GARD : An in vitro platform for toxicological assay development

Sammanfattning: Life in modern society is intricately intertwined with the results of continuous technological advances. Thishas given rise to daily routines where people are frequently exposed to a wide variety of chemicals.Though many of the chemicals do not generally induce adverse health effects upon normal exposure,several of them has the potential to negatively impact health. Indeed, in order to create products that aresafe for the general population, potential hazards must be considered and characterized. However, manyof the potential adverse health effects are challenging to assess due to the complexity of their underlyingmechanisms.Therefore, hazard assessment has traditionally been based on animal models, since the availableknowledge has failed to reduce the complexity to a state that allows the creation of simpler yet effectivealternative assays. However, animal models are problematic for several reasons, which makes thedevelopment of accurate non-animal alternatives for hazard assessment a sought-after endpoint.The GARD platform has been developed towards this end, and it permits the development of effective nonanimalassays, even for mechanistically complex endpoints. The method exploits the technologicaladvances enabling transcriptomic analysis, following controlled exposure experiments, with machinelearning techniques to identify predictive biomarkers and to define high-performing classification models.This thesis presents the GARD platform and its technological constituents and highlights how it can beused to create assays aimed towards mechanistically complex endpoints, while simultaneously generatingnew information that can aid the understanding of said endpoints. Further, two of the developed GARDassays, GARDskin and GARDpotency, are described in more detail. Both assays have been developedtoward the hazard endpoint of skin sensitization and provide cutting edge performances in hazardidentification and hazard characterization, and represent viable alternatives for eventually eliminating theneed for animal testing.