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Biomarkers of Exposure, Effect, and Susceptibility in Workers Exposed to Nitrotoluenes

¹ Institute of Environmental and Occupational Toxicology, Airolo, Switzerland; ² Walther-Straub-Institut für Pharmakologie und Toxikologie, Ludwig-Maximilians-Universität München, Munich, Germany; ³ Department of Environmental and Occupational Medicine, The Medical School, University of Newcastle-upon-Tyne, Newcastle-upon-Tyne, United Kingdom; ⁴ Department of Industrial Hygiene and Toxicology, Finnish Institute of Occupational Health, Helsinki, Finland; ⁵ Department of Toxicology, German Institute of Human Nutrition, Potsdam-Rehbrücke, Germany; ⁶ Institute of Occupational Medicine, Chinese Academy of Preventive Medicine, Beijing, P.R. China; and ⁷ Environmental Carcinogenesis Division, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina

Requests for reprints: Gabriele Sabbioni, Institute of Environmental and Occupational Toxicology, Casella Postale 108, 6780 Airolo, Switzerland. E-mail: gabriele.sabbioni{at}bluewin.ch.

Nitrotoluenes, such as 2-nitrotoluene, 2,4-dinitrotoluene (24DNT), and 26DNT, are carcinogenic in animal experiments. Humans are exposed to such chemicals in the workplace and in the environment. It is therefore important to develop methods to biomonitor people exposed to nitrotoluenes to prevent the potential harmful effects. For the present study, workers exposed to high levels of these chemicals were investigated. The external dose (air levels), the internal dose (urine metabolites), the biologically effective dose [hemoglobin (Hb) adducts and urine mutagenicity], and biological effects (chromosomal aberrations and health effects) were determined. Individual susceptibility was assessed by determining genetic polymorphisms of enzymes assumed to function in nitrotoluene metabolism, namely glutathione S-transferases (GSTM1, GSTT1, GSTP1), N-acetyltransferases (NAT1, NAT2), and sulfotransferases (SULT1A1, SULT1A2). The levels of urinary metabolites did not correlate with the air levels. The urinary mutagenicity levels determined in a subset of workers correlated with the levels of a benzylalcohol metabolite of DNT. The Hb-adducts correlated with the urine metabolites but not with the air levels. The frequency of chromosomal aberrations (gaps included) was increased (P < 0.05) in the exposed workers in comparison with a group of factory controls and correlated with the level of 24DNT Hb-adducts in young subjects (<31 years). The GSTM1-null genotype was significantly more prevalent in the controls than in the exposed group, which probably reflected an elevated susceptibility of the GSTM1-null genotype to adverse health effects of DNT exposure, such as nausea (odds ratio, 8.8; 95% confidence interval, 2.4-32.2). A statistically significant effect was seen for SULT1A2 genotype on a 24DNT Hb-adduct; GSTP1 genotype on a 2,4,6-trinitrotoluene Hb-adduct; and SULT1A1, SULT1A2, NAT1, GSTT1, and GSTP1 genotypes on chromosomal aberrations in the exposed workers. (Cancer Epidemiol Biomarkers Prev 2006;15(3):559–66)