WP-4 will integrate the results of the different ‘omics’ technologies aiming at connecting the environmental exposure to disease outcomes and identify molecular signatures on different levels of biological organization in order to develop the relevant AOPs.
Genetic and environmental factors/markers will be identified relevant to one or several health outcomes. They will be analysed using network visualization environments (such as Agilent GeneSpring, MetacoreTM, Reactome), so as to create systems biology hypotheses from human data, with emphasis on inter-organ systems changes. Bioinformatics algorithms will be used to identify common nodes across several pathways.
That would allow us to identify the most critical regulatory pathway nodes perturbed beyond cellular homeostasis; these would be candidates for adverse outcome pathways (AOPs).
A major component of linking HBM data to human exposure and internal tissue dosimetry to target tissue is the development of a lifetime (including gestation and breastfeeding) generic physiology based biokinetic (PBBK) model incorporating interactions between components of common chemical mixtures and a framework for biomonitoring data assimilation (through exposure reconstruction).
The generic PBBK model will cover as much as possible the chemical space. For that, parameterisation of the model for known and new chemicals with limited information will be done through the use of QSAR models.
In the context of the development/ parameterisation of the PBBK model, optimization and automated modelling methods will be used. The PBBK model will also be used to reconstruct exposure from the HBM data analysed in WP6. After having reconstructed external exposure from HBM data we would be able to run forward the model and reckon the biologically effective dose at the target tissue. Polymorphisms associated to xenobiotics metabolism (identified in WP6) will be taken into account when building individual internal exposure profiles.
This analysis will allow us to properly identify internal exposure differences (the biologically effective relevant doses inducing observable toxicity) starting from the collated HBM data.
