the brain of long-term users of toluene-based products. Based on these studies, it is generally accepted that toluene is a white matter toxin. Neurotoxicity can be manifested by loss of vision, hearing loss, and lack of coordination, among other effects. Chronic solvent users complain of frequent headaches and sleep disturbances, and suffer from a high rate of comorbid psychiatric disorders, including paranoia, major depression, anxiety, and dementia. Not surprisingly, solvent misuse is associated with an increased risk of suicide. Solvents are highly lipophilic, that is, they have high affinity for lipids and therefore can readily cross the placenta in a pregnant female. Chronic toluene exposure has been associated with abnormal embryonic development similar to fetal alcohol syndrome, both in humans and animals.
Studies conducted with several samples of adolescent and young adults who chronically misused volatile substances relay that it can lead, in some cases, to dependence.
A mild syndrome can also sometimes occur after discontinuation of chronic exposure to high solvent concentrations, although compared with other drugs, withdrawal results from continuous use over a shorter period (e.g., one day of binging). Symptoms include sleep disturbances, headaches, irritability, general disorientations, cravings, and muscle cramps.
Brain magnetic resonance imaging shows cerebral and hippocampal atrophy as well as a loss in brain volume in toluene/solvent abusers.

The latest evidence in the neuroscience of solvent misuse: an article written for service providers, 2011

PRINCIPAL MECHANISMS OF ACTION ON THE BRAIN

It is reasonable to hypothesize that the cellular basis for the abuse of toluene may have much in common with the effects of alcohol and possibly with barbiturates and benzodiazepines as well. The idea that abused solvents may share cellular actions with GABAergic drugs, such as barbiturates, benzodiazepines and alcohol, receives support from recent research.
Toluene exposure results in differential expression of genes involved in processes important for neuronal function. In general, processes most significantly affected by toluene exposure were strongly associated with neurological structure and function.
Toluene inhibits excitatory ion channels including the N-methyl-D-aspartate (NMDA) glutamate and nicotinic acetylcholine receptors (nAChRs) and potentiates the function of inhibitory ion channels such as the gamma-aminobutyric acid receptor type A , glycine, and serotonin receptors. In addition, toluene disrupt voltage-gated calcium channels and ATP-gated ion channels.

The fact that transcripts associated with synaptic plasticity and bioenergetic pathways were strongly induced by the toluene exposure suggests that some remodeling of CNS structures may take place.
Because Toluene is known to facilitate ion flux through inhibitory ion channels (e.g., GABAA and glycine) and to inhibit flux through excitatory ion channels (e.g., NMDA, nicotinic ACh), these immediate effects perturb the normal balance of excitatory and inhibitory processes in the CNS, which may then induce compensatory processes acting to restore an appropriate balance in the system. Such compensations are clearly evident at the behavioral level in the form of tolerance to toluene and have been well documented for other compounds with similar effects in the CNS, including trichloroethylene and ethanol. For instance if toluene acutely facilitates chloride flux through GABAA channels, this should lead to down-regulation of GABA receptors and/or inhibition of the release of GABA from the presynaptic terminal to compensate for the enhanced ion flux through the channels. Subsequent removal of the toluene at the end of exposure would then leave the CNS in an overcompensated state, and thus stimulate up-regulation of this pathway as a component of the processes involved in homeostatic return to the “normal” state.
Moreover toluene exposure is associated with induction or repression of genes in pathways associated with synaptic plasticity, including long-term depression, GABA receptor signaling and mitochondrial function. In each of these pathways, responses were characterized by changes in a certain number of transcripts.

Action on GABA receptor

Toluene increase the actions of gamma aminobutyric acid (GABA), the main inhibitory neurotransmitter in the nervous system. These solvents positively modulate the activity of a specific GABA receptor subtype, GABAA, which is a channel formed by five different subunits with receptor sites for alcohol, barbiturates, and benzodiazepines. This similarity in action mechanisms may explain why animals discriminate solvents as CNS depressants, and why there is cross tolerance between the effects of solvents and other depressant drugs.

This figure shows how toluene exposure results in up-regulation of GABA Receptor Signaling Pathways. Pathway analysis reveals general post-synaptic up-regulation in transcripts associated inhibitory GABAA receptor signaling. Nodes highlighted in red indicate induction of a specific transcript, while those highlighted in green indicate reduction. Nodes highlighted in both red and green indicate a transcript altered differently between samples.

