Toluene (toxicology) - AbsoluteAstronomy.com

Metabolism in humans

While a significant amount of toluene

Toluene

Toluene, formerly known as toluol, is a clear, water-insoluble liquid with the typical smell of paint thinners. It is a mono-substituted benzene derivative, i.e., one in which a single hydrogen atom from the benzene molecule has been replaced by a univalent group, in this case CH3.It is an aromatic...

, 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

Hydroxylation

Hydroxylation is a chemical process that introduces a hydroxyl group into an organic compound. In biochemistry, hydroxylation reactions are often facilitated by enzymes called hydroxylases. Hydroxylation is the first step in the oxidative degradation of organic compounds in air...

to benzyl alcohol

Benzyl alcohol

Benzyl alcohol is an organic compound with the formula C6H5CH2OH. The benzyl group is often abbreviated "Bn", thus benzyl alcohol is denoted as BnOH. Benzyl alcohol is a colorless liquid with a mild pleasant aromatic odor. It is a useful solvent due to its polarity, low toxicity, and low vapor...

by members of the cytochrome P450 (CYP) superfamily. There are five CYPs which are important in toluene metabolism, CYP1A2

CYP1A2

Cytochrome P450 1A2 , a member of the cytochrome P450 mixed-function oxidase system, is involved in the metabolism of xenobiotics in the body...

, CYP2B6

CYP2B6

Cytochrome P450 2B6 is an enzyme that in humans is encoded by the CYP2B6 gene. CYP2B6 is a member of the Cytochrome P450 group of enzymes. Along with CYP2A6, it is involved with metabolizing nicotine, along with many other substances.- Function :...

, CYP2E1

CYP2E1

Cytochrome P450 2E1 , a member of the cytochrome P450 mixed-function oxidase system, is involved in the metabolism of xenobiotics in the body. In humans, the CYP2E1 enzyme is encoded by the CYP2E1 gene...

, CYP2C8

CYP2C8

Cytochrome P4502C8 , a member of the cytochrome P450 mixed-function oxidase system, is involved in the metabolism of xenobiotics in the body.- CYP2C8 Ligands :...

, and CYP1A1

CYP1A1

Cytochrome P450, family 1, subfamily A, polypeptide 1 is a protein that in humans is encoded by the CYP1A1 gene. The protein is a member of the cytochrome P450 superfamily of enzymes.-Function:...

. 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, in the Finnish population for example the primary enzyme is CYP2B6

CYP2B6

. CYP2E1 catalyses the formation of benzyl alcohol and p-cresol, while CYP2B6 produces comparatively little p-cresol

P-Cresol

p-Cresol, also 4-methylphenol, is a phenol, with formula C6H4.It is a positional isomer; the other two are m-cresol and o-cresol. P-cresol is a major component in pig odor. . For more information see cresol. 4-methylphenol is a component in human sweat. It is a component of human odour attractive...

.

It is believed that in humans, benzyl alcohol is metabolised to benzaldehyde

Benzaldehyde

Benzaldehyde is an organic compound consisting of a benzene ring with a formyl substituent. It is the simplest aromatic aldehyde and one of the most industrially useful. This colorless liquid has a characteristic pleasant almond-like odor...

by CYP rather than alcohol dehydrogenase

Alcohol dehydrogenase

Alcohol dehydrogenases are a group of dehydrogenase enzymes that occur in many organisms and facilitate the interconversion between alcohols and aldehydes or ketones with the reduction of nicotinamide adenine dinucleotide...

; however, this belief does not appear to be universal. Benzaldehyde is in turn metabolised to benzoic acid

Benzoic acid

Benzoic acid , C7H6O2 , is a colorless crystalline solid and the simplest aromatic carboxylic acid. The name derived from gum benzoin, which was for a long time the only source for benzoic acid. Its salts are used as a food preservative and benzoic acid is an important precursor for the synthesis...

