Toxicology Letters 213 (2012) 57–62 Contents lists available at ScienceDirect Toxicology Letters jou rn al h om epage: www.elsevier.com/locate/toxlet Low occupational exposure to benzene in a petrochemical plant: Modulating effect of genetic polymorphisms and smoking habit on the urinary t,t-MA/SPMA ratio Antonella Mansi a , Roberta Bruni a , Pasquale Capone a , Enrico Paci b , Daniela Pigini a , Carla Simeoni c , Rossella Gnerre c , Maddalena Papacchini c , Giovanna Tranfo b,∗ a INAIL Research, Department of Occupational Hygiene, Via di Fontana Candida 1, 00040 Monteporzio Catone, Rome, Italy b INAIL Research, Department of Occupational Medicine, Via di Fontana Candida 1, 00040 Monteporzio Catone, Rome, Italy c INAIL Research, Department for Production Plants and Interactions with the Environment, Via di Fontana Candida 1, 00040 Monteporzio Catone, Rome, Italy a r t i c l e i n f o Article history: Available online 5 February 2011 Keywords: Benzene Low exposure t,t-MA/SPMA ratio Genetic polymorphism Risk assessment a b s t r a c t The identification of reliable biomarkers is critical for the assessment of occupational exposure of ben- zene: S-phenylmercapturic acid (SPMA) and trans,trans-muconic acid (t,t-MA) are the most currently used. t,t-MA is an open-ring metabolite, but it is also a metabolite of the food preservative sorbic acid, while SPMA is formed by conjugation with glutathione, and several studies suggested that the genetic polymorphism of glutathione S-transferases modulates its production. This study compared the ability of these metabolites to assess the benzene exposure in a big group of petrochemical workers. Further- more, investigated how genetic polymorphism of glutathione S-transferase theta 1 (GSTT1), glutathione S-transferase mu 1 (GSTM1), glutathione S-transferase pi 1 (GSTP1) and smoking habits, may influence their excretion. Results showed that occupational exposure to benzene was negligible compared to that from smoking and confirmed the modulating effect of the genetic polymorphism of GSTT1 on the urinary excretion of SPMA, but not of t, t-MA, even at very low levels of benzene exposure. The same effect was found for GSTM1, but only for smokers. The t,t-MA/SPMA ratio was not a constant value and resulted to be higher than the corresponding Biological Exposure Index (BEI) ratio, which is currently equal to 20. Higher values of metabolite have been associated with the GSTT1 or GSTM1 null genotype and these are responsible for increase health risk. We suggest that this ratio could be used as a marker of individual susceptibility for subjects with benzene exposure. © 2011 Elsevier Ireland Ltd. All rights reserved. 1. Introduction Occupational exposure to benzene occurs primarily in the petro- chemical industries, coke oven and steel plants, chemical and associated industries. In several developed countries, airborne benzene levels in polluted working settings have progressively decreased because of preventive and control measures. On the other hand, several studies reported that even in the indoor envi- ronment, benzene concentration could reach levels of concern for public health. For this reason, the identification of specific and sensitive biological markers has become a critical factor for the definition of how relevant is exposure to low benzene levels for ∗ Corresponding author. Tel.: +39 06 97896054; fax: +39 06 94181410. E-mail addresses: antonella.mansi@ispesl.it (A. Mansi), carla.simeoni@ispesl.it (C. Simeoni), maddalena.papacchini@ispesl.it (M. Papacchini), giovanna.tranfo@ispesl.it (G. Tranfo). health risk assessment (Fustinoni et al., 2005). In the outdoor environment, petroleum products, such as traffic, driving, vehicles refuelling in gasoline stations are the main sources of exposure to benzene for the general population (Dougherty et al., 2008). The other major source of environmental exposure to benzene is cigarette smoking. It has been estimated that smokers receive about 90% of their benzene intake from smoking (Johnson et al., 2007). Since 1982 benzene has been classified as a potential carcino- gen (leukemogen) in humans (Group I) by the International Agency for Research on Cancer (IARC, 1987). Exposure to benzene can lead to multiple alterations that contribute to the leukemogenic pro- cess, indicating a multimodal mechanism of action. Further studies are needed to clarify the different roles of multiple metabolites in benzene toxicity (Smith, 2010). The biotransformation of benzene leads to hydroquinone and catechol metabolites, which are able to generate semiquinones and reactive oxygen species via redox cycling mechanisms (Barreto et al., 2009). A pathway catalyzed by glutathione S-transferase (GSTM1 or GSTT1) leads from benzene 0378-4274/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.toxlet.2011.02.001