This pathway shows strong induction of GABAA subunit transcripts, which is notable because GABAA receptors are sensitive to modulation by toluene.
Prolonged treatment of neurons with toluene produced a substantial and significant decrease in the amplitude of spontaneous miniature GABA currents with no significant change in the frequency of these events.
Toluene-induced enhancement of NMDA receptor function coupled with reduced GABAergic activity would be expected to result in increased behavioral activity during withdrawal from chronic toluene exposure. Withdrawal-related hyperexcitability has been noted in both animal and human studies although the severity of withdrawal is often less than that observed with other CNS depressants. Neurons respond to the chronic presence of toluene by altering the expression and function of key ion channels that regulate neuronal excitability.

Acute toluene exposure alters expression of genes in the central nervous system associated with synaptic structure and function, 2011
The latest evidence in the neuroscience of solvent misuse: an article written for service providers, 2011
Alterations in glutamatergic and gabaergic ion channel activity in hippocampal neurons following exposure to the abused inhalant toluene, 2005

Action on NMDA receptor

Toluene acts on a specific subtype of receptors (N-methyl-d-aspartate or NMDA receptors) to glutamate, the main excitatory neurotransmitter in the nervous system. These receptors are made up of five different subunits that form a channel. The subunits have recognition sites for several ligands, including glutamate, NMDA (a closely related compound), and other substances that modulate or block channel function. When cells are in a resting state, NMDA receptors are inactive. If there is an excitatory signal or if glutamate or NMDA is added to the cell, the channels open, and sodium and calcium ions enter to activate the cell.
It was found that several solvents, including toluene, benzene, xylene, and TCE (but not flurothyl), potently block NMDA receptors, thereby decreasing the ability of cells to respond to stimulant signals.
This action is similar to what has been described for alcohol. It is particularly important to point out that NMDA receptors are involved in learning and memory processes; the most abundant NMDA receptor form in the brain during adolescence is also the most sensitive to solvents. Individuals who misuse volatile substances are often adolescents, and NMDA antagonism produced by solvents may be related to impaired cognition and learning functions found in some young patients.
Toluene and related alkylbenzenes have been shown to inhibit N-methyl--aspartate (NMDA) receptors with varying degrees of inhibition depending on the NR2 subunit expressed. NR2B containing NMDA receptors are 10-fold more sensitive to toluene and related analogs as compared with those containing either NR2A or NR2C-containing subunits. Toluene is able to almost completely abolish NMDA-stimulated currents with low millimolar potency. The most sensitive NR2B subunit shows inhibition with an IC50 of 0.2 mM. This is considerably more potent than ethanol and close to estimates of blood concentrations encountered in toluene abuse situations.
So toluene inhibits NMDA receptors in a dose-dependent and subunit-dependent manner. This inhibition occurred at concentrations of toluene (<10 mM) that did not significantly alter the resting membrane conductance.
Toluene, like ethanol and other long-chain alcohols, may alter NMDA receptor function via an interaction with a hydrophobic site. Although it is not known where such a site might exist, it is clear that toluene and ethanol do not act as simple competitive inhibitors of glutamate or glycine binding as their inhibition persists in the presence of high concentrations of the agonists. The inhibitory effects of these agents are also not voltage-dependent suggesting that they are not acting as direct channel blockers such as is found for magnesium. It is possible that toluene, ethanol and other long-chain alcohols may disrupt receptor gating processes by interfering with the subtle movements of transmembrane domains that mark the transition between closed and open states of the channel.
But neurons monitor NMDA receptor-mediated activity and adjust subunit levels in response to changes in neuronal firing. Toluene treatment enhances synaptic NMDA receptors as measured by the increase in the NMDA component of the glutamatergic EPSC. These results suggest that NMDA receptors are preferentially recruited into synapses in response to toluene-induced alterations in neuronal signaling.
These results suggest that blockade of NMDA receptors by toluene may induce a compensatory increase in the use and distribution of unassembled NR1 subunits in response to diminished synaptic activity. This activity-dependent regulation of the cellular distribution of NMDA subunits may represent a mechanism to quickly recruit active receptors when faced with diminished excitatory synaptic signaling.
As we said before toluene-induced enhancement of NMDA receptor function coupled with reduced GABAergic activity would be expected to result in increased behavioral activity during withdrawal from chronic toluene exposure. Withdrawal-related hyperexcitability has been noted in both animal and human studies although the severity of withdrawal is often less than that observed with other CNS depressants. Neurons respond to the chronic presence of toluene by altering the expression and function of key ion channels that regulate neuronal excitability.

