Owing to their ecological importance, freshwaters provide important services which leads to a strong societal demand concerning the preservation of their quality. They are the receptors of many contaminants emitted by human activities and more specifically by wastewater treatment plants effluents. Water resources of the Meuse watershed are used on both sides of the French-Belgian border which involves a coherent and joint management. In that framework, the DIADeM project suggests developing and spreading out a cross-border multidisciplinary approach to improve the diagnosis and the chemical and biological (biomarkers) monitoring of freshwaters using the Meuse river as a case study. In the past, results from chemical surface water monitoring of the Meuse has revealed the occurrence of numerous substances and more particularly pharmaceuticals. Overall, the project suggests coupling chemical and biomarkers analysis on caged organisms (a crustacean, a mollusk, a moss and a fish species) with predictive mathematical population level models. In order to calibrate and validate these models, a lotic mesocosm experiment was set up. Five substances were chosen: diclofenac, carbamazepine, naproxen, paracetamol and irbesartan. An environmental realistic mixture M of the five substances was tested along with MX10 and MX100. The study was carried out in twelve 20 m long lotic channels. The mesocosms were set up with artificial sediments, macrophytes, periphyton, benthic and pelagic invertebrates, decomposers and one fish species (Gasterosteus aculeatus), zebra mussels, Fontinalis antipyretica and Gammarus fossarum were also caged in the mesocosms. After 3 months of stabilization, treatment lasted 5 months. Periphyton biomass, macrophyte biovolume, zebra mussel biomarkers and growth, G. fossarum survival, reproduction and growth, F. antipyretica biomarkers and growth, zooplankton and invertebrate abundance and diversity, and fish individual physiological responses along with population dynamics were the main measured biological endpoints. The concentrations of each substance in water was monitored monthly along with some physico-chemical parameters. The overall experimental design will be presented along with the results related to the monitoring of substance concentrations in water, physico-chemical parameters, macrophyte biovolume, invertebrate community response, fish larvae densities. A brief discussion of the direct and/or indirect effects will then be performed.