Genotoxic effect of polycyclic aromatic hydrocarbons alone or in mixture
Résumé
Polycyclic Aromatic Hydrocarbons (PAHs) are a family of more than one hundred compounds and are potentially carcinogenic to humans. Hazard characterization of PAH complex mixtures is currently based on Toxicity Equivalent Factors (TEFs). However, this method present some limits and it is relevant to define new TEFs for a large number of PAH in order to improve cancer risk assessment for humans. In this study, we used a new genotoxic assay (based on gH2AX quantification) to analyze the genotoxicity of 27 PAHs on three human cell lines representative of major target organs of PAHs: liver (Hep3B), colon (LS-174T) and lung (NCI-H358). Mathematical models were used to determine new TEFs values for PAHs. Dose-genotoxic response modelling was performed using a Hill model, with a focus on effects equivalency between PAHs at low dose. We observed a significant dose-response of genotoxicity in the three cell lines tested for 16 tested compounds and developed new TEFs that we named GEF for Genotoxic Equivalent Factor. Calculated GEFs for the tested PAHs were generally higher than usually utilized TEFs. We further explored the effect of PAH mixtures by testing 16 binary mixtures on LS-174T cells. In some cases, antagonistic, potentiation or synergic actions, or a variation of the maximum response were observed in relation to concentration addition. To confirm these interactions, DNA adducts quantification and metabolic studies are under investigation. Finally, more complex mixtures of PAHs based on 4, 8 or 16 compounds were tested and the genotoxic effect of these mixtures was predicted with concentration addition. In this study, we proposed new TEFs for PAHs based on their genotoxic effects on human cells investigated at low doses. Moreover, we developed mathematical models to predict PAH mixtures genotoxic effect. This method will be useful to improve cancer risk assessment for humans exposed to PAHs.