Meet our EDC-MixRisk scientists and learn more about the work they are doing. This time in the spotlight is Barbara Demeneix, Professor at the French National Museum of Natural History. She is an internationally recognized expert on thyroid function and endocrine disruption. In the EDC-MixRisk project, her group studies how chemical mixtures affect thyroid hormone signalling. She is also the work package leader of WP4 on identification of molecular initiating events.

Hi Barbara – What are you and your research group studying in the project?

We are using an amphibian embryo to study how the different chemical mixtures affect thyroid hormone signalling. We have known for decades that thyroid hormone is essential for brain development in all vertebrates. This is why all babies born today are tested in the first few days after birth to check that they have sufficiently thyroid hormone to ensure proper brain development. More recently, we have learned from epidemiological studies that during pregnancy, especially the first few months, a mother’s thyroid hormone levels are associated with the developing child’s IQ and even the structure of their brain.

We also know that children who were born before universal screening for thyroid hormone at birth and who were not diagnosed as lacking thyroid hormone could become cretins. Such unfortunate children had very low IQs but also were small in height. This pathology was one of the first examples of the integrating role of thyroid hormone in coordinating growth and brain development, both before and after birth.

This is why we focus on the thyroid axis and how the maternal exposures found in EDC-MixRisk affect thyroid signalling. We use the frog tadpole because thyroid hormone has been conserved through 450 million years of evolution! It is exactly the same molecule in fish, amphibians, reptiles, birds, mammals – including us humans!

As tadpoles are virtually transparent, we could take the advantage of this feature in our research. We created a new line of tadpoles with a fluorescent protein under the control of thyroid-responsive gene. These tadpoles change their light emission (fluorescence) up if there is a problem with thyroid hormone signalling, making screening of chemicals and mixtures faster and easier.

What have you discovered so far?

In the beginning of the project, epidemiological data from the Swedish SELMA pregnancy cohort was used to establish relevant mixtures to be tested in the various animal and cell models and to address the three health domains (neurodevelopment, metabolism and growth, and sexual development). Many of the chemicals that were identified both in the mixture associated with language delay and the mixture associated with low birth weight are known to affect thyroid hormone signalling. This is the case for some of the phthalates and perfluorinated compounds found in the low birth weight and language delay mixtures. Also triclosan (in the low birth weight mixture) is a well characterized thyroid hormone disruptor.

Both of the mixtures (low birth weight and language delay) significantly affected thyroid hormone signalling at environmentally relevant, human exposure levels! In addition, we showed that the mixtures affected expression of key genes in the brain and slowed down tadpole behaviour.

Importantly, researchers working on other (cell and animal) models within the project also showed that thyroid hormone dependent genes were modified after exposure to the mixtures. This further strengthens the generalizability of our results.

We consider that thyroid signalling during early pregnancy is particularly vulnerable to endocrine disruption and can affect both brain development and birth weight.

What are the potential implications of your findings?

We have found that the mixtures are harmful at the levels found in mothers of the SELMA study. So some of these substances should be clearly banned from the market. Also, the combined exposures and mixture effects should be better considered in regulatory arenas.

In this sense, the implications of our findings are very much linked to the project’s expected outcomes in the end. We want to first, assess risk and second, be able to recommend new approaches as well as policy proposals for decision-makers and regulators in Europe to improve the current situation.


A joint stakeholder workshop entitled “the Chemical Cocktail Challenge”, will be held by the two H2020-funded projects, EDC-MixRisk & EuroMix, in Brussels on March 26, 2019.

The event will serve as the final conference of the two successful EU projects, EDC-MixRisk and EuroMix, bringing together key scientists, researchers, policy makers, and stakeholders from authorities, industry and civil society. Both projects will present key results and demonstrate new tools and approaches for risk assessment of combined exposure to multiple chemicals (mixtures) and how these could benefit future European food and chemical safety policy.

The Chemical Cocktail Challenge stakeholder workshop will be followed by project-specific stakeholder meetings on March 27, 2019.

