Toluene toxicity

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Toluene toxicity
Chemical structure of toluene
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Toluene toxicity refers to the harmful effects caused by toluene on the body.


Metabolism in humans

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 (CYP) superfamily. [1] There are five CYPs which are important in toluene metabolism, CYP1A2, CYP2B6, CYP2E1, CYP2C8, and CYP1A1. [2] 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; [1] however, there is a great deal of ethnic variability, in the Finnish population for example the primary enzyme is CYP2B6. CYP2E1 catalyses the formation of benzyl alcohol and p-cresol, [1] [2] while CYP2B6 produces comparatively little p-cresol. [2]

It is believed that in humans, benzyl alcohol is metabolised to benzaldehyde by CYP rather than alcohol dehydrogenase; [3] however, this belief does not appear to be universal. [4] [5] Benzaldehyde is in turn metabolised to benzoic acid, primarily by mitochondrial aldehyde dehydrogenase-2 (ALDH-2), while only a small percentage is metabolised by cytosolic ALDH-1. [5]

Benzoic acid is metabolised to either benzoyl glucuronide or hippuric acid. [4] [6] 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. [7] Hippuric acid is the primary urinary metabolite of toluene. [4]

Toluene metabolism.png

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 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. [8] o-cresol appears to be excreted mostly unchanged in urine or as the glucuronide or sulfate conjugate. [9] There appears to be some dispute over whether m-cresol is produced as a metabolite of toluene or not. [4] [10]

Toluene to cresols.png

Environmental influences

When exposure to toluene occurs there is usually simultaneous exposure to several other chemicals. [4] Often toluene exposure occurs in conjunction with benzene and since they are to some degree metabolised by the same enzymes, the relative concentrations will determine their rate of elimination. [4] 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. [11] Other studies have shown that chronic ethanol consumption can enhance toluene metabolism via the induction of CYP2E1. [12] Smoking has been shown to enhance the elimination rate of toluene from the body, perhaps as a result of enzyme induction. [13]

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. [12] A low protein diet may decrease total CYP content and thereby reduce the elimination rate of the drug. [12]

Measure of exposure

Hippuric acid has long been used as an indicator of toluene exposure; [14] however, there appears to be some doubt about its validity. [15] 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. [15] This suggests that hippuric acid may be an unreliable indicator of toluene exposure. [15] [16] 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. [17] This has led to the investigation of other metabolites as markers for toluene exposure. [16]

Urinary o-cresol may be more reliable for the biomonitoring of toluene exposure because, unlike hippuric acid, o-cresol is not found at detectable levels in unexposed subjects. [16] o-Cresol may be a less sensitive marker of toluene exposure than hippuric acid. [18] o-Cresol excretion may be an unreliable method for measuring toluene exposure because o-cresol makes up <1% of total toluene elimination. [14]

Benzylmercapturic acid, a minor metabolite of toluene, is produced from benzaldehyde. [19] In more recent years, studies have suggested the use of urinary benzylmercapturic acid as 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. [20] [21]

Effects of long-term exposure

Serious adverse behavioural effects are often associated with chronic occupational exposure [22] and toluene abuse related to the deliberate inhalation of solvents. [23] Long-term toluene exposure is often associated with effects such as: psychoorganic syndrome; [24] visual evoked potential (VEP) abnormality; [24] toxic polyneuropathy, cerebellar, cognitive, and pyramidal dysfunctions; [23] [24] optic atrophy; hearing disorders [25] [26] and brain lesions. [23]

The neurotoxic effects of long-term use (in particular repeated withdrawals) of toluene may cause postural tremors by downregulating GABA receptors within the cerebellar cortex. [23] Treatment with GABA agonists such as benzodiazepines provide some relief from toluene-induced tremor and ataxia. [23] An alternative to drug treatment is ventral intermediate nucleus (vim) thalamotomy. [23] 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. [23]

There is some evidence that low-level toluene exposure may cause disruption in the differentiation of astrocyte precursor cells. [27] 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. [27]

Related Research Articles

Benzoic acid Chemical compound

Benzoic acid is a white (or colorless) solid with the formula C6H5CO2H. It is the simplest aromatic carboxylic acid. The name is derived from gum benzoin, which was for a long time its only source. Benzoic acid occurs naturally in many plants and serves as an intermediate in the biosynthesis of many secondary metabolites. Salts of benzoic acid are used as food preservatives. Benzoic acid is an important precursor for the industrial synthesis of many other organic substances. The salts and esters of benzoic acid are known as benzoates.