The Abused Inhalant Toluene Differentially Modulates Excitatory and Inhibitory Synaptic Transmission in Deep-Layer Neurons of the Medial Prefrontal Cortex, 2011
The latest evidence in the neuroscience of solvent misuse: an article written for service providers, 2011
Alterations in glutamatergic and gabaergic ion channel activity in hippocampal neurons following exposure to the abused inhalant toluene, 2005

Other effects

Toluene, like other drugs of misuse, acts as a salient stimulus in the rat brain by increasing dopamine levels. High concentrations of dopamine in the brain reward system are associated with pleasurable effects that can lead to a repetition of drug use and, eventually, to addiction.
Although it has been hard to develop appropriate models for self-administration studies of abused solvents and anesthetics, there have been some demonstrations of reinforcing effects in animals and humans. Abused solvents might affect brain systems involved in reinforcement, but clearly much more research would need to be done to support this conclusion very strongly.
The latest evidence in the neuroscience of solvent misuse: an article written for service providers, 2011

Besides toluene induce a delayed but persistent decrease in evoked or spontaneous AMPA-mediated excitatory postsynaptic currents (EPSCs).
This effect is prevented by an intracellular calcium chelator or by the ryanodine receptor and SERCA inhibitors, dantrolene or thapsigargin, respectively, suggesting that toluene may mobilize intracellular calcium pools.
The toluene-induced reduction in AMPA EPSCs is also prevented by a cannabinoid receptor (CB1R) antagonist, and was occluded by the CB1 agonist WIN 55,212-2 that itself induced a profound decrease in AMPA-mediated EPSCs. This suggest that toluene enhanced a calcium-dependent process or mediator that reduced AMPA-mediated responses. A candidate for this type of mediator are endocannabinoids (EC) that are synthesized in a calcium-dependent manner and act as retrograde messengers to reduce the release of neurotransmitter. In some brain areas, EC synthesis is coupled to the activation of mGluR5 receptors that activate calcium-mobilizing pathways. Because EC synthesis is calcium dependent, toluene may produce its effects through an action on channels that gate the release of Ca2+ from an intracellular pool.
The Abused Inhalant Toluene Differentially Modulates Excitatory and Inhibitory Synaptic Transmission in Deep-Layer Neurons of the Medial Prefrontal Cortex, 2011

Furthermore the LTD pathway shows a high number of transcripts modified by the action of toluene, indicating that it represents an important pathway for this substance. While the pathway name is annotated as Synaptic-LTD, closer inspection of the genes comprising this pathway revealed two metabotropic glutamate receptors (mGluRs) — mGluR1 (type I) and mGluR7 (type III) that are expressed in many regions of the rat brain and are involved in the regulation of a variety of neuronal and synaptic activities. For example, group I mGluRs (mGluR1 and mGluR5 subtypes) are expressed in striatal medium spiny output neurons and are believed to play a significant role in the modulation of cellular responses to stimulation of dopaminergic pathways with psychostimulants.

This figure shows how toluene treatment results in altered transcript levels of genes in a canonical pathway of Synaptic Long-term Depression. In this illustration, red indicates that a gene product is significantly induced compared to control and green indicates significant repression of that gene product. Nodes with mixed colors indicate multiple probesets for that gene responded with a range of intensities.

Finally the last significant pathway is related to cellular bioenergetics. This pathway indicates significant altered expression of gene transcripts important to mitochondrial structure and function, detailing both repression and induction across mitochondrial complexes I through V and spanning the outer and inner mitochondrial membranes. Toluene and other hydrocarbons have effects on mitochondrial dysfunction, Ca2+ handling, and formation of reactive oxygen and nitrogen species. Altered production of ROS in the mitochondrial pathways may result in damage to cellular membranes, receptors, enzymes, and ion pumps which, when combined, could contribute to pathological alterations reported following abuse of toluene-containing inhalants.

Acute toluene exposure alters expression of genes in the central nervous system associated with synaptic structure and function, 2011
Evaluating the NMDA-glutamate receptor as a site of action for toluene, in vivo, 2007