Registration for public to both events will open later & more details will follow in due course.


EDC-MixRisk will organize its Steering Committee meeting in Helsinki 3-4 December. The meeting will be hosted by the Finnish project partner, the National Institute of Health and Welfare (THL), and it will gather the Principal Investigators to discuss the overall progress and highlight the key results generated within the project.

The purpose of the meeting is to present and discuss the key findings so far and to review the status of the agreed tasks. Furthermore, the meeting will facilitate coordinating the work for the remaining period, and it will provide a great forum for discussing and identifying the best strategies and solutions to deliver the expected outputs and outcomes towards the end of the project.



EU-funded EDC-MixRisk Project Highlights Importance of Considering Combined Exposure to Multiple Chemicals

19 Sep 2018

We are exposed to multiple man-made chemicals from various sources. The EDC-MixRisk research project, coordinated by Karolinska Institutet, Swetox, emphasizes the need to address the effects of chemicals as mixtures in order not to underestimate the risks they pose. The current risk assessment paradigm seems to be falling short as it is largely based on considering one chemical at a time.

The EDC-MixRisk research project studies the effects of endocrine-disrupting chemicals (EDCs), focusing on EDC-mixtures and their effects on the developing foetus. Endocrine disruptors are chemicals that interfere with our hormonal system, and they have been linked to various diseases and disorders, e.g., infertility, cancer, obesity and impaired neurodevelopment.

EDCs are ubiquitous contaminants in our environment as they can be found in everyday products, such as in plastic bottles, toys, cosmetics, electronics, textiles and even in food as pesticide residues and as additives in food contact materials. The chemicals used in various products and materials leak and migrate to the environment reaching also us, human beings.

“To study effects of these chemicals in mixtures, we used real-life exposure data from the Swedish SELMA pregnancy cohort to see which chemicals the mothers and their children were exposed to, and identified EDC mixtures in prenatal urine and blood that were associated with adverse health outcomes in the children as a first step,” explains Carl-Gustaf Bornehag, Professor in Public Health Sciences at Karlstad University, Sweden.

“Based on the chemicals measured in mothers’ serum and urine, we established reference chemical mixtures in the project. They were then tested in experimental models for potential adverse effects in terms of growth and metabolism, neurodevelopment and sexual development,” he continues.

“We observed clear effects on behavior, metabolism, and development in cell and animal models,” says Joëlle Rüegg, Associate Professor at Karolinska Institutet, Sweden and Vice-Coordinator of EDC-MixRisk project.  “We also identified common molecular targets of these mixtures, for example the thyroid hormone signaling pathway. As proper levels of thyroid hormone are essential for foetal development, interference can lead to increased susceptibility to diseases later in life,” she explains.

“We also tested selected single chemicals and compared their effects to the mixtures. In most cases, the single substances did not have an effect at concentrations comparable to the mixtures,” she adds. This points to the importance of assessing mixture effects which are often overlooked, although evidence from research is mounting.

Finally, novel approaches for a more systematic risk assessment are being developed in the project to find better models for addressing mixture effects on human health. One of the key findings by EDC-MixRisk researchers underscores that the regulatory guideline values for various single chemicals should be lower than the current ones because of the combination effects. The results suggest that the currently used chemical-by-chemical approaches underestimate risk by a factor that ranges from 1 to 100 for different chemicals. An article describing these findings was recently published in Environment International.

“We have to intensify our efforts in order to increase our understanding and most important of all, to take proper approaches and strategies that will reduce the harm and risks to human health and environment from these hazardous mixtures,” concludes Dr. Rüegg.

EDC-MixRisk has received funding from the European Union’s Horizon 2020 research and innovation programme. It has been highlighted as a success story among EU-funded research projects.

Watch a short video about the EDC-MixRisk Project here.

