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By their definition, inadvertent exposure to endocrine disrupting compounds (EDCs) intervenes with the endocrine signalling system, even at low dose. On the one hand, some EDCs are used as important pharmaceutical drugs that one would not want to dismiss. On the other hand, these pharmaceutical drugs are having off-target effects and increasingly significant exposure to the general population with unwanted health implications. Flutamide, one of the top pharmaceutical products marketed all over the world for the treatment of prostate cancer, is also a pollutant. Its therapeutic action mainly depends on targeting the androgen receptors and inhibiting the androgen action that is essential for growth and survival of prostate tissue. Currently flutamide is of concern with respect to its categorization as an endocrine disruptor. In this work we have developed a physiologically based pharmacokinetic (PBPK) model of flutamide that could serve as a standard tool for its human risk assessment. First we built the model for rat (where many parameters have been measured). The rat PBPK model was extrapolated to human where the re-parameterization involved human-specific physiology, metabolic kinetics derived from in-vitro studies, and the partition coefficient same as the rat model. We have harmonized the model by integrating different sets of in-vitro, in-vivo and physiological data into a PBPK model. Then the model was used to simulate different exposure scenarios and the results were compared against the observed data. Both uncertainty and sensitivity analysis was done. Since this new whole-body PBPK model can predict flutamide concentrations not only in plasma but also in various organs, the model may have clinical applications in efficacy and safety assessment of flutamide. The model can also be used for reverse dosimetry in the context of interpreting the available biomonitoring data to estimate the degree to which the population is currently being exposed, and a tool for the pharmaceutical companies to validate the estimated Permitted Daily Exposure (PDE) for flutamide.

The workshop participants received funding from the European Union Seventh Program for Research, Technological Development and Demonstration (FP7) and Horizon Research and Innovation Program (H2020) and other European Union programs under the following grant agreements: AETIONOMY (Developing an Aetiology-based Taxonomy of Human Disease—Approaches to Develop a New Taxonomy for Neurological Disorders, IMI-no115568), ANTI-SUPERBUG PCP (ANTISUPERBUG Precommercial Procurement, H2020-no688878), B-CAST (Breast CAncer Stratification understanding the determinants of risk and prognosis of molecular sub-types, H2020-no633784), BRIDGE Health (Bridging information and data generation for evidence-based health policy and research, H2020-no664691), CASyM (Coordinating Action Systems Medicine—Implementation of Systems Medicine across Europe, FP7-n°305033), CENTER-TBI (Collaborative European NeuroTrauma Effectiveness Research in TBI, FP7-no602150), CECM (Centre for New Methods in Computational Diagnostics and Personalized Therapy, H2020-no763734), COLOSSUS (Advancing a Precision Medicine Paradigm in Metastatic Colorectal Cancer: Systems based patient stratification solutions, H2020-no754923), COMPARE (COllaborative Management Platform for detection and Analyses of (Re-)emerging and foodborne outbreaks in Europe, H2020-no643476), CONNECARE (Personalized Connected Care for Complex Chronic Patients, H2020-no689802), CREATIVE (Collaborative REsearch on ACute Traumatic brain Injury in intensiVe care medicine in Europe, FP7-no602714), DEFORM (Define the global and financial impact of research misconduct H2020-no710246), ECCTR (European Cornea and Cell Transplant Registry, FP7-n°709723), E-COMPARED (European COMPARative Effectiveness Research on online Depression, FP7-no603098), ECRIN-IA (European Clinical Research Infrastructures Network- Integrating Activity, FP7-no284395), EHR4CR (Electronic Health Records Systems for Clinical Research, IMI-no115189) eInfraCentral (European E-infrastructures Services Gateway, H2020-no731049), ELIXIR (European Life-science Infrastructure for Biological Information, FP7-n°211601), ELIXIR-EXCELERATE (Fast track ELIXIR implementation and drive early user exploitation across the life sciences, H2020-no676559), eMEN (e-mental health innovation and transnational implementation platform North West Europe, H2020), EMIF (European Medical Information Framework, IMI-no115372), ERA PerMed (ERA-net Cofund in Personalized