Human and wildlife animals are exposed to multiple sources of environmental stressors including chemicals such as persistent organic pollutants (POPs) and endocrine disrupting compounds (EDCs). In addition to the important public health issues related to such exposures, EDCs are suspected to elicit ecosystems toxicity with an impact on the food chain and biodiversity and a significant economic burden linked to the increase of metabolic and neurodevelopmental disorders. In this complex and multifactorial context, new and innovative approaches are warranted to address potential linkages between such environmental exposure and health outcomes. Whereas exposure models in toxicology and ecotoxicology traditionally link a given external exposure source with a target organism, the vision of CREATIvE is to consider the organism as both an internal exposure source and a target. Specifically, its ambition is to assess potential health consequences from the release of POP mixtures from an internal storage site (the source) by understanding their complex biological modes of action (MoAs) on the target tissues of the same organism. It is well known that POPs bio-accumulate in living organisms and are stored in specific tissues e.g. adipose tissue (AT) brain, and liver, for long periods of time. Therefore, these tissues represent internal chronic sources of pollutants possibly leading to various disorders including metabolic and neurodegenerative diseases. Such “internal” exposures are not satisfactorily captured by current methods based on investigating different types of external POPs exposure via gavage, injection or acute inhalation. The proposed protocol will not replace the existing ones but will be complementary, taking into account for the first time internal sources of exposure. The aim of CREATIvE is to develop a novel strategy exploring the effects of an internal exposure from grafted contaminated AT. The kinetics and consequences from a redistribution of POPs and their metabolites from grafted contaminated AT on several tissues and organs, e.g. liver, brain and host AT will be studied. The proposed integrated approach is a combination of experimental studies (chemical quantitative measurements in tissues, metabolomics, transcriptomics) and computational modeling (PBPK and systems biology approaches). The advantage of developing such integrated approaches is the possibility to identify the systemic effects of internal mixture exposure at different biological levels, by mimicking the reality of human and animal exposure. As results, new biomarkers will be characterized, and novel complementary models will be proposed which will help at increasing Agregated Exposure Pathways (AEPs) information. To our knowledge such a strategy is clearly innovative and different from existing studies. In a recent preliminary study, an allograft model was developed at Paris Descartes, consisting in a mouse graft of contaminated AT to a non-contaminated mouse. We demonstrated that four weeks after transplantation, the grafts are vascularized and functional. In those initial studies, donor AT was contaminated by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), and we showed that this contaminant was indeed redistributed to different tissues with different kinetics. Based on this acquired proof of concept, CREATIvE will explore the kinetics of a low dose POP mixture release from an internal source of exposure, and most importantly will assess the toxic effects of such mixtures on other tissues and organs. After improvement of the experimental model, a mixture of twelve environmentally relevant POPs will be studied at low doses with the aim to better understand the consequences of POP mixture release from a unique internal source of exposure.