Carcinogenesis Advance Access first published online on October 7, 2004
This version published online on October 7, 2004
Carcinogenesis, doi:10.1093/carcin/bgh286
© 2004 by Oxford University Press
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1 Department of Environmental and Occupational Medicine, The Medical School, University of Newcastle upon Tyne, Newcastle Upon Tyne, UK; Walther-Straub-Institut fuer Pharmakologie und Toxikologie, Ludwig-Maximilians-Universitaet Muenchen, 80336 Muenchen
* To whom correspondence should be addressed. E-mail: gabriele.sabbioni{at}bluewin.ch.
Nitrotoluenes are important intermediates in the chemical industry. 2,6-Dinitrotoluene (26DNT), 2,4-dinitrotoluene (24DNT), and 2-nitrotoluene are carcinogenic in animals and possibly carcinogenic in humans. It is therefore important to develop methods to biomonitor workers exposed to such chemicals. Hemoglobin (Hb)-adducts of nitroarenes are established markers of the biological effective dose. We developed a method to measure Hb-adducts in biological samples. Hb-adducts were measured in rats after a single exposure (0.5 mmol/kg) of 24DNT, 26DNT, 2,4-toluenediamine (24TDA) and 26TDA. Hydrolysis of Hb from rats dosed with 24DNT yields, 4-amino-2-nitrotoluene (4A2NT) (16.3 nmol/g Hb), 24TDA (4.3 nmol/g Hb) and 4-acetylamino-2-amino-toluene (4AA2AT) (0.51 nmol/g Hb). Hydrolysis of Hb from rats dosed with 26DNT yields three amines, 2-amino-6-nitrotoluene (2A6NT) (2.5 nmol/g Hb), 26TDA (1.2 nmol/g Hb) and 6-acetylamino-2-amino-toluene (2AA6AT) (0.17 nmol/g Hb). A similar Hb-adduct pattern was found in Chinese workers exposed to nitrotoluenes. With respect to 24DNT, 4A2NT was the predominant adduct, and the amount was approximately 24 fold higher than 24TDA. With respect to 26DNT, 2A6NT was the predominant adduct, and the amount was approximately 20 fold higher than 26TDA. With respect to the mononitrotoluenes, the Hb-adduct of 2NT was present in the highest concentrations. Each worker was examined for adverse health effects linked to exposure to DNT. The health effects were compared to the Hb-adduct levels using logistic regression analysis. The odds of suffering from inertia were 3.2 times higher (95% confidential interval (CI) =1.8-5.8) when the level of 4A2NT Hb-adducts increased by one log-unit. Similar odds ratio's were observed with somnolence (3.1, CI=1.4-6.9), nausea (2.4, CI=1.3-4.3) and dizziness (5.5, CI=1.3-24.2). These results inferred that quantitation of DNT-Hb adducts provided an effective biomarker of toxicity and could be used estimate the risk associated with a particular exposure to DNT.
Revised September 7, 2004
Accepted September 16, 2004
MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION
Hemoglobin adducts in workers exposed to nitrotoluenes
2 Walther-Straub-Institut fuer Pharmakologie und Toxikologie, Ludwig-Maximilians-Universitaet Muenchen, 80336 Muenchen
3 Chinese Academy of Preventive Medicine, Nan Wei Road 29, Beijing, P.R. China 100050
4 Institute of Environmental and Occupational Toxicology, Casella Postale 108, 6780 Airolo, Switzerland; Walther-Straub-Institut fuer Pharmakologie und Toxikologie, Ludwig-Maximilians-Universitaet Muenchen, 80336 Muenchen
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