Toluene, also known as toluol, is a substituted aromatic hydrocarbon. It is a colorless, water-insoluble liquid with the smell associated with paint thinners. It is a mono-substituted benzene derivative, consisting of a methyl group (CH3) attached to a phenyl group. As such, its systematic IUPAC name is methylbenzene. Toluene is predominantly used as an industrial feedstock and a solvent.

Acetonitrile, often abbreviated MeCN, is the chemical compound with the formula CH
. This colourless liquid is the simplest organic nitrile. It is produced mainly as a byproduct of acrylonitrile manufacture. It is used as a polar aprotic solvent in organic synthesis and in the purification of butadiene. The N≡C−C skeleton is linear with a short C≡N distance of 1.16 Å.

Xylene Organic compound with the formula (CH3)2C6H4

Xylene (from Greek ξύλον xylon, "wood"), xylol or dimethylbenzene is any one of three isomers of dimethylbenzene, or a combination thereof. With the formula (CH3)2C6H4, in each of the three compounds two hydrogen atoms in the benzene ring are substituted by two methyl groups. They are all colorless, flammable, slightly greasy liquids. They are of great industrial value. The mixture is referred to as both xylene and, more precisely, xylenes. Mixed xylenes refers to a mixture of the xylenes plus ethylbenzene. The four compounds have identical empirical formulas C8H10. Typically the four compounds are produced together by various catalytic reforming and pyrolysis methods.

Benzoyl peroxide Chemical compound with uses in industry and acne treatment

Benzoyl peroxide is a chemical compound (specifically, an organic peroxide) with structural formula (C6H5−C(=O)O−)2, often abbreviated as (BzO)2. In terms of its structure, the molecule can be described as two benzoyl (C6H5−C(=O)−, Bz) groups connected by a peroxide (−O−O−). It is a white granular solid with a faint odour of benzaldehyde, poorly soluble in water but soluble in acetone, ethanol, and many other organic solvents. Benzoyl peroxide is an oxidizer, which is principally used as in the production of polymers.

Benzyl alcohol Chemical compound

Benzyl alcohol is an aromatic alcohol with the formula C6H5CH2OH. The benzyl group is often abbreviated "Bn" (not to be confused with "Bz" which is used for benzoyl), 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 pressure. Benzyl alcohol has moderate solubility in water (4 g/100 mL) and is miscible in alcohols and diethyl ether. The anion produced by deprotonation of the alcohol group is known as benzylate or benzyloxide.

Sodium benzoate Chemical compound

Sodium benzoate is the sodium salt of benzoic acid, widely used as a food preservative and pickling agent. A white crystalline chemical with the formula C6H5COONa, it has an E number of E211. It can be produced by reacting sodium hydroxide with benzoic acid.

Drug metabolism is the metabolic breakdown of drugs by living organisms, usually through specialized enzymatic systems. More generally, xenobiotic metabolism is the set of metabolic pathways that modify the chemical structure of xenobiotics, which are compounds foreign to an organism's normal biochemistry, such as any drug or poison. These pathways are a form of biotransformation present in all major groups of organisms and are considered to be of ancient origin. These reactions often act to detoxify poisonous compounds. The study of drug metabolism is called pharmacokinetics.

Hippuric acid Chemical compound

Hippuric acid is a carboxylic acid and organic compound. It is found in urine and is formed from the combination of benzoic acid and glycine. Levels of hippuric acid rise with the consumption of phenolic compounds. The phenols are first converted to benzoic acid, and then to hippuric acid and excreted in urine.

Aldrin Chemical compound

Aldrin is an organochlorine insecticide that was widely used until the 1990s, when it was banned in most countries. Aldrin is a member of the so-called "classic organochlorines" (COC) group of pesticides. COCs enjoyed a very sharp rise in popularity during and after The Second World War. Other noteworthy examples of COCs include DDT. After research showed that organochlorines can be highly toxic to the ecosystem through bioaccumulation, most were banned from use. It is a colourless solid. Before the ban, it was heavily used as a pesticide to treat seed and soil. Aldrin and related "cyclodiene" pesticides became notorious as persistent organic pollutants.

