Health impacts of endocrine-disrupting chemicals: bridging science-policy gaps by addressing persistent scientific uncertainties The function and regulation of the endocrine system in humans and other species is of high biological complexity. Endocrine disrupting chemicals (EDCs or endocrine disruptors) are chemical substances that alter the functioning of the endocrine system and negatively affect the health of humans and animals. They may either be of synthetic or natural origin.EDCs are of increasing importance in chemical regulations in the European Union. According to the Comprehensive European Union Framework on Endocrine Disruptors, adopted in 2018, the EU strategic approach on endocrine disruptors for the years to come should be based on the application of the precautionary principle. This approach would aim at, inter alia, minimising overall exposure of humans and the environment to endocrine disruptors, paying particular attention to exposures during important periods of development of an organism, such as foetal development and puberty, possibly integrating a life course approach, as well as accelerating the development of a thorough research basis for effective and forward-looking decision-making. This includes research for the further management of chemicals (including multi-constituent chemicals as well as chemical mixtures), the understanding of the mechanistic effects of endocrine disruptors and their dose-response relationships (including at the molecular and cellular level through the use of new approach methodologies, such as ‘multiomics’, cheminformatics, in vitro 2D and 3D models, in vivo models and computational approaches), and the collection, sharing, harmonisation and combination of robust data sources.Closing existing knowledge gaps in the understanding of EDC effects will support more effective and evidence-based regulations at the European level.Bringing together, inter alia, (molecular) epidemiologists, exposure scientists, toxicologists, endocrinologists, health care practitioners and risk assessors, research actions under this topic should focus on the understanding of the impact of exposures at critical life stages as regards development of diseases later in life, focusing on the several health endpoints for which there is currently less information available. Advantage should be taken of existing biobanks and disease registries and/or cohorts, with carefully planned measurement strategies and clearly worked-out hypotheses. The nature of the dose-response relationships and whether effects are threshold-dependent should be addressed in the study designs. Similarities between endocrine systems and certain health outcomes across species should be exploited to improve understanding of functioning of the endocrine system. Finally, research should attempt at identifying predictive biomarkers (e.g. from liquid biopsies such as saliva, urine, blood) that would allow the tracing of endocrine disrupter-mediated health effects in a shorter period of time than normally would be required for epidemiological studies.Research actions under this topic should provide forward-looking mechanistic information on potential hazards and health risks of exposures to EDCs, through innovative molecular epidemiological, multifactorial models and systems biology approaches, exploiting the use of state of the art non-animal methodologies when relevant, and should include several of the following activities:Studying the impact of EDCs on target organs and in multi-organ models, and physiological barriers, such as the placenta, the blood-brain barrier, the blood-saliva barrier, intestinal, pulmonary and immune cells as well as their interaction with microbiota. This should include the provision of a thorough understanding of dose-response relationships;Elucidating health endpoints for which insufficient data exist, such as disturbances in the development and functioning of the nervous and cardiovascular systems, the immune system, bone development and disease, obesity, diabetes, hormone-dependent cancers and fertility (e.g. minipuberty, prepuberty and puberty);Providing better biological and imaging biomarkers to predict EDC-mediated health outcomes, including the quantitative probabilities of having an adverse effect based on such biomarkers;Gaining better insights into the developmental origins of health and disease, especially for those where less data are available. Assessing the occurrence and relevance of multi- and transgenerationally inherited effects, including molecular and epigenetic mechanisms that drive multigenerational effects;Gaining better insights into the most sensitive windows of susceptibility, during which exposure are of particular importance for health effects;Better understanding of the effects of chemicals and chemical mixtures on the underlying mechanistic crosstalk between endocrine axes, endocrine pathways and other key biological systems, including immune, neurological and metabolic functions;Improving the understanding of chemical mixture effects, including with other toxins and at low doses. The role of the microbiome in the activation or detoxification of these chemicals should be explored where relevant.Investigating biological effects of realistic mixtures to get a more detailed understanding of the endocrine effectome, taking advantage of computational toxicology and development of up-to-date models;Performing comparative analysis between species, assessing similarities to human endocrine system and health outcomes and exploiting non-mammalian species as test organisms, e.g. non-mammalian vertebrates and invertebrates to predict effects or raise concern about potential effects in humans or vice versa;Exploiting systems biology approaches in order to understand how exposure to an EDC results in an altered phenotype, a process that implies complex interactions across multiple levels of biological organisation. Aspects such as gender, regional variations, socioeconomics and culture should be considered, where appropriate. Proposals should ensure that chemical monitoring data are shared in IPCHEM[[ IPCheM Portal (europa.eu)]] through involvement with the European Commission's Joint Research Centre (JRC). Proposals should also consider involving JRC with respect to the value it could bring in providing an effective interface between the research activities and regulatory aspects and/or to translating the research results into validated test methods and strategies fit for regulatory purpose. In that respect, the JRC will collaborate with any successful proposal and this collaboration, when relevant, should be established after the proposal’s approval.Applicants should be acquainted with planned activities under the European partnership for the assessment of risks from chemicals PARC[[ https://ec.europa.eu/info/funding-tenders/opportunities/portal/screen/opportunities/topic-details/horizon-hlth-2021-envhlth-03-01]]. PARC will be informed about successful proposals. Successful proposals will be invited to establish synergies with PARC and take advantage of the partnership as a facilitator for open data and methodology sharing with risk assessors and their scientific networks.This topic requires the effective contribution of social sciences and humanities (SSH) disciplines and the involvement of SSH experts, institutions as well as the inclusion of relevant SSH expertise, in order to produce meaningful and significant effects enhancing the societal impact of the related research activities.In order to optimise synergies and increase the impact of the projects, all projects selected for funding from this topic will form a cluster and be required to participate in common networking and joint activities. Without the prerequisite to detail concrete joint activities, proposals should allocate a sufficient budget for the attendance to regular joint meetings and to cover the costs of any other potential common networking and joint activities.Applicants envisaging to include clinical studies should provide details of their clinical studies in the dedicated annex using the template provided in the submission system. See definition of clinical studies in the introduction to this work programme part.