3. Minimizing Experimental Testing on Fish for Legacy Pharmaceuticals, Environ. Sci. Technol. 2023
Anja Coors, A. Ross Brown, Samuel K. Maynard, Alison Nimrod Perkins, Stewart Owen, Charles R. Tyler
There was no regulatory requirement for ecotoxicological testing of human pharmaceuticals authorized before 2006, and many of these have little or no data available to assess their environmental risk. Motivated by animal welfare considerations, we developed a decision tree to minimize in vivo fish testing for such legacy active pharmaceutical ingredients (APIs). The minimum no observed effect concentration (NOECmin, the lowest NOEC from chronic Daphnia and algal toxicity studies), the theoretical therapeutic water concentration (TWC, calculated using the fish plasma model), and the predicted environmental concentration (PEC) were used to derive API risk quotients (PEC/NOECmin and PEC/TWC). Based on a verification data set of 96 APIs, we show that by setting a threshold value of 0.001 for both risk quotients, the need for in vivo fish testing could potentially be reduced by around 35% without lowering the level of environmental protection. Hence, for most APIs, applying an assessment factor of 1000 (equivalent to the threshold of 0.001) to NOECmin substituted reliably for NOECfish, and TWC acted as an effective safety net for the others. In silico and in vitro data and mammalian toxicity data may further support the final decision on the need for fish testing.
2. GREENER Pharmaceuticals for More Sustainable Healthcare, Environ. Sci. Technol. Lett. 2022
Caroline T. A. Moermond, Neele Puhlmann, Stewart F. Owen, Jim Ryan, Jason Snape, Bastiaan J. Venhuis, Klaus Kümmerer
Medicines are essential to human health but can also impact the aquatic and terrestrial environment after use by patients and release via excreta into wastewater. We highlight the need for a GREENER approach to identify and meet important environmental criteria, which will help reduce the impact of medicinal residues on the environment. These criteria include effect reduction by avoiding nontarget effects or undesirable moieties, exposure reduction via lower emissions or environmental (bio)degradability, no PBT (persistent, bioaccumulative, and toxic) substances, and risk mitigation. With all of these criteria, however, patient health is of primary importance as medicines are required to be safe and efficacious for treating diseases. We discuss the feasibility of including these criteria for green by design active pharmaceutical ingredients in the process of drug discovery and development and which tools or assays are needed to accomplish this. The integrated GREENER approach can be used to accelerate discussions about future innovations in drug discovery and development.
1. A Generalized Physiologically Based Kinetic Model for Fish for Environmental Risk Assessment of Pharmaceuticals, Environ. Sci. Technol. 2022
Jiaqi Wang, Tom M. Nolte, Stewart F. Owen, Rémy Beaudouin, A. Jan Hendriks and Ad M.J. Ragas
An increasing number of pharmaceuticals found in the environment potentially impose adverse effects on organisms such as fish. Physiologically based kinetic (PBK) models are essential risk assessment tools, allowing a mechanistic approach to understanding chemical effects within organisms. However, fish PBK models have been restricted to a few species, limiting the overall applicability given the countless species. Moreover, many pharmaceuticals are ionizable, and fish PBK models accounting for ionization are rare. Here, we developed a generalized PBK model, estimating required parameters as functions of fish and chemical properties. We assessed the model performance for five pharmaceuticals (covering neutral and ionic structures). With biotransformation half-lives (HLs) from EPI Suite, 73 and 41% of the time-course estimations were within a 10-fold and a 3-fold difference from measurements, respectively. The performance improved using experimental biotransformation HLs (87 and 59%, respectively). Estimations for ionizable substances were more accurate than any of the existing species-specific PBK models. The present study is the first to develop a generalized fish PBK model focusing on mechanism-based parameterization and explicitly accounting for ionization. Our generalized model facilitates its application across chemicals and species, improving efficiency for environmental risk assessment and supporting an animal-free toxicity testing paradigm.