[Evaluating the Validity of the Action Limit and Predicted Environmental Concentration (PEC) in Environmental Risk...

As human pharmaceuticals are physiologically active substances, it is essential to assess their potential risk to ecosystems after being released into the environment. In Japan, the "Guidance on the Environmental Risk Assessment in New Pharmaceutical Development" (hereafter referred to as "the guidance") was issued in 2016. The guidance includes the environmental risk assessment (ERA) workflow, in which novel pharmaceuticals subjected to ecotoxicity testing are selected based on n-octanol/water partition coefficient (log K_ow), action limit (0.01 µg/L), and predicted environmental concentration (PEC). However, for the ERA workflow, neither the action limit has been completely validated nor a method to calculate PEC has been sufficiently established. The objective of this study was to demonstrate the effectiveness and issues of the ERA workflow in the guidance. Using data accumulated from ecotoxicity studies and measured environmental concentration (MEC) data of human pharmaceuticals, we evaluated the validity of the action limit and PEC values. The action limit was found to be sufficiently on the safe side, and the PEC values (to median or 95th percentile MEC values) were generally on the safe side for the evaluated pharmaceuticals. Conversely, issues were also identified, which included a need to establish exemption rules for some specific pharmaceuticals with toxicological concerns at a concentration below the action limit and to refine the PEC calculation method based on the consideration of drug metabolism and environmental fate. The endeavor to address these issues will increase the reliability and effectiveness of the workflow.