Media contacts:

Joëlle Rüegg,
Vice-Coordinator of EDC-MixRisk, Associate Professor
Karolinska Institutet, Swetox & Institute for Environmental Medicine, Sweden
joelle.ruegg@ki.se, Tel: +46 73 712 1592

Carl-Gustaf Bornehag
Professor, Karlstad University, Sweden and
Icahn School of Medicine at Mount Sinai, New York City, USA
carl-gustaf.bornehag@kau.se, Tel: +46 70 586 6565

Elina Drakvik,
Project and Communications Manager,
EDC-MixRisk Coordination Office
Karolinska Institutet, Swetox, Sweden
elina.drakvik@ki.se, Tel: +46 76 239 4813

 

Further information

About EDC-MixRisk: The project focuses on the effects of mixtures of endocrine-disrupting chemicals on children – with the ultimate aim of promoting safer use of chemicals.

Full name: “Integrating Epidemiology and Experimental Biology to Improve Risk Assessment of Exposure to Mixtures of Endocrine Disruptive Compounds — EDC-MixRisk”

Project period: from 2015-05-01 to 2019-05-01

Funding: EC contribution EUR 6 223 330, Grant agreement No 634880

Website: http://edcmixrisk.ki.se/

 

Recent publication by EDC-MixRisk researchers:

Gennings, C., et al. “Incorporating Regulatory Guideline Values In Analysis Of Epidemiology Data”, Env. Int. 120 (2018)

 

Overview of mixture research activities at EU-level:

Bopp, S., et al. “Current EU research activities on combined exposure to multiple chemicals”, Env. Int. 120 (2018)

 


A joint article “Current EU research activities on combined exposure to multiple chemicals” was recently published in Environment International by experts from the five EU-funded research projects, i.e. EDC-MixRisk, EuroMix, EU-ToxRisk, HBM4EU and SOLUTIONS, and European Commission Services and EU Agencies. The paper aims to map current progress, gaps and remaining challenges for the assessment of chemical mixtures.

The paper provides an overview of the various research projects’ activities, as well as the activities of European Food Safety Authority and Joint Research Centre in the area of mixture risk assessment. It describes how the ongoing projects and initiatives are bringing new knowledge and developing tools and approaches for facilitating and improving mixture risk assessment.

In addition, the paper highlights that despite the progress in the area and increased knowledge for taking combined exposures into account, several gaps prevail. These gaps are especially linked to lack of data on toxicological properties of chemical substances and realistic co-exposure scenarios hampering thus the efforts for carrying out proper mixture risk assessment.

Furthermore, different uses and different types of chemicals are regulated by different agencies and sectors, which is hindering the cross-talk and more holistic considerations of unintentional mixtures.

The paper concludes that more harmonised approaches are needed in order to make progress in combined exposure and combination effects of multiple chemicals. The needs for harmonization range from terminology, grouping, data formats, and methodology to the harmonization of regulatory approaches. Also legislative requirements are brought up in the paper.

Further information:

Bopp, S., et al. (2018):
Current EU research activities on combined exposure to multiple chemicals”,
Environment International. Vol. 120. Pages 544-562.
doi.org/10.1016/j.envint.2018.07.037


The European Commission (EC) has highlighted EDC-MixRisk research project as a success story among EU-funded research. EDC-MixRisk was selected to the spotlight for the thematic “Health month”, as it has great potential to influence future policies and thus have impact and contribute to better health and lives of numerous people.

The success story article “Protecting children from dangerous chemicals” is available via the EC Research and Innovation Information Centre:
http://ec.europa.eu/research/infocentre/article_en.cfm?artid=49577


EDC-MixRisk project has started its final year. It is time to take stock on what has been accomplished in the project so far as well as to take a look at the progress and key results at this stage.

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 are addressed in the project (growth and metabolism, neurodevelopment, and sexual development).

