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  • Periodic Reporting for period 1 - EDC-MixRisk (Integrating Epidemiology and Experimental Biology to Improve Risk Assessment of Exposure to Mixtures of Endocrine Disruptive Compounds)

EDC-MixRisk Report Summary

Project ID: 634880
Funded under: H2020-EU.3.1.1.

Periodic Reporting for period 1 - EDC-MixRisk (Integrating Epidemiology and Experimental Biology to Improve Risk Assessment of Exposure to Mixtures of Endocrine Disruptive Compounds)

Reporting period: 2015-05-01 to 2016-10-31

Summary of the context and overall objectives of the project

Today we know that the endocrine system is of greatest importance for a healthy development and life - from the time of conception until death - for both animals and humans. It is of global concern that the entire human population, fetuses, infants, children and adults, are constantly exposed to low levels of anthropogenic chemicals, some of which are endocrine disrupting chemicals (EDCs) or potential EDCs that interact with our natural endocrine functions. This will potentially lead to adverse health effects in humans unless these chemicals are reduced for human exposure. There are an uncountable number of common consumer products, articles and materials that contain actual or potential EDCs, among which many migrate out of the materials over their lifespan. In fact, everyone is exposed. Global biomonitoring data has shown that EDCs and/or their metabolites are routinely detected in e.g. urine, blood, breast milk, and amniotic fluid. Exposure to EDCs during windows of susceptibility, even at low doses, is of particular concern as this may program the organism to develop disorders that manifest later in life and contribute to “diseased ageing”.

The long reaching goal of EDC-MixRisk is to move forward and meet the societal need of improved decision making regarding human exposure risks to mixtures of anthropogenic chemicals over the whole life span. Hence the project will determine and assess the risk for multiple adverse health outcomes based on molecular mechanisms involved, after early life exposure to complex mixtures of EDCs. The project relies on the interaction between advanced expertise in exposure assessment, epidemiology, experimental toxicology and risk assessment.

The overall objectives of the project are
i) Identification of mixtures of EDCs that are associated with multiple adverse health outcomes;
ii) Identification of molecular mechanisms and pathways underlying these associations; and
iii) Development of methods for risk assessment of EDC mixtures and interactions with policy makers to increase societal impact.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

The overall concept underpinning EDC-MixRisk is that early life exposure to EDC mixtures induces changes in the organism that underlie increased susceptibility to diseases during the entire life span. Three health domains will be covered: growth and metabolism, neurodevelopment, and sexual development. The project integrates research from three relevant scientific modules: 1) epidemiology, 2) experimental systems and 3) risk assessment and societal impact. These modules interact as follows: In the epidemiological module, mixtures of EDCs are identified, through associations between exposure and health outcomes in the three domains. These mixtures are tested in different experimental systems relevant for the respective health outcomes. The experimental data are integrated into the risk assessment methods developed in module 3.

In module 1, the Swedish mother-child pregnancy cohort SELMA was used to identify the first relevant EDC mixtures. The mixtures are based on analyses of mothers’ urine and serum at pregnancy week 10. As health outcomes, birth weight (growth and metabolism), language delay at age 2.5 (neurodevelopment) and anogenital distance in boys (sexual development) were chosen. All of these outcomes are early signs for adversity. Using these data and a novel biostatistical method, we identified so-called bad actors, chemicals that contribute to the association between exposure and adverse health outcome. These bad actors were mixed in ratios corresponding to their geometric mean exposure concentrations to be used in the experimental systems. Three more complex mixtures (mixtures I) have been established based on analyses of 54 chemicals in the mothers. Mixtures I are under preparation.

In the experimental module, mixtures 0 are tested in various animal and cell models that have been carefully established to give relevant read-outs for the respective health domains. Further, the cell and animal models are used to identify molecular actions of the mixtures that could underlie their adversity. First results have been obtained in mice, tadpoles, zebrafish, and cell models. Most of them indicate effects of the mixtures on the experimental models on the level of both molecular events and adverse outcomes. In some of the assays, effects are observed even at the lowest concentrations tested, which correspond to the actual levels of the SELMA mothers. These findings are being confirmed and extended to include other experimental systems and readouts. Further, chemical analyses on the exposed models will be performed to assess actual exposure levels and chemical ratios.

The risk assessment and societal impact module focuses on improving the regulatory risk assessment of mixtures and policy impact. A systematic process has taken place for selecting case study chemicals that included setting up criteria for selection as well as consultation of all partners of EDC-MixRisk and other stakeholders including relevant Governmental Agencies. A number of dissemination tools have been set (e.g. Web page and Information leaflets). The activities have included contacts and meetings at several levels within the EU including physical meetings with EU officials, participation in preparation of a consensus document regarding EDCs, other written articles and interviews.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

By integrating epidemiological data into experimental research, EDC-MixRisk will progress beyond the state of the art. In contrast to the vast majority of studies that focus on one chemical and one physiological outcome at the time, EDC-MixRisk has developed a multiple-exposure-to-multiple-outcome approach, which mimics the real life situation much better. Our first results demonstrate that EDC mixtures associated with adverse health outcomes in population based epidemiology evoke relevant molecular and physiological effects in experimental systems in cells and animals, even at low concentrations. This demonstrates the validity of our approach in interacting between epidemiology and experimental toxicology and the need to take mixture effects into account for risk assessment.

The major innovative potential of EDC-MixRisk lies within the improved risk assessment methodologies directly linked to the data obtained in the project, and strategies to systematically engage policy-relevant stakeholders. Improved regulatory processes will be important for the general populations globally, for national regulatory agencies and organizations; for chemicals manufacturing industry and down-stream users of these chemicals.

In summary, the project refines and strengthens the existing knowledge by exploiting the interaction of epidemiologists and experimentalists and by identifying novel modes of actions and relevant test model systems to test EDCs. This will result in novel strategies for risk assessment and ultimately impact on policy-making.

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