The OLIGO project aims at stimulating and supporting a thorough risk assessment related to the dietary exposure of the French population to cyclic oligoesters migrating from polyester-based coatings into canned foodstuffs. It addresses a timely and important public health issue related to the chemical safety of food that has not yet been resolved Epoxy-resins based on bisphenol A (BPA) diglycidyl ether have traditionally been used worldwide in internal coatings applied to metallic food contact materials. Due to concerns of both consumers and the scientific community, restrictions have been applied at the EU scale on the use of BPA, including a ban in baby bottles and a drastic specific migration limit from plastics or varnishes and coatings to food. In France, a complete ban of BPA entered into force in 2015. Industrial stakeholders have conceded enormous efforts to adapt through the evolution of technologies and conservation processes. Polyester-based coatings have grown into predominant alternatives to BPA-based epoxy resins. A large range of polyol- and polyacid-monomers, for which migration into foodstuffs is under control, may be used, offering numerous polyester combinations. However, oligoesters, which are non-intentionally added substances (NIAS) constitutive of polyester-based coatings arising from incomplete polymerisation reactions (up to 2% of the resin's weight, mostly cyclic combinations of 4 to 8 monomers), have not yet been subjected to a robust and transparent risk assessment, their wide chemical diversity raising analytical issues. So far, missing data relate to (i) our knowledge on the extent of polyester-based coatings' use on the market (France standing apart), (ii) the comprehensive identification of oligoesters, (iii) the related human exposure following migration into food, and (iv) their fate (e.g. liver biotransformation and potential bioactivation triggering adverse effects). Within the project OLIGO, the main scientific bottleneck – the unavailability of representative authentic standards – will be tackled through the organic synthesis of native compounds as well as deuterium- and radio-labelled compounds, in order to (i) comprehensively identify the oligoesters present in marketed cans, (ii) quantify their migration into food and (iii) assess in vitro their metabolism and potential toxicity to human. Exposure assessment of the French population will be balanced with hazard identification aspects in order to establish a provisional risk assessment and further recommendations. Addressing the challenge of characterising NIAS such as oligoesters requires resources and information which are not available to most of the agro-industrial stakeholders. Five public and academic partners are involved in OLIGO. CEISAM (CNRS UMR 6230, Nantes) will provide other partners with a set of representative authentic standards to be synthesised stepwise. LABERCA (INRAE UMR 1329, Nantes) will coordinate the project and will achieve oligoesters’ identification in coatings and their quantification in foodstuffs. To this end, a previously developed workflow will be applied to identify oligoesters, with much attention paid to the sample preparation of foodstuffs. LNC (INSERM UMR 1231, Dijon) will study genotoxicity, performing in vitro regulatory bioassays based on OECD guidelines, and endocrine disruption potencies, performing bioassays of the level 2 (mode of action) of OCDE framework. TOXALIM (INRAE UMR 1331, Toulouse) will carry out in vitro human liver biotransformation assays (hazard identification, biomarker metabolites) and gain a broader understanding of the fate of oligoesters. ANSES, the French agency for food, environmental and occupational health & safety, will define a sound sampling plan and lead the output provisional risk assessment.

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.

Endometriosis is a chronic hormone-dependent disease affecting 10% of women. Endocrine-disruptors have been suspected to play a role in endometriosis etiology, and several persistent organic pollutants (POPs) have been associated with endometriosis risk. However, despite experimental evidence of an impact of POPs on endometriosis lesion growth, no previous study has formally tested the hypothesis of an influence of POPs on the severity of endometriosis. POPENDO aims to examine associations between internal exposure levels of 4 families of POPs (dioxins, polychlorinated biphenyls, organochlorine pesticides, perfluorinated alkylated substances, totaling 81 substances) and endometriosis severity in a sample of 650 women participating in ComPaRe-Endometriosis, a prospective e-cohort of over 12,000 endometriosis patients. The findings will provide novel information on the impact of POP exposure on endometriosis that will contribute to inform prevention and reduce the impact of the disease.

