An integrated One Health framework for holistic evaluation of risks from antifungal agents in a large-scale multi-city study.

A new framework for retrospective mass spectral data mining for antifungal agents (AFs) and Wastewater-Based Epidemiology (WBE) was developed as part of One Health framework to tackle risks from AFs. A large scale, multi-city study was undertaken in South-West England. Key drivers of AFs in the catchment were identified with communal wastewater discharges being the main driver for human AFs (fluconazole, ketoconazole) and agricultural runoff being the main driver for pesticide AFs (prochloraz, prothioconazole and tebuconazole). Average WBE-estimated human used fluconazole and ketoconazole PNDIs (population normalised daily intake) exceeded 300 mg day 1000 inh and 2000 mg day 1000 inh. This is much higher than PNDPs (population normalised daily prescriptions <40 mg day 1000 inh and <80 mg day 1000 inh for fluconazole and ketoconazole respectively). This was expected due to both prescription and over-the-counter usage, and both oral and topical applications. Pesticide AF, prothioconazole had PNDIs <40,000 mg day 1000 inh , which gave intake: 0.43, 0.26, 0.07 mg kg in City A, B, and C, likely due to accounting for external/non-human sources. This is higher than the acceptable daily intake (ADI) of 0.01 mg kgbw day, which warrants further study. Intake per kg of body weight estimated using tebuconazole was 0.86, 1.39, 0.12, 0.13, and 2.7 mg kg in City A-E respectively and is likely due to external/non-human sources. Intake calculated using its metabolite was 0.02 and 0.01 mg kg in City B and C respectively, which aligned with ADI (0.03 mg kgbw day). The environmental risk assessment of AFs indicated low/medium risk from fluconazole, prochloraz, and tebuconazole, medium risk from epoxiconazole, prothioconazole's metabolite, and tebuconazole, and high risk for prothioconazole in river water. High risk was estimated from fluconazole, epoxiconazole, prothioconazole and its metabolite, tebuconazole, ketoconazole in wastewater samples, which is important during raw sewage discharge events via sewer overflows.