Integrative Systems Toxicology For Human Health

Identificador:  TDX:2903

Handle: https://hdl.handle.net/20.500.11797/TDX2903

Autors:  Sharma, Raju Prasad

Resum:
Endocrine disrupting chemicals (EDCs) are natural or anthropogenic substances in the environment, food, or consumer products that can disrupt hormonal balances in humans and wildlife, and result in adverse health effects even at low dosages. To date, many test methods have been developed under EU and OECD guidance with the aim to perform Quantitative Risk Assessments for these chemicals. However, these methods still lack the confidence on their safety level of exposure to human. Quantitative Prediction of EDCs' adverse effect on human health poses several challenges associated with their complex exposure, nonlinear kinetics, metabolite (s), and complex mechanism or the complex response of organisms over different life stages or time scales. Emerging high-throughput analysis (OMICS) and in-silico tools such as physiologically based pharmacokinetic/pharmacodynamics (PBPK/PD), Systems biology and Adverse Outcome Pathways (AOPs) offer an opportunity to understand the biological complexity and their multilevel connectivity. The objective of this thesis is to build an integrative systems toxicology model for predicting EDCs-induced adverse effects on human health. The first part of this work focuses on the development and the validation of the detailed tissue-dosimetry model integrating species and population specific physiological data, in-vitro and in-silico derived data. The second part focuses on the development and validation of integrative systems toxicology model that includes Systems biology, signalling network/AOPs pathway model development and validation, and coupling of these models with detailed PBPK model. This integrative systems toxicology model will thereby provide a robust predictive models platform for chemicals/EDCs qualified to support regulatory requirements.