The present project focuses on substitutes and derivatives of bisphenol A (BPA) which are used in the manufacture of polycarbonate and epoxy resins, including food contact materials. Indeed, a growing attention has been paid to BPA in recent years, giving rise to an intense debate concerning its endocrine disrupting properties and in fine the associated risk for humans. If BPA is still under the spotlights, the study of other related substances used as derivatives or substitutes must be given a high priority. Indeed, a gap was observed during the “BPA crisis” between the scientifically documented risk assessment approach and a risk management position rapidly adopting the precautionary principle. This was a damageable experience from which lessons have to be learnt. The present project aims to avoid the reoccurrence of such a situation for a new generation of BPA analogues for which risk assessment has not yet been performed. Our primary targeted substances will be two main BPA substitutes/derivatives namely bisphenol S (BPS) and bisphenol A diglycidyl ether (BADGE), and our aim will be to generate appropriate data as regards (i) their biotransformation and biological impact on the human hepatic function, (ii) their biotransformation and biological impact on the human reproductive function, (iii) their modes of actions at molecular level through ligand-receptor binding / transactivation mechanisms, (iv) the human external and internal exposure assessment. A set of secondary targeted substances (BPA analogues including bisphenols B, C, E, F, M, AP and AF) will also be considered for human exposure and ligand-receptor activities. The common guiding principles considered throughout the project will concern: the considered biological models / sub-populations (humans, and more particularly pregnant women, foetus/newborn and adult males), and the consideration of realistic exposure conditions for toxicological tests (low doses, compounds alone versus mixtures representative of the real human exposure).

In a report published in 2011 defining the main prospects of the organic food sector, the French Scientific Council for Organic Agriculture underlined that food safety was the prime motivation driving 95% of the consumers of organic food, although very few scientific data were available to support the presumption of a health benefit associated with organic products. The issue is critical for animal-derived food products whose reputation of safety suffers from the multiple cattle crises of the last decades. In particular, the question arises of whether meat and other animal-derived products such as offal from organic production may accumulate environmental contaminants (pesticides, organic pollutants, toxic metals and mycotoxins) or antibiotics. The SOMEAT project aims to provide scientific data to fuel the debate on the presumed health benefit of organic meat products in regard to their possible chemical contaminant contents and the putative resulting toxicity potential for consumers. The project will also give new insights into socio-economic determinants of organic meat consumption and propose new strategies to back-trace contaminants in the meat chain. The first objective of SOMEAT is to assess the chemical contaminant status of both conventional and organic meat. The priority contaminants will be listed, method specifications and sampling strategies will be defined, and targeted environmental micropollutants, antibiotics, pesticides, mycotoxins and heavy metals will be quantified by National Reference Laboratories (NRLs) on a large sample set (n > 250) including both conventional and organic raw meat. The second objective is to assess the corresponding chemical risk for conventional and organic meat consumers. The project will investigate the three main technological and physiological processes that may modulate the toxicological impact of meat contaminants: (i) effects of cooking on the meat contaminants on the priority list, (ii) their bioaccessibility for intestinal absorption based on in vitro digester experiments and (iii) their toxicity in mixtures by assessing cytotoxicty, genotoxicity and PXR activation on in vitro cell cultures of human enterocytes, hepatocytes and hepatomes exposed to realistic mixtures of meat contaminants. The third objective is to identify the socio-demographic variables explaining the consumption of organic meat. To make up for the poor precision of existing data, a field survey and a lab experiment of experimental economics will be undertaken. The survey will be carried out in-store to precisely characterize the consumers' motivation toward organic or conventional meat. The lab experiment will estimate participants' purchase choices under different certification labels or promotion configurations. This characterization of the organic consumption will allow a risk-benefit analysis linked to organic meat consumption. The fourth objective of SOMEAT is to investigate biomarkers to develop new analytical strategies based on their profiling in meat products to back-trace the exposure of meat chain to contaminants. Animal tests on poultry will provide control and diet-contaminated liver and fat. Levels of contamination will be established by NRLs. Metabolomic and transcriptomic analyses will be undertaken on the samples to determine biomarkers of animal exposure to be further validated on real-life samples. This multidisciplinary project covers both basic and industrial research. It addresses, through its main outcomes, the environmental, economic and social dimensions of food sustainability. Novel research and development will be undertaken in analytical chemistry, food chemistry, food engineering, toxicology, risk analysis, experimental economics, metabolomics, transcriptomics and chemometrics. SOMEAT involves 14 partners from both scientific institutes (INRA, ANSES, ONIRIS, AgroParisTech) and research and development organizations of the meat sector (IFIP, ITAVI and IDELE).