Toluene (toxicology)

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.cite journal| last =Shou| first =M| coauthors =Lu T, Krausz KW, Sai Y, Yang T, Korzekwa KR, Gonzalez FJ, Gelboin HV| title =Use of inhibitory monoclonal antibodies to assess the contribution of cytochromes P450 to human drug metabolism| journal =European Journal of Pharmacology| volume =394| issue =2-3| pages =199–209| date =2000-04-14| doi =10.1016/S0014-2999(00)00079-0 | pmid =10771285] There are five CYPs which are important in toluene metabolism, CYP1A2, CYP2B6, CYP2E1, CYP2C8, and CYP1A1.cite journal| last =Nakajima| first =T| coauthors =Wang RS, Elovaara E, Gonzalez FJ, Gelboin HV, Raunio H, Pelkonen O, Vainio H, Aoyama T| title =Toluene metabolism by cDNA-expressed human hepatic cytochrome P450| journal =Biochemical Pharmacology| volume =53| issue =3| pages =271–7| date =1997-02-07| doi =10.1016/S0006-2952(96)00652-1 | pmid =9065730] The first four seem to be involved in the hydroxylation of toluene to benzyl alcohol. CYP2El 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. 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;cite journal| last =Chapman| first =DE| authorlink =| coauthors =Moore TJ, Michener SR, Powis G| title =Metabolism and covalent binding of [14C] toluene by human and rat liver microsomal fractions and liver slices| journal =Drug Metabolism and Disposition| volume =18| issue =6| pages =929–36| date =November-December 1990|doi= | pmid =1981539 ] however, this belief does not appear to be universal.cite book |author=Agency for Toxic Substances and Disease Registry| title =Toxicological profile for toluene| publisher =Agency for Toxic Substances and Disease Registry| month =September | year =2000| location =Atlanta, GA| url =http://www.atsdr.cdc.gov/toxprofiles/tp56.html|oclc=47129207] cite journal| last =Kawamoto| first =T| authorlink =| coauthors =Matsuno K, Kodama Y, Murata K, Matsuda S| title =ALDH2 polymorphism and biological monitoring of toluene| journal =Archives of Environmental Health| volume =49| issue =5| pages =332–6| date =September-October 1994 |doi=| pmid =7944563] 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.

Benzoic acid is metabolised to either benzoyl glucuronide or hippuric acid.cite book| author=World Health Organization| title =Environmental Health Criteria No. 52 (Toluene)| publisher =World Health Organization| year =1985| location =Geneva| url =http://www.inchem.org/documents/ehc/ehc/ehc52.htm| isbn =92-4-154192-X ] 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.cite journal| last =Gregus| first =Z| authorlink =| coauthors =Fekete T, Halászi E, Klaassen CD| title =Lipoic acid impairs glycine conjugation of benzoic acid and renal excretion of benzoylglycine| journal =Drug Metabolism and Disposition| volume =24| issue =6| pages =682–8| month =June | year =1996| doi =| pmid =8781786] 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 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.cite journal| last =Lesaffer| first =G| authorlink =| coauthors =De Smet R, D'Heuvaert T, Belpaire FM, Lameire N, Vanholder R| title =Comparative kinetics of the uremic toxin p-cresol versus creatinine in rats with and without renal failure| journal =Kidney International| volume =64| issue =4| pages =1365–73| month =October | year =2003| url =| doi =10.1046/j.1523-1755.2003.00228.x| pmid =12969155] o-cresol appears to be excreted mostly unchanged in urine or as the glucuronide or sulfate conjugate.cite journal| last =Wilkins-Haug| first =L| authorlink =| title =Teratogen update: toluene| journal =Teratology| volume =55| issue =2| pages =145–51| month =February | year =1997| url =| doi =10.1002/(SICI)1096-9926(199702)55:2<145::AID-TERA5>3.0.CO;2-2| pmid =9143096| doilabel =10.1002/(SICI)1096-9926(199702)55:2145::AID-TERA53.0.CO;2-2] There appears to be some dispute over whether m-cresol is produced as a metabolite of toluene or not.cite journal| last =Tassaneeyakul| first =W| authorlink =| coauthors =Birkett DJ, Edwards JW, Veronese ME, Tassaneeyakul W, Tukey RH, Miners JO| title =Human cytochrome P450 isoform specificity in the regioselective metabolism of toluene and o-, m- and p-xylene| journal =Journal of Pharmacology and Experimental Therapeutics| volume =276| issue =1| pages =101–8| month =January | year =1996| url =| doi =| pmid =8558417]

Environmental influences

When exposure to toluene occurs there is usually simultaneous exposure to several other chemicals. 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. 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.cite journal| last =Wallen| first =M| authorlink =| coauthors =Näslund PH, Nordqvist MB| title =The effects of ethanol on the kinetics of toluene in man| journal =Toxicology and Applied Pharmacology| volume =76| issue =3| pages =414–9| month =December | year =1984| url =| doi =| pmid =6506069] Other studies have shown that chronic ethanol consumption can enhance toluene metabolism via the induction of CYP2E1.cite journal| last =Nakajima| first =T| authorlink =| coauthors =Wang RS, Murayama N| title =Immunochemical assessment of the influence of nutritional, physiological and environmental factors on the metabolism of toluene| journal =International Archives of Occupational and Environmental Health| volume =65| issue =1 Supplement| pages =S127–30| year =1993| url =| doi =10.1007/BF00381323| pmid =8406908] Smoking has been shown to enhance the elimination rate of toluene from the body, this perhaps occurs as a result of enzyme induction.cite journal| last =Hjelm| first =EW| authorlink =| coauthors =Näslund PH, Wallén M| title =Influence of cigarette smoking on the toxicokinetics of toluene in humans| journal =Journal of Toxicology and Environmental Health| volume =25| issue =2| pages =155–63| year =1988| url =| doi =| pmid =3172270]

