Bio: Dr. Daniela M. Leme is a professor of Genetics and Toxicology at the Federal University of Paraná (UFPR) in Curitiba, Brazil, where she also coordinates the In Vitro (Eco)Toxicology Laboratory, an associated laboratory to the Brazilian National Network of Alternative Methods (RENAMA). Her research focuses on developing and applying NAMs, particularly in vitro methods, for chemical risk assessment. Driven by a commitment to advancing knowledge on human health and environmental hazards, the funded projects of her laboratory aim to support the development of safer chemical products, improve understanding of data-poor chemicals, and contribute to assessing complex endpoints, such as carcinogenicity.

Abstract: Microcystins (MCs) are cyclic peptides produced by cyanobacteria, with approximately 310 known congeners. These stable contaminants in water and food pose significant hepatotoxic risks to humans. As with other natural toxins, there is an urgent need to establish or revise health-based guidance values to ensure safe exposure levels. However, this process is challenged by the limited availability of high-purity natural toxin standards required for toxicity testing, and no specific regulatory data requirement exists. For MCs, most toxicity data focus on MC-leucine arginine (MC-LR), the best-studied congener known for its liver effects, including tumor promotion activity (Group 2B – possibly carcinogenic to humans). Nonetheless, the mechanistic understanding of hepatotoxicity remains incomplete, and the toxicity of individual congeners, despite structural similarities, is not fully understood. NAMs, as mechanism-driven approaches, can address these challenges. This lecture will highlight examples of NAMs applied to MCs to better understand congener-specific toxicity and hepatotoxic mechanisms. Topics include the Network Medicine approach (data-driven), in silico predictions, and omics-based techniques (e.g., transcriptomics and metabolomics) in a human hepatocyte model. A read-across exercise based on ECHA’s Read-Across Assessment Framework (RAAF) will also be demonstrated to assess the tumor promotion activity of MC congeners. Key findings, limitations, and uncertainties of each NAM will be critically addressed, as well as their potential to advance MC toxicity assessment.