Tobacco smoking and high-energy visible blue (HEV; 400-500 nm) light exposure are major environmental risk factors for age-related macular degeneration (AMD), the leading cause of blindness in industrialized countries. Individually, they have been shown to cause damage to the retina. We have identified indenopyrene (IcdP), an important organic combustion-derived polycyclic aromatic hydrocarbon (PAH), which can accumulate in the retina, as an exogenous HEV light photosensitizer. HEV-light absorption by nanomolar concentrations of IcdP present in retinal cells promotes degenerative changes comparable to the ones observed in AMD. Using human retinal cells simultaneously exposed to individually low-toxic doses of IcdP and HEV light wavelengths from solar simulator, we found that, in spite of oxidative stress generation, IcdP-HEV light toxic impact on cells is not a direct consequence of photosensitized oxidation reactions. Instead, their interaction results in loss of the tight coupling between the two metabolic phases ensuring IcdP efficient detoxification. Indeed, IcdP/HEV co-exposure induces an over-activation of the aryl hydrocarbon receptor (AhR) signalling – dependent transcription of CYP1 genes and an accumulation of the cytochrome P450 monooxygenase CYP1A2 involved in phase I of metabolism. In addition, IcdP/HEV interaction is associated with a loss of nuclear factor erythroid-2 related factor-2 (Nrf2) and of Nrf2-controled maintenance of glutathione S transferase (GST) proteins, responsible for phase II. Our data thus indicate a phase II hindered in response to co-exposure and insufficient to sustain the enhanced phase I induction. This is reflected by an accelerated endogenous reactive oxygen species (ROS) production and an increased accumulation of IcdP-related bulky DNA damage in retinal cells. Our work raises the prospect that lifestyle and environmental pollution may be significant modulators of HEV light toxicity in the retina.