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;cite journal| last =Duydu| first =Y| authorlink =| coauthors =Süzen S, Erdem N, Uysal H, Vural N| title =Validation of hippuric acid as a biomarker of toluene exposure| journal =Bulletin of Environmental Contamination and Toxicology| volume =63| issue =1| pages =1–8| month =July | year =1999| url =| doi =10.1007/s001289900940| pmid =10423476] however, there appears to be some doubt about its validity.cite journal| last =Angerer| first =J| authorlink =| title =Occupational chronic exposure to organic solvents. XII. O-cresol excretion after toluene exposure| journal =International Archive of Occupational and Environmental Health| volume =56| issue =4| pages =323–8| year =1985| url =| doi =10.1007/BF00405273| pmid =4066055] 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.cite journal| last =Angerer| first =J| authorlink =| coauthors =Krämer A| title =Occupational chronic exposure to organic solvents. XVI. Ambient and biological monitoring of workers exposed to toluene| journal =International Archives of Occupational and Environmental Health| volume =69| issue =2| pages =91–6| year =1997| url =| doi =10.1007/s004200050121| pmid =9001914] 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.cite journal| last =Inoue| first =O| authorlink =| coauthors =Seiji K, Watanabe T, Nakatsuka H, Jin C, Liu SJ, Ikeda M| title =Effects of smoking and drinking on excretion of hippuric acid among toluene-exposed workers| journal =International Archives of Occupational and Environmental Health| volume =64| issue =6| pages =425–30| year =1993| url =| doi =10.1007/BF00517948| pmid =8458658] This has led to the investigation of other metabolites as markers for toluene exposure.

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. o-Cresol may be a less sensitive marker of toluene exposure than hippuric acid.cite journal| last =Inoue| first =O| authorlink =| coauthors =Seiji K, Watanabe T, Chen Z, Huang MY, Xu XP, Qiao X, Ikeda M| title =Effects of smoking and drinking habits on urinary o-cresol excretion after occupational exposure to toluene vapor among Chinese workers| journal =American Journal of Industrial Medicine| volume =25| issue =5| pages =697–708| month =May | year =1994| url =| doi =| pmid =8030640] o-Cresol excretion may be an unreliable method for measuring toluene exposure because o-cresol makes up <1% of total toluene elimination.

Benzylmercapturic acid, a minor metabolite of toluene, is produced from benzaldehyde.cite journal| last =Laham| first =S| authorlink =| coauthors =Potvin M| title =Biological conversion of benzaldehyde to benzylmercapturic acid in the Sprague-Dawley rat| journal =Drug and Chemical Toxicology| volume =10| issue =3-4| pages =209–25| year =1987| url =| doi =| pmid =3428183] 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.cite journal| last =Inoue| first =O| authorlink =| coauthors =Kanno E, Kasai K, Ukai H, Okamoto S, Ikeda M| title =Benzylmercapturic acid is superior to hippuric acid and o-cresol as a urinary marker of occupational exposure to toluene| journal =Toxicology Letters| volume =147| issue =2| pages =177–86| date =2004-03-01| url =| doi =10.1016/j.toxlet.2003.11.003 | pmid =14757321] cite journal| last =Inoue| first =O| authorlink =| coauthors =Kanno E, Yusa T, Kakizaki M, Ukai H, Okamoto S, Higashikawa K, Ikeda M| title =Urinary benzylmercapturic acid as a marker of occupational exposure to toluene| journal =International Archives of Occupational and Environmental Health| volume =75| issue =5| pages =341–7| month =June | year =2002| url =| doi =10.1007/s00420-002-0322-8| pmid =11981673]

Effects of long term exposure

Serious adverse behavioural effects are often associated with toluene abuse related to the deliberate inhalation of solvents.cite journal| last =Miyagi| first =Y| authorlink =| coauthors =Shima F, Ishido K, Yasutake T, Kamikaseda K| title =| journal =Journal of Neurology Neurosurgery and Psychiatry| volume =66| issue =6| pages =794–6| month =June | year =1999| url =| doi =| pmid =10329759] Long term toluene exposure is often associated with effects such as: psychoorganic syndrome;cite journal| last =Urban| first =P| authorlink =| coauthors =Lukáš E, Pelclová D "et al."| title =Neurological and neurophysiological follow-up on workers with severe chronic exposure to toluene| journal =Neurotoxicity| volume =P25| issue =s130| pages =| year =2003| url =| doi =| id =] visual evoked potential (VEP) abnormality; toxic polyneuropathy, cerebellar, cognitive, and pyramidal dysfunctions; optic atrophy; and brain lesions.

Toluene causes postural tremors by increasing extracellular concentrations of γ-aminobutyric acid (GABA) within the cerebellar cortex. Treatment with GABA agonists such as, benzodiazepines provide some relief from toluene induced tremor and ataxia. An alternative to drug treatment is vim thalamotomy. 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 precursor cells.cite journal| last =Yamaguchi| first =H| authorlink =| coauthors =Kidachi Y, Ryoyama K| title =Toluene at environmentally relevant low levels disrupts differentiation of astrocyte precursor cells| journal =Archives of Environmental Health| volume =57| issue =3| pages =232–8| date =May-June 2002| url =| doi =| pmid =12507177] 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.

References

External links

* [http://www.atsdr.cdc.gov/csem/toluene/ ATSDR - Case Studies in Environmental Medicine: Toluene Toxicity] U.S. Department of Health and Human Services (public domain)