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

Abstract

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 Hbadducts 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.

Genetic Susceptibility and Health Effects of Occupational Exposure to Nitroaromatic Compounds in Ammunition Industry (B)

“…Among the exposed workers, chromosomal aberrations were more frequent among carriers of GSTP1 mutant allele than among wild gene group. These data suggest that GSTP1 variant allele may be associated with a lowered protection against reactive metabolites of TNT (Sabbioni et al, 2006). …”

“…These results indicate that using a set of well-selected biomarkers may give more information regarding exposure and effect than routinely performed chemical measurements of pollutants in the air or on the skin (Sabbioni et al, 2006). Personal susceptibility to occupational toxins in general and particularly nitroaromatic compounds is still a new era of research with very limited studies.…”

“…carrying the GST polymorphic genotype are supposed to be more susceptible to some nitroaromatic compounds health hazards thus studying individual susceptibility (genetic polymorphisms of nitroaromatic compounds metabolizing enzymes such as GST) is one of the variables of bio monitoring paradigm (Sabbioni et al, 2006).…”

DNA damage and estrogenic activity induced by the environmental pollutant 2-nitrotoluene and its metabolite

“…The tumorigenicity in reproductive organs, such as the mammary gland fibroadenoma and epidermis mesothelioma, and the male reproductive toxicity suggest certain endocrine-disrupting effects. Some reports indicate that 2-NO 2 -T may contribute to genetic lesions [2,5,6]. The carcinogenic and reproductively toxic mechanisms of 2-NO 2 -T are not fully established.…”

2,4,6‐Trinitrotoluol (und Isomeren in techn. Gemischen) [MAK Value Documentation in German language, 2008]

“…Bei Kontrollpersonen wurden keine Addukte nachgewiesen (Sabbioni et al 1996). Auch anschließende Untersuchungen an Arbeitern, die gegen 2,4,6-Trinitrotoluol exponiert waren, bestätigten eine erhöhte 4-Amino-2,6-dinitrotoluol-Hämoglobinad-duktbildung (Hagmann et al 2004;Jones et al 2005 b;Sabbioni et al 2005Sabbioni et al , 2006. Bei zwei Arbeitern, die in dem Bodenlager eines Rüstungsaltstandortes beschäftigt waren, und bei 45 Bewohnern von Grundstücken mit 2,4,6-Trinitrotoluol-kontaminierten Böden dieses Rüstungsaltstandortes waren die Hämoglobinaddukte nachweisbar, aber im Vergleich zu 48 Kontrollpersonen nicht signifikant erhöht, woraus auf eine weit verbreitete Hintergrundbelastung geschlossen wurde.…”