(175o) Emerging Role of Polycyclic Aromatic Hydrocarbons (PAHs) in the Development of Adverse Outcome Pathways (AOPs) Linking Human Exposure and Health Outcomes

Human Biomonitoring for Europe (HBM4EU) is a European project, which is coordinating and advancing human biomonitoring in Europe in order to provide better evidence of the actual exposure of citizens to chemicals. One of the goals of the project is to generate scientific evidence on the causal links between human exposure to chemicals and health outcomes. Towards this aim, research is ongoing related to the development of adverse outcome pathways (AOPs) related to polycyclic aromatic hydrocarbons (PAHs). This will result in the elucidation of the mechanisms of action of these specific chemical substances and their impact on health effect. In order to identify the most significant PAHs related to the health effects and to target specific AOPs and mechanisms of action, an extended literature review was performed. The following substances accounted for: Benzo(a)pyrene, Dibenzo(def,p)chrysene, Phenanthrene (PHE), Napthalene (NAPH) and 2-Acetylaminofluorene (2-AFF). The latter chemical substances were chosen based of their importance and the priority given for research and production of significant data by the European Commission and the European Food Safety Agency (EFSA).

The review revealed very important targets for further research in order to identify novel AOPs and biomarkers of exposure. More specifically, different AOPs have been identified related to carcinogenicity, reproductive toxicity and genotoxicity. All the relevant AOPs were identified from the OECD database and the AOP-wiki. In vivo experiments using rats showed that Benzo(a)pyrene has been associated with DNA adducts formation, decreased testosterone levels, reduced male fertility, cell death through steatosis, and dysregulation of Aryl Hydrocarbon Receptor (AhR). Dibenzo(def,p)chrysene has been linked to AOPs leading to DNA adducts formation, transplacental carcinogenesis, p53 gene regulation, cell cycle and DNA damage and activation of DNA-reactive metabolites. Experiments with fish models (Oryzias Melastigma) showed a specific effect of phenanthrene on inhibition of ovary development in low and high doses (0.06 – 60 µg/L). In addition, Naphthalene, has shown to be involved in biochemical pathways leading to nasal and alveolar epithelium adenomas. Moreover, genotoxic effect of naphthalene was shown due to chromosome damage in human and rat cell-lines. Finally, 2-acetylaminofluorene in experiments using mice, has shown the formation of DNA adducts in liver.

In general, the mechanisms underlying PAHs toxicity are poorly studied. Nevertheless, recent studies showed indications for further research for specific PAHs in the direction of the development of AOPs. Adverse outcome pathways identified in the current study should be further investigated experimentally with a combination of in vivo, in vitro, and in silico experiments. The series of experiments should be focused on common AOPs in which PAHs analysed in this study are involved, including: cell death and apoptosis, aryl hydrocarbon receptor activation, DNA adducts formation and hormone regulation. In the near future and within HBM4EU project, novel insights are about to be gained, and novel experiments will shed light on these mechanisms, which are involved in specific biochemical pathways and new biomarkers of toxicity will be identified.