Carcinogenesis Advance Access originally published online on October 7, 2004
Carcinogenesis 2005 26(1):133-143; doi:10.1093/carcin/bgh286
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Carcinogenesis vol.26 no.1 © Oxford University Press 2005; all rights reserved.
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Hemoglobin adducts in workers exposed to nitrotoluenes
1 Institute of Environmental and Occupational Toxicology, Casella Postale 108, 6780 Airolo, Switzerland, 2 Department of Environmental and Occupational Medicine, The Medical School, University of Newcastle Upon Tyne, Newcastle Upon Tyne, UK, 3 Walther-Straub-Institut fuer Pharmakologie und Toxikologie, Ludwig-Maximilians-Universitaet Muenchen, 80336 Muenchen, Germany and 4 Chinese Academy of Preventive Medicine, Nan Wei Road 29, Beijing, P. R. China 100050
5 To whom correspondence should be addressed Email: 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-aminotoluene (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 2-acetylamino-6-aminotoluene (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 
24-fold higher than 24TDA. With respect to 26DNT, 2A6NT was the predominant adduct, and the amount was 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 with the Hb adduct levels using logistic regression analysis. The odds of suffering from inertia were 3.2 times higher [95% confidence interval (CI) = 1.8–5.8] when the level of 4A2NT Hb adducts increased by one log-unit. Similar odds ratios 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 quantification of DNT–Hb adducts provided an effective biomarker of toxicity and could be used to estimate the risk associated with a particular exposure to DNT.
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