A hybrid qualitative–quantitative framework for risk informed prioritization of legacy anticancer drugs in aquatic matrices

Legacy anticancer drugs authorized before 2006 often lack formal environmental risk assessments (ERA), while occurrence, fate, and ecotoxicity data remain scarce in Morocco’s water-stressed semi-arid regions. Guided by relevant principles of the EMA 2024 guideline, we developed a qualitative–quantitative framework to prioritize five anticancer drugs; cyclophosphamide (CP), ifosfamide (IF), 5-fluorouracil (5-FU), doxorubicin (DOX), and etoposide (ETO); in hospital wastewater (HWW), wastewater treatment plant (WWTP) effluents, and groundwater (GW) in Oujda, Morocco. The qualitative component integrated regional epidemiology, consumption, mode of action, physicochemical properties, WWTP removal, environmental occurrence, and ecotoxicological data gaps. Maximum measured environmental concentrations (MECmax) were used to calculate harmonized chronic screening risk quotient (RQs) for algal growth and crustacean reproduction. Genotoxicity was evaluated separately using assay-specific exploratory screening quotients (GSQ geno ). Mixture RQs were calculated only within harmonized species–endpoint combinations under concentration addition; groundwater was assessed separately using PNEC SW /10. All compounds received high or very high qualitative priority. Chronic RQs ranged from low to extremely high risk, while GSQ geno values were ≥1 for nearly all compounds assessed within their respective assay groups. At both individual-compound and mixture levels, HWW and WWTP prioritization was driven by 5-FU for chronic risk and co-dominant ETO, DOX in HWW for genotoxicity-screening signals. In groundwater, the corresponding priorities were driven by 5-FU and DOX, respectively. Mixture RQs indicated cumulative concern under additivity, not synergy. Integrating qualitative and endpoint-specific quantitative evidence supported monitoring and data-generation priorities without creating a combined risk index or replacing an EMA 2024-compliant ERA.