Chemicals that resist degradation in the environment, referred to as “persistent”, result in long-term exposure for humans and ecosystems. Persistence leads to the gradual accumulation of these pollutants in the environment, creating an increasing environmental stock that may impact populations over very long timescales (decades to centuries). Assessing the effects—and consequently the risks—of persistent substances at low concentrations and over relevant timescales therefore represents a major challenge. The objective of this PhD project is therefore to propose a New Approach Methodology (NAM) based on multigenerational studies, in accordance with the 3Rs principle (Replacement, Reduction, and Refinement). This approach aims to improve environmental risk assessment for persistent substances. Among persistent chemicals, trifluoroacetic acid (TFA) will be investigated as a final degradation product of PFAS. Nematodes are excellent models for multigenerational studies of persistent pollutants due to their very short life cycle (96 h) and the possibility to measure multiple endpoints at infra-individual, individual, and population levels. In addition, mechanistic and statistical modeling (e.g., DEB TK-TD models) allows the integration of biological and toxicological processes into the analysis of ecotoxicological data and enables the study of interactions between these processes.