Antineoplastic Agents: Environmental Prevalence and Adverse Outcomes in Aquatic Organisms

Abstract

Cancer is the second leading cause of death worldwide, with 9.6 million cancer‐related deaths in 2018. Cancer incidence has increased over time, and so has the prescription rate of chemotherapeutic drugs. These pharmaceuticals, known as antineoplastic agents, enter the aquatic environment via human excretion and wastewater. The objectives of the present critical review were to investigate the risk of antineoplastics to aquatic species and to summarize the current state of knowledge regarding their levels in the environment, because many antineoplastics are not adequately removed during wastewater treatment. We conducted 2 separate literature reviews to synthesize data on the global environmental prevalence and toxicity of antineoplastics. The antineoplastics most frequently detected in the environment included cyclophosphamide, ifosfamide, tamoxifen, methotrexate, and 5‐fluorouracil; all were detectable in multiple water sources, including effluent and surface waters. These antineoplastics span 3 different mechanistic classes, with cyclophosphamide and ifosfamide classified as alkylating agents, tamoxifen as a hormonal agent, and methotrexate and 5‐fluorouracil as antimetabolites. Studies that characterize the risk of antineoplastics released into aquatic environments are scarce. We summarize the biological impacts of the most environmentally prevalent antineoplastics on aquatic organisms and propose an adverse outcome pathway for cyclophosphamide and ifosfamide, 2 widely prescribed drugs with a similar immunotoxic mode of action. Acute and chronic ecotoxicity studies using aquatic models are needed for risk characterization of antineoplastics. Environ Toxicol Chem 2020;39:967–985. © 2020 SETAC

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“…Cyclophosphamide (log K OW = 0.63), an alkylating prodrug used in chemotherapy, and its metabolite ifosfamide ( K OW = 0.83; Kosjek & Heath, 2011) have proved to be highly persistent under laboratory simulation of WWTP and surface water conditions (Buerge et al, 2006). In fact, a recent review, which gathered data on environmental concentrations of antineoplastic agents, listed alkylating agents as the most detected antineoplastic agents in environmental matrices, with measured concentrations of cyclophosphamide as high as 86 µg/L in a hospital effluent (Buerge et al, 2006; Franquet‐Griell, Gómez‐Canela, et al, 2017; Nassour et al, 2020; Wormington et al, 2020). Although the presence of antineoplastic agents in the environment is acknowledged, information regarding their related biological effects on organisms is scarce.…”