Predicted No Effect Concentrations (PNECs) of antifungals for wastewater management and agricultural use

D. Gil¹S. José¹A. Ascenso¹Monika Novak Babič²Esther Segal³Joseph Meletiadis⁴J. P. Gangneux^5,6C. J. Weiskerger⁷Helena Solo-Gabriele⁸Elisabete Valério^1,9João Brandão^10,9*

• ¹Instituto Nacional de Saude Doutor Ricardo Jorge, Lisbon, Portugal
• ²Univerza v Ljubljani Biotehniska fakulteta, Ljubljana, Slovenia
• ³Tel Aviv University Faculty of Medical and Health Sciences, Tel Aviv-Yafo, Israel
• ⁴University of Athens, Medical School, Athens, Greece
• ⁵Centre Hospitalier Universitaire de Rennes, Rennes, France
• ⁶Institut de Recherche en Sante Environnement et Travail, Rennes, France
• ⁷US Environmental Protection Agency Region 4, Atlanta, United States
• ⁸University of Miami, Coral Gables, United States
• ⁹Centre for Ecology, Evolution and Environmental Changes (CE3C), Lisbon, Portugal
• ¹⁰National Health Institute Doutor Ricardo Jorge (INSA), Lisbon, Portugal

Antifungal resistance is an on-growing public health concern due to the difficulty in managing or treating medical conditions that often favour fatal fungal infections. The changing climate and globalisation, which increase fungal persistence and propagation, adds to that concern. Wastewater disposal is one potential source to the environment as antifungals are released into it. Considering that most fungal infections originate from the environment and considering the One Health principle, introducing antifungals through wastewater effluents has the potential to promote the emergence and dissemination ofwill inevitably potentiate further antifungal resistance. The objective of this study was to generate knowledge that can assist regulating the release of antifungals in the environment by quantifying predicted no-effect concentrations (PNECs) that would not promote antifungal resistance. For this purpose, a systematic review was performed to consolidate information on antifungals released to the environment and respective concentrations. The systematic literature review followed Preferred Reporting Items for Systematic literature reviews and Meta Analyses extension for Scoping Reviews (PRISMA-SLR). The analysis of 122 reviewed articles using this approach showed high concentrations and dispersion of antifungals in water, wastewater or soil. This highlights their potential dispersion in the environment, thus increasing the potential of fungal antimicrobial resistance. Due to the lack of PNEC values using fungi as model organisms in this review, PNECs for 17 antifungals were calculated using Candida albicans as model, as it is done for clinical purposes. We consider that the antifungal PNECs calculated and consolidated from the literature can be used to prioritise them for regulation and to determine acceptable levels in wastewater effluents. Lay abstract Antifungals in wastewater and soil can drive drug resistance in fungi. We reviewed global studies and calculated safe environmental levels (PNECs) to guide regulation and protect human, animal, and environmental health.