, primarily by mitochondrial aldehyde dehydrogenase-2

Aldehyde dehydrogenase

Aldehyde dehydrogenases are a group of enzymes that catalyse the oxidation of aldehydes.- Function :Aldehyde dehydrogenase is a polymorphic enzyme responsible for the oxidation of aldehydes to carboxylic acids, which leave the liver and are metabolized by the body’s muscle and heart...

(ALDH-2), while only a small percentage is metabolised by cytosolic ALDH-1.

Benzoic acid is metabolised to either benzoyl glucuronide or hippuric acid

Hippuric acid

Hippuric acid is a carboxylic acid found in the urine of horses and other herbivores. Hippuric acid crystallizes in rhombic prisms which are readily soluble in hot water, melt at 187 °C and decompose at about 240 °C...

. 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.

Ring hydroxylation to cresols is a minor pathway in the metabolism of toluene. The majority of the cresol is excreted unchanged in urine; however, some of the p-cresol and o-cresol

O-Cresol

ortho-Cresol, also 2-methylphenol, is a phenol, with formula C6H4.It is an isomer of p-cresol, m-cresol and anisole-Chemistry:...

is excreted as a conjugate. Studies in rats have shown that p-cresol is primarily conjugated with glucuronide to produce p-cresylglucuronide, though this may not be applicable to humans. o-cresol appears to be excreted mostly unchanged in urine or as the glucuronide or sulfate conjugate. There appears to be some dispute over whether m-cresol

M-Cresol

m-Cresol, also 3-methylphenol, is a phenol, with formula C6H4.Amongst its uses it can be used as a solvent for dissolving polymers, most notably the conducting polymer polyaniline...

is produced as a metabolite of toluene or not.

Environmental influences

When exposure to toluene occurs there is usually simultaneous exposure to several other chemicals. Often toluene exposure occurs in conjunction with benzene

Benzene

Benzene is an organic chemical compound. It is composed of 6 carbon atoms in a ring, with 1 hydrogen atom attached to each carbon atom, with the molecular formula C6H6....

and since they are to some degree metabolised by the same enzymes, the relative concentrations will determine their rate of elimination. Of course the longer it takes for toluene to be eliminated the more harm it is likely to do.

The smoking and drinking habits of those exposed to toluene will partially determine the elimination of toluene. Studies have shown that even a modest amount of acute ethanol consumption can significantly decrease the distribution or elimination of toluene from the blood resulting in increased tissue exposure. Other studies have shown that chronic ethanol consumption can enhance toluene metabolism via the induction of CYP2E1. Smoking has been shown to enhance the elimination rate of toluene from the body, perhaps as a result of enzyme induction.

The diet can also influence toluene elimination. Both a low-carbohydrate diet and fasting have been shown to induce CYP2E1 and as a result increase toluene metabolism. A low protein diet may decrease total CYP content and thereby reduce the elimination rate of the drug.

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

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.

Urinary o-cresol

O-Cresol

ortho-Cresol, also 2-methylphenol, is a phenol, with formula C6H4.It is an isomer of p-cresol, m-cresol and anisole-Chemistry:...

may be more reliable for the biomonitoring of toluene exposure because, unlike hippuric acid

Hippuric acid

, o-cresol

O-Cresol

ortho-Cresol, also 2-methylphenol, is a phenol, with formula C6H4.It is an isomer of p-cresol, m-cresol and anisole-Chemistry:...

is not found at detectable levels in unexposed subjects. o-Cresol may be a less sensitive marker of toluene exposure than hippuric acid. o-Cresol excretion may be an unreliable method for measuring toluene exposure because o-cresol makes up <1% of total toluene elimination.

Benzylmercapturic acid

Benzylmercapturic acid

Benzylmercapturic acid is a minor metabolite of toluene in humans. It is used in the diagnosis of toluene exposure. As its name indicates, is a benzyl derivative of mercapturic acid ....

