http://informahealthcare.com/dct ISSN: 0148-0545 (print), 1525-6014 (electronic) Drug Chem Toxicol, Early Online: 1–8 ! 2013 Informa Healthcare USA, Inc. DOI: 10.3109/01480545.2013.806529 RESEARCH ARTICLE Cytotoxic effects induced in vitro by organic extracts from urban air particulate matter in human leukocytes Francesco Cimino 1 , Antonio Speciale 1 , Laura Siracusa 2 , Clara Naccari 1 , Antonella Saija 1 , Ferdinando Mancari 1 , Roberto Raciti 1 , Mariateresa Cristani 1 , and Domenico Trombetta 1 1 Department Farmaco-Biologico, School of Pharmacy, University of Messina, Viale Annunziata, Messina, Italy and 2 Istituto del CNR di Chimica Biomolecolare, Catania, Italy Abstract Urban areas represent major pollution sources as a result of anthropogenic activities located in these districts. Among the legislated air pollutants, polycyclic aromatic hydrocarbons (PAHs), which are mostly adsorbed on the surface of dust particles, are known for their adverse health effects. The present study has been carried out to examine the cytotoxic effects induced in vitro on human peripheral monocytes (PBMCs) by extractable organic matter (EOM) from PM10 (characterized for its PAH content) collected at four sites in the urban center of Messina, Italy. Chromatographic analyses showed the presence of PAHs in all EOM. Only EOM from one site induced a marked cell death probably resulting from the highest PAH content in this sample. Conversely, apoptosis activation was evident after PBMC exposure to all the EOM tested. These apoptotic effects do not appear related only to the total PAH content, but are probably influenced by chemical composition. In conclusion, our findings confirm that the cytotoxic potential of organic matter associated to ambient respirable air particles depends predom- inantly on the quantity and quality of the chemicals contained in it. In particular, the present data strongly evidence that the only evaluation of air concentration of particulate matter and benzo[a]pyrene, as well as the generally used risk models based on additivity, are not sufficient to evaluate air quality and PAH effect on human health because they do not take into account the possible inhibitory or synergic or antagonistic effect of combined exposure and the interference of other organic compounds present in respirable matter. Keywords Air particulate matter, cytotoxicity, human leukocytes History Received 29 October 2012 Revised 20 April 2013 Accepted 20 April 2013 Published online 6 November 2013 Introduction There is wide evidence that the toxic effects of ambient air particulate matter (PM) are related to chemical compounds bound onto the particles or to particles themselves. Assessment of the toxicity of mixtures of organic chemicals to which humans are exposed through air pollution is a major issue in public health, because humans, and especially the general population, are rarely exposed to pure chemicals, but rather to complex mixtures. Unfortunately, this appears to be a difficult task because of the modulation of the toxic properties of a chemical by the other molecules present in the mixture. This issue, besides being rarely studied, has been generally investigated using artificial extractable organic matter (EOM), and there are no reports that compare the biological effects of chemically different environmental EOM. Most studies con- cerning the toxic effect of environmental EOM are focused on polycyclic aromatic hydrocarbons (PAHs) and their deriva- tives. In fact, PAHs are a ubiquitous group of chemical compounds polluting the environment, but in the ambient air, they are mostly adsorbed on the surface of dust particles (Hanzalova et al., 2010), including respirable PM (Calle ´n et al., 2010). Mostly produced by the incomplete combustion of organic material, their source in cities is exclusively anthropogenic and automobile exhaust is recog- nized as one of the main PAHs contributor in urban areas. Among the legislated air pollutants, because of their adverse effects on health, PAHs are controlled under Directive 2004/107/EC of the European Parliament and of the Council (concerning arsenic, cadmium, mercury and nickel, besides PAHs). First, although several PAHs are classified as possible or probable human carcinogens by the International Agency of Research on Cancer (IARC, 2008) and by the European Union (EU), benzo[a]pyrene (B[a]P) is a PAH of particular interest because it is the only one classified as a recognized carcinogen to humans by the IARC (Tarantini et al., 2009). Upon entering the organism, PAHs are first metabolized to transdihydrodiols by the activity of cytochrome P450 (CYP) enzymes and epoxide hydrolase and then oxidized to reactive electrophiles by two pathways (Hanzalova et al., 2010). PAHs can indirectly give rise to oxidative damage as the result of the release of reactive oxygen species during their metabolization and by the redox cycling of PAH o-quinone (Tarantini et al., 2009). Further, PAHs and PM can lead to the Address for Correspondence: Domenico Trombetta, Department Farmaco-Biologico, School of Pharmacy, University of Messina, Viale Annunziata, 98168 Messina, Italy. 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