Toxic and genotoxic effects of azaarenes: Isomers and metabolites

Heterocyclic PAH and their metabolites can show toxic, mutagenic, carcinogenic and teratogenic effects. In this study, a relation between toxic and mutagenic effects, and chemical structures of nitrogen substituted polycyclic hetero-aromatic hydrocarbons was sought using seven azaarenes and two azaarene metabolites. Survival of first instar larvae of the midge Chironomus riparius was determined to measure toxicity. Mortality increased with increasing number of aromatic rings of the compound, but metabolism of acridine and phenanthridine to 9(10H)-acridone and 6(5H)-phenanthridinone, respectively, strongly decreased toxicity. However, acridone was the most genotoxic of the azaarenes tested in the Mutatox(TM) test. Although mortality and genotoxic activity are well described by molecular descriptors relevant to bioaccumulation, in both cases exceptions are found on this general rule, even between isomers. Furthermore, it is shown that metabolism of azaarenes changed the impact on different biological end-points, clearly putting severe limitations on environmental standards solely based on the narcotic effects of parent PAH.