In the epidemiological module, mixtures of EDCs are identified, exposure to which is associated to adverse health outcomes in the three domains. These mixtures are subsequently composed and tested in different experimental systems relevant for the respective health outcomes. To test mixtures that are composed based on epidemiological data is a novel strategy to tackle the mixture issue. The experimental data are then on one hand, integrated into the risk assessment methods developed in the project, and, on the other hand, used to refine the biostatistical analyses. Two sets of mixtures have been established for metabolism and growth (G), neurodevelopment (N) and sexual development (S). The mixtures are based on data from the Swedish mother-child pregnancy cohort SELMA.

In the experimental module, mixtures 0 and 1 are tested in various animal and cell models to identify molecular actions of the mixtures that could underlie their adversity. Results obtained in mice, tadpoles, zebrafish, and cell models show that mixtures 0 for all the health domains induce negative effects on the molecular, cellular, and organismal level. In some of the assays, effects were observed even at the lowest concentrations tested, which correspond to the actual levels of the SELMA mothers.

Interestingly, the mixtures disrupted common signalling pathways in cell and in animal models, which enabled us to link the molecular effects to adverse outcomes such as increased adipose tissue, behavioural changes, and disruption of sexual organ development. Selected single chemicals were also tested and their effects compared to the mixtures. In most cases, the single compounds did not have an effect at concentrations comparable to the mixtures.

An important part of the project is the improvement of the regulatory risk assessment of mixtures as well as science-to-policy interaction. Three different novel mixture risk assessment methods have been established and are now being elaborated on by conducting case studies using EDC-MixRisk and published data.

The EDC-MixRisk approach of identifying EDC mixtures associated with adverse health outcomes in a pregnancy cohort, preparing artificial mixtures of the bad actors for toxicological testing and using the experimental data for risk assessment is a novel approach and one of the major outcomes of the project. More specifically, this proof-of-concept, will enable more systematic integration of epidemiological and experimental evidence into mixture risk assessment strategies.

By applying the novel approach, which is based on real life exposure data, we could find a higher rate of pregnant women at risk when compared with more traditional models of additivity. This adds to the evidence that cocktail effects of manmade chemicals are not properly taken into account in risk assessment and management of chemicals. More systematic approaches are needed, both in terms of science and regulations. The improved testing strategies and risk assessment methodologies developed in the project are important for the regulatory processes to protect public health and to avoid hazardous chemicals, whether they come in mixtures or as single substances.

Read the full summary of the project progress here.


Five EU-funded H2020 and FP7 research projects i.e. EDC-MixRisk, EuroMix, EU-ToxRisk, HBM4EU and SOLUTIONS, are working together to address different aspects of the impacts of chemical mixtures and combined exposure. The projects have engaged into an exchange between the consortia, European Commission Services and relevant EU Agencies in order to identify remaining gaps in mixture research and policy. As a result of this effort, a joint workshop entitled “Advancing the Assessment of Chemical Mixtures and their Risks for Human Health and the Environment” was organized at Joint Research Centre (JRC), Ispra, 29-30 May 2018. The workshop brought together around 60 experts working in the field of chemical mixtures.

Photo: © European Union, 2018

The workshop provided a great forum to discuss the latest advancements in science as well as research and policy needs in order to make progress in mixture risk assessment and management. The topics of the workshop included hazard and exposure assessment, data and tools, and risk analysis and governance. The international horizons and developments outside the EU were covered by keynote speakers from USA, Japan and OECD.

Although much progress has been achieved over the recent years, the participants stated that it is evident that more needs to be done to better address the combined exposure of multiple chemicals, both in terms of intentional (e.g. pesticides and cosmetic products) and unintentional mixtures (e.g. contaminants via air). One of the major gaps continues to be the lack and availability of data. The Information Platform for Chemical Monitoring, IPCHEM is addressing the gap for chemical monitoring data. However, another big challenge remains in the accessibility and quality of data on (eco)toxicological properties and on the types of use of chemicals.

In the group and plenary discussions, ideas were brought up on improving governance aspects to better protect public health and environment from hazardous chemical mixtures. The proposals from many project participants