<i>p</i>-Cresol Chemical compound

para-Cresol, also 4-methylphenol, is an organic compound with the formula CH3C6H4(OH). It is a colourless solid that is widely used intermediate in the production of other chemicals. It is a derivative of phenol and is an isomer of o-cresol and m-cresol.

Benzyl benzoate

Benzyl benzoate is an organic compound which is used as a medication and insect repellent. As a medication it is used to treat scabies and lice. For scabies either permethrin or malathion is typically preferred. It is applied to the skin as a lotion. Typically two to three applications are needed. It is also present in Balsam of Peru, Tolu balsam, and in a number of flowers.

Azinphos-methyl Chemical compound

Azinphos-methyl (Guthion) is a broad spectrum organophosphate insecticide manufactured by Bayer CropScience, Gowan Co., and Makhteshim Agan. Like other pesticides in this class, it owes its insecticidal properties to the fact that it is an acetylcholinesterase inhibitor. It is classified as an extremely hazardous substance in the United States as defined in Section 302 of the U.S. Emergency Planning and Community Right-to-Know Act, and is subject to strict reporting requirements by facilities which produce, store, or use it in significant quantities.

4-Aminobiphenyl (4-APB) is an organic compound with the formula C6H5C6H4NH2. It is an amine derivative of biphenyl. It is a colorless solid, although aged samples can appear colored. 4-Aminobiphenyl was commonly used in the past as a rubber antioxidant and an intermediate for dyes. Exposure to this aryl-amine can happen through contact with chemical dyes and from inhalation of cigarette smoke. Researches showed that 4-aminobiphenyl is responsible for bladder cancer in humans and dogs by damaging DNA. Due to its carcinogenic effects, commercial production of 4-aminobiphenyl ceased in the United States in the 1950s.

Benzotrichloride Chemical compound

Benzotrichloride (BTC), also known as α,α,α-trichlorotoluene, phenyl chloroform or (trichloromethyl)benzene, is an organic compound with the formula C6H5CCl3. Benzotrichloride is an unstable, colorless (to yellowish), viscous, chlorinated hydrocarbon with a penetrating odor. Benzotrichloride is used extensively as a chemical intermediate for products of various classes, i.e. dyes and antimicrobial agents.

<i>o</i>-Toluidine Aryl amine

o-Toluidine (ortho-toluidine) is an organic compound with the chemical formula CH3C6H4NH2. It is the most important of the three isomeric toluidines. It is a colorless liquid although commercial samples are often yellowish. It is a precursor to the herbicides metolachlor and acetochlor.

Benzene Organic chemical compound

Benzene (also called cyclohexatriene) is an organic chemical compound with the molecular formula C6H6. The benzene molecule is composed of six carbon atoms joined in a planar ring with one hydrogen atom attached to each. Because it contains only carbon and hydrogen atoms, benzene is classed as a hydrocarbon.

ortho-Cresol, also called 2-methylphenol, or 2-hydroxytoluene, is an organic compound with the formula CH3C6H4(OH). It is a colourless solid that is widely used intermediate in the production of other chemicals. It is a derivative of phenol and is an isomer of p-cresol and m-cresol.

Terbufos Chemical compound

Terbufos is a chemical compound used in insecticides and nematicides. Terbufos is part of the chemical family of organophosphates. It is a clear, colourless to pale yellow or reddish-brown liquid and sold commercially as granulate.

Methylhippuric acid Chemical compound

Methylhippuric acid is a carboxylic acid and organic compound. Methylhippuric acid has three isomers. The isomers include 2-, 3-, and 4-methylhippuric acid.


