Biomarkers of exposure, effect, and susceptibility in workers exposed to nitrotoluenes.
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Jones, Christopher R.
Brooks, Lance R.
Warren, Sarah H.
Demarini, David M.
MetadataShow full item record
AbstractNitrotoluenes, 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.
CitationCancer Epidemiol. Biomarkers Prev. 2006, 15 (3):559-66
DescriptionBiomarkers of exposure & effect: validationBiomarker: hemoglobin (Hb) adductsExposure/effect represented: Nitrotoluenes, such as 2-nitrotoluene, 2,4-dinitrotoluene (24DNT), and 26DNTStudy type (in vitro, animals, humans): humansStudy design (if human):case-controlStudy size (if human): exposed (n = 104), control (n = 72)Mode of exposure (if in vivo) (acute, chronic, root of exposure):air monitoringMethod of analysis: questionnairesSensitivity (LOD):Specificity:Accuracy:Intraday precision: Interday precision: Intralaboratory repeatability:Interlaboratory repeatability:Intra-individual variation:Inter-individual variation:Half-life:Dose-response:Stability in stored sample:High-throughput automation:Notes:Biomarkers of individual susceptibility: field studiesBiomarker (including alleles if genetic): (GSTM1, GSTT1, GSTP1), N-acetyltransferases (NAT1, NAT2), and sulfotransferases (SULT1A1, SULT1A2)Effect studied (phenotype/pathology):chromosomal aberrations Tissue/biological material/sample size: 5ml samples of heparinized peripheral bloodMethod of analysis: multiplex PCRStudy design: case-controlStudy size: exposed (n = 104), control (n = 72)Impact on outcome (including dose-response): The total frequency of chromatid-type aberrations (breaks, exchanges, and gaps) and the total chromosomal aberration frequency (chromatid type + chromosome type + gaps) were significantly higher in the exposed group than the controls (P < 0.05, Mann-Whitney-test, independent t testTotal chromosomal aberration frequency was significantly higher in the exposed workers compared with a group of workers exposed only to TNT (2.67 F 1.77)Correlation with other biomarkers:There was a significant increase for the major adduct 4ADNT deriving from exposure to TNT (P < 0.05) of TNT-adduct levels in individuals who carried the GSTP1 Val variant alleles.An increase of borderline significance (P < 0.1) was seen for TNT-Hb-adduct levels in GSTM1-null subjects and for the levels of 24DNT and 26DNT adducts in workers with the rapid NAT1 genotype.The levels of one of the 24DNT adducts (24TDA) was significantly lower (P < 0.05) in carriers of the SULT1A2.In workers with the GSTP1 homozygous wild-type genotype, the increase of the 24DNTHb- adducts among subjects with the NAT1 rapid genotype was significant (P < 0.05) compared with the workers with the NAT1 slow genotype. KEYWORDS CLASSIFICATION: adverse effects;analysis;Adult;Air Pollutants;Air Pollutants,Occupational;biomarkers of exposure & effect: validation;biomarkers of individual susceptibility: field studies;Biological Markers;chemically induced;chemistry;Case-Control Studies;Chemical Industry;diagnosis;Disease Susceptibility;epidemiology;Environmental Monitoring;Female;Follow-Up Studies;genetics;Glutathione;Glutathione Transferase;Hematologic Neoplasms;Hematologic Tests;Hemoglobins;Humans;metabolism;methods;Male;Maximum Allowable Concentration;Middle Aged;Occupational Exposure;Research;Risk Assessment;Sensitivity and Specificity;Toluene;Toxicology;urine;Urinalysis;Urinary Bladder Neoplasms;validation;field studies;genetic;blood.
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