, a minor metabolite of toluene, is produced from benzaldehyde

Benzaldehyde

. In more recent years, studies have suggested the use of urinary benzylmercapturic acid

Benzylmercapturic acid

Benzylmercapturic acid is a minor metabolite of toluene in humans. It is used in the diagnosis of toluene exposure. As its name indicates, is a benzyl derivative of mercapturic acid ....

as the best marker for toluene exposure, because: it is not detected in non-exposed subjects; it is more sensitive than hippuric acid

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

Quantitative property

A quantitative property is one that exists in a range of magnitudes, and can therefore be measured with a number. Measurements of any particular quantitative property are expressed as a specific quantity, referred to as a unit, multiplied by a number. Examples of physical quantities are distance,...

relationship with toluene than hippuric acid

Hippuric acid

or o-cresol

O-Cresol

ortho-Cresol, also 2-methylphenol, is a phenol, with formula C6H4.It is an isomer of p-cresol, m-cresol and anisole-Chemistry:...

Effects of long term exposure

Serious adverse behavioural effects are often associated with toluene abuse related to the deliberate inhalation of solvents. Long term toluene exposure is often associated with effects such as: psychoorganic syndrome

Psychoorganic syndrome

Psychoorganic syndrome is a progressive disease comparable to presenile dementia. It is caused by exposure to organic solvents such as toluene....

; visual evoked potential (VEP) abnormality; toxic polyneuropathy, cerebellar

Cerebellum

The cerebellum is a region of the brain that plays an important role in motor control. It may also be involved in some cognitive functions such as attention and language, and in regulating fear and pleasure responses, but its movement-related functions are the most solidly established...

, cognitive, and pyramidal dysfunctions; optic atrophy

Atrophy

Atrophy is the partial or complete wasting away of a part of the body. Causes of atrophy include mutations , poor nourishment, poor circulation, loss of hormonal support, loss of nerve supply to the target organ, disuse or lack of exercise or disease intrinsic to the tissue itself...

; and brain lesions

Lesion

A lesion is any abnormality in the tissue of an organism , usually caused by disease or trauma. Lesion is derived from the Latin word laesio which means injury.- Types :...

.

The neurotoxic effects of long term use (in particular repeated withdrawals

Kindling (substance withdrawal)

Kindling due to substance withdrawal, refers to the neurological condition which results from repeated withdrawal episodes from sedative-hypnotic drugs such as alcohol or benzodiazepines. Each withdrawal leads to more severe withdrawal symptoms than the first withdrawal syndrome...

) of toluene may cause postural tremors by upregulating GABA receptors

GABA receptor

The GABA receptors are a class of receptors that respond to the neurotransmitter gamma-aminobutyric acid , the chief inhibitory neurotransmitter in the vertebrate central nervous system...

within the cerebellar cortex. Treatment with GABA

Gabâ

Gabâ or gabaa, for the people in many parts of the Philippines), is the concept of a non-human and non-divine, imminent retribution. A sort of negative karma, it is generally seen as an evil effect on a person because of their wrongdoings or transgressions...

agonists such as, benzodiazepines provide some relief from toluene induced tremor and ataxia

Ataxia

Ataxia is a neurological sign and symptom that consists of gross lack of coordination of muscle movements. Ataxia is a non-specific clinical manifestation implying dysfunction of the parts of the nervous system that coordinate movement, such as the cerebellum...

. An alternative to drug treatment is vim thalamotomy

Thalamotomy

First introduced in the 1950s, thalamotomy is an invasive procedure, primarily effective for tremors such as those associated with Parkinson's Disease , where a selected portion of the thalamus is surgically destroyed...

. The tremors associated with toluene misuse do not seem to be a transient symptom, but an irreversible and progressive symptom which continues after solvent abuse has been discontinued.

There is some evidence that low level toluene exposure may cause disruption in the differentiation of astrocyte

Astrocyte

Astrocytes , also known collectively as astroglia, are characteristic star-shaped glial cells in the brain and spinal cord...

precursor cells. This does not appear to be a major hazard to adults; however, exposure of pregnant women to toluene during critical stages of fetal development could cause serious disruption to neuronal development.

External links

ATSDR - Case Studies in Environmental Medicine: Toluene Toxicity U.S. Department of Health and Human Services (public domain)

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