Neuroactive psychotropic drugs in aquatic systems and the co-treatment of non-target organisms

• Neuroaktive Psychopharmaka in aquatischen Systemen und die Mitbehandlung von Nicht-Zielorganismen

Gundlach, Michael; Hollert, Henner (Thesis advisor); Schäffer, Andreas (Thesis advisor)

Aachen : RWTH Aachen University (2021, 2022)
Dissertation / PhD Thesis

Dissertation, RWTH Aachen University, 2021

Abstract

The focus on the analysis of the major consequences of human impact on Earth for different ecosystems has been constantly changing over the last centuries. A brief overview of the current situation reveals the drastic consequences of climate change and the loss of different species for life on earth and shows how much humans are changing their environment. A serious but much less visible environmental problem is the contamination of freshwater systems by micropollutants, as the resulting consequences cause massive damage at aquatic species communities and have negative impacts on human health due to the closely connected circular systems. Micropollutants are an inhomogeneous group of various microparticles and chemicals that deteriorate the quality of drinking water and which can only be insufficiently eliminated by conventional purification methods. One group of micropollutants whose concentration in the environment has been steadily increasing are human psychotropic drugs. Increasing stress in different life areas is one reason for mental illnesses like depressions and burnout, which leads to an annual increase in the development and use of neuroactive pharmaceuticals. These substances finally enter the aquatic environment through excretion or incorrect disposal and cause ecological changes in the structure of the ecosystems. The European Medicines Agency has formulated a guideline to counteract these consequences, which clearly defines a two-stage procedure for testing the environmental hazard of active pharmaceutical ingredients. However, this system operates on the principle that not all pharmaceuticals need to pass through both stages and that only OECD and ISO-validated standard tests may be used for data generation in the selection of biological test methods. This approach has clear limitations in the effect analysis of neuroactive substances because they are designed to trigger a specific effect at a specific concentration range in the nervous system. The effects that occur at the molecular and physiological levels could not uniformly be measured by general standard test methods and many problems caused by these substances could not be quantified completely. This problem has not yet been sufficiently investigated for the mixtures of these substances that always occur in the environment. A tiered approach was used to investigate the pure substance mirtazapine, artificially prepared mixtures of various neuroactive substances, and native samples from hospital wastewater. The swimming behavior of zebrafish embryos, showed a decreased activity of more than 45 % for mirtazapine concentrations of more than 1 mg/L compared to the control groups. In comparison, the swimming activity of Daphnia magna increased concentration-dependently for the measured concentrations from 0.1 - 200 µg/L mirtazapine. Sedative effects on the swimming behavior of zebrafish embryos could be measured in the more complex samples that were artificially produced as well as in the native environmental samples. The activity decreases were also measurable for substance combinations with complementary modes of action. At gene regulatory level, increases of 8-fold were measured compared to the control group for genes of the serotonin- and dopamine-systems (slc17a6a, slc2a2, slc6a3a). The analysis of native hospital wastewater samples was carried out in an interdisciplinary cooperation i.e. with the Psychiatry Department of the University Hospital Aachen and the Environmental Research Center in Leipzig. The results show a decreased activity for the swimming behavior of zebrafish embryos in relation to the concentration of the recovered neuropharmaceuticals. Activity decreases were measured at the beginning of the day and in the early afternoon. At the gene level, an increase in genes i.e. of the serotonin system could be measured. The behavioral effects can probably be attributed to an overload of the central neural system, which is responsible for the coordination of the movements. The central objective of this work was the development of a tiered test approach on different biological levels to improve the environmental risk assessment for neuroactive substances. Therefore, different quantification methods on physiological level and various ways of quantification these effects on cellular and molecular level are tested and improved. Finally, the results should help to set up recommendations on regulatory level for a better protection of aquatic non-target organisms against these substances in the future.