  1. 1 2 3 Shou, M; Lu T; Krausz KW; Sai Y; Yang T; Korzekwa KR; Gonzalez FJ; Gelboin HV (2000-04-14). "Use of inhibitory monoclonal antibodies to assess the contribution of cytochromes P450 to human drug metabolism". European Journal of Pharmacology . 394 (2–3): 199–209. doi:10.1016/S0014-2999(00)00079-0. PMID   10771285.
  2. 1 2 3 Nakajima, T; Wang RS; Elovaara E; Gonzalez FJ; Gelboin HV; Raunio H; Pelkonen O; Vainio H; Aoyama T (1997-02-07). "Toluene metabolism by cDNA-expressed human hepatic cytochrome P450". Biochemical Pharmacology . 53 (3): 271–7. doi:10.1016/S0006-2952(96)00652-1. PMID   9065730.
  3. Chapman, DE; Moore TJ; Michener SR; Powis G (November–December 1990). "Metabolism and covalent binding of [14C]toluene by human and rat liver microsomal fractions and liver slices". Drug Metabolism and Disposition . 18 (6): 929–36. PMID   1981539.
  4. 1 2 3 4 5 6 Agency for Toxic Substances and Disease Registry (September 2000). Toxicological profile for toluene. Atlanta, GA: Agency for Toxic Substances and Disease Registry. OCLC   47129207.
  5. 1 2 Kawamoto, T; Matsuno K; Kodama Y; Murata K; Matsuda S (September–October 1994). "ALDH2 polymorphism and biological monitoring of toluene". Archives of Environmental Health . 49 (5): 332–6. doi:10.1080/00039896.1994.9954983. PMID   7944563.
  6. World Health Organization (1985). Environmental Health Criteria No. 52 (Toluene). Geneva: World Health Organization. ISBN   978-92-4-154192-3.
  7. Gregus, Z; Fekete T; Halászi E; Klaassen CD (June 1996). "Lipoic acid impairs glycine conjugation of benzoic acid and renal excretion of benzoylglycine". Drug Metabolism and Disposition . 24 (6): 682–8. PMID   8781786.
  8. Lesaffer G, De Smet R, D'Heuvaert T, Belpaire FM, Lameire N, Vanholder R (October 2003). "Comparative kinetics of the uremic toxin p-cresol versus creatinine in rats with and without renal failure". Kidney International . 64 (4): 1365–73. doi: 10.1046/j.1523-1755.2003.00228.x . PMID   12969155.
  9. Wilkins-Haug, L (February 1997). "Teratogen update: toluene". Teratology . 55 (2): 145–51. doi:10.1002/(SICI)1096-9926(199702)55:2<145::AID-TERA5>3.0.CO;2-2. PMID   9143096.
  10. Tassaneeyakul, W; Birkett DJ; Edwards JW; Veronese ME; Tassaneeyakul W; Tukey RH; Miners JO (January 1996). "Human cytochrome P450 isoform specificity in the regioselective metabolism of toluene and o-, m- and p-xylene". Journal of Pharmacology and Experimental Therapeutics . 276 (1): 101–8. doi:10.1163/2211730x96x00063. PMID   8558417.
  11. Wallen, M; Näslund PH; Nordqvist MB (December 1984). "The effects of ethanol on the kinetics of toluene in man". Toxicology and Applied Pharmacology . 76 (3): 414–9. doi:10.1016/0041-008X(84)90345-4. PMID   6506069.
  12. 1 2 3 Nakajima, T; Wang RS; Murayama N (1993). "Immunochemical assessment of the influence of nutritional, physiological and environmental factors on the metabolism of toluene". International Archives of Occupational and Environmental Health . 65 (1 Supplement): S127–30. doi:10.1007/BF00381323. PMID   8406908. S2CID   41730461.
  13. Hjelm, EW; Näslund PH; Wallén M (1988). "Influence of cigarette smoking on the toxicokinetics of toluene in humans". Journal of Toxicology and Environmental Health . 25 (2): 155–63. doi:10.1080/15287398809531197. PMID   3172270.
  14. 1 2 Duydu, Y; Süzen S; Erdem N; Uysal H; Vural N (July 1999). "Validation of hippuric acid as a biomarker of toluene exposure". Bulletin of Environmental Contamination and Toxicology . 63 (1): 1–8. doi:10.1007/s001289900940. PMID   10423476. S2CID   41078122.