Medicine, H2020-no779282), eTRIKS (Delivering European Translational Information and Knowledge Management Services, IMI-1-no115446), EuroPOND (Data-driven models for progression of neurological diseases, H2020-n°666992), EurValve (Personalized Decision Support for Heart Valve disease, H2020-no689617), HBP SGA1/SGA2 (Human Brain Project specific grant agreements, H2020-n°720270/785907), ICT4DEPRESSION (User-friendly ICT tools to enhance self-management and effective treatment of depression in the EU, FP7-n°248778), ImpleMentAll (Towards evidence-based tailored implementation strategies for eHealth, H2020-no733025), INSTRUCT-ULTRA (Releasing the full potential of instruct to expand and consolidate infrastructure services for integrated structural life sciences research, H2020-no731005), MASTERMIND (Management of Mental Disorders through Advanced Technologies, CIP-no621000), MeDALL (Mechanisms of the Development of ALLergy, FP7-n°261357), MedBioinformatics (Creating medically-driven integrative bioinformatics applications focused on oncology, CNS disorders and their comorbidities, H2020-n°634143), MIDAS (Meaningful Integration of Data, Analytics and Services, H2020-no727721), MultipleMS (Multiple manifestations of genetic and non-genetic factors in Multiple Sclerosis disentangled with a multi-omics approach to accelerate personalized medicine, H2020-no733161), myPEBS (Randomized Comparison Of Risk-Stratified versus Standard Breast Cancer Screening European Women Aged 40–74, H2020-no755394), OpenAIRE-Advance (Advancing Open Scholarship, H2020-no777541), OpenMedicine (OpenMedicine, H2020-n°643796), PanCareSurFup (PanCare Childhood and Adolescent Cancer Survival Care and Follow-up Studies, FP7-n°257505), PIONEER (Prostate Cancer DIagnOsis and TreatmeNt Enhancement through the Power of Big Data in EuRope, H2020-IMI-2-n°777492), PREPARE (Platform for European Preparedness Against (Re-)emerging Epidemics, FP7-n°602525), Regions4PerMed (Interregional coordination for a deep and fast uptake of personalized health, H2020-no825812), RD-CONNECT (An integrated platform connecting registries, biobanks and clinical bioinformatics for rare disease research, FP7-no305344), Solve-RD (Solving the unsolved Rare Diseases, H2020-no779257), SPIDIA4P (SPIDIA for Personalized Medicine-Standardization of generic Pre-analytical procedures for In-vitro DIAgnostics for Personalized Medicine, H2020-no733112), SYSCID (A Systems medicine approach to chronic inflammatory disease, H2020-no733100), SysCLAD (Systems prediction of Chronic Allograft Dysfunction, FP7-n°305457), SYSCOL (Systems Biology of Colorectal Cancer, FP7-no258236), SysMedPD (Systems Medicine of Mitochondrial Parkinson’s Disease, H2020-n°668738), U-BIOPRED (Unbiased BIOmarkers for the PREDiction of respiratory disease outcomes, IMI-n°115010), VPH-share (Virtual Physiological Human: Sharing for Healthcare—A Research Environment, FP7-n°269978). The European Union (EU) initiative on the Digital Transformation of Health and Care (Digicare) aims to provide the conditions necessary for building a secure, flexible, and decentralized digital health infrastructure. Creating a European Health Research and Innovation Cloud (HRIC) within this environment should enable data sharing and analysis for health research across the EU, in compliance with data protection legislation while preserving the full trust of the participants. Such a HRIC should learn from and build on existing data infrastructures, integrate best practices, and focus on the concrete needs of the community in terms of technologies, governance, management, regulation, and ethics requirements. Here, we describe the vision and expected benefits of digital data sharing in health research activities and present a roadmap that fosters the opportunities while answering the challenges of implementing a HRIC. For this, we put forward five specific recommendations and action points to ensure that a European HRIC: i) is built on established standards and guidelines, providing cloud technologies through an open and decentralized infrastructure; ii) is developed and certified to the highest standards of interoperability and data security that can be trusted by all stakeholders; iii) is supported by a robust ethical and legal framework that is compliant with the EU General Data Protection Regulation (GDPR); iv) establishes a proper environment for the training of new generations of data and medical scientists; and v) stimulates research and innovation in transnational collaborations through public and private initiatives and partnerships funded by the EU through Horizon 2020 and Horizon Europe.