  15. 1 2 3 Angerer, J (1985). "Occupational chronic exposure to organic solvents. XII. O-cresol excretion after toluene exposure". International Archives of Occupational and Environmental Health . 56 (4): 323–8. doi:10.1007/BF00405273. PMID   4066055. S2CID   11705704.
  16. 1 2 3 Angerer, J; Krämer A (1997). "Occupational chronic exposure to organic solvents. XVI. Ambient and biological monitoring of workers exposed to toluene". International Archives of Occupational and Environmental Health. 69 (2): 91–6. doi:10.1007/s004200050121. PMID   9001914. S2CID   46369295.
  17. Inoue, O; Seiji K; Watanabe T; Nakatsuka H; Jin C; Liu SJ; Ikeda M (1993). "Effects of smoking and drinking on excretion of hippuric acid among toluene-exposed workers". International Archives of Occupational and Environmental Health. 64 (6): 425–30. doi:10.1007/BF00517948. PMID   8458658. S2CID   23244308.
  18. Inoue, O; Seiji K; Watanabe T; Chen Z; Huang MY; Xu XP; Qiao X; Ikeda M (May 1994). "Effects of smoking and drinking habits on urinary o-cresol excretion after occupational exposure to toluene vapor among Chinese workers". American Journal of Industrial Medicine . 25 (5): 697–708. doi:10.1002/ajim.4700250509. PMID   8030640.
  19. Laham, S; Potvin M (1987). "Biological conversion of benzaldehyde to benzylmercapturic acid in the Sprague-Dawley rat". Drug and Chemical Toxicology . 10 (3–4): 209–25. doi:10.3109/01480548709042983. PMID   3428183.
  20. Inoue, O; Kanno E; Kasai K; Ukai H; Okamoto S; Ikeda M (2004-03-01). "Benzylmercapturic acid is superior to hippuric acid and o-cresol as a urinary marker of occupational exposure to toluene". Toxicology Letters . 147 (2): 177–86. doi:10.1016/j.toxlet.2003.11.003. PMID   14757321.
  21. Inoue, O; Kanno E; Yusa T; Kakizaki M; Ukai H; Okamoto S; Higashikawa K; Ikeda M (June 2002). "Urinary benzylmercapturic acid as a marker of occupational exposure to toluene". International Archives of Occupational and Environmental Health. 75 (5): 341–7. doi:10.1007/s00420-002-0322-8. PMID   11981673. S2CID   1992662.
  22. Feldman RG, Ratner MH, Ptak T (May 1999). "Chronic toxic encephalopathy in a painter exposed to mixed solvents". Environ Health Perspect. 107 (5): 417–22. doi:10.1289/ehp.99107417. PMC   1566426 . PMID   10210698.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  23. 1 2 3 4 5 6 7 Miyagi, Y; Shima F; Ishido K; Yasutake T; Kamikaseda K (June 1999). "Tremor induced by toluene misuse successfully treated by a Vim thalamotomy". Journal of Neurology, Neurosurgery, and Psychiatry . 66 (6): 794–6. doi:10.1136/jnnp.66.6.794. PMC   1736379 . PMID   10329759.
  24. 1 2 3 Urban, P; Lukáš E; Pelclová D; et al. (2003). "Neurological and neurophysiological follow-up on workers with severe chronic exposure to toluene". Neurotoxicity . P25 (s130).
  25. Schäper, Michael; Seeber, Andreas; van Thriel, Christoph (2008-01-01). "The Effects of Toluene Plus Noise on Hearing Thresholds: An Evaluation Based on Repeated Measurements in the German Printing Industry". International Journal of Occupational Medicine and Environmental Health. 21 (3): 191–200. doi:10.2478/v10001-008-0030-z. ISSN   1896-494X. PMID   19042192.
  26. Yılmaz, Omer Hinc; Kos, Mehmet; Basturk, Arzu; Kesici, Gulin Gokcen; Unlu, Ilhan (2014-11-01). "A comparison of the effects of solvent and noise exposure on hearing, together and separately". Noise and Health. 16 (73): 410–5. doi: 10.4103/1463-1741.144422 . ISSN   1463-1741. PMID   25387537.
  27. 1 2 Yamaguchi, H; Kidachi Y; Ryoyama K (May–June 2002). "Toluene at environmentally relevant low levels disrupts differentiation of astrocyte precursor cells". Archives of Environmental Health. 57 (3): 232–8. doi:10.1080/00039890209602942. PMID   12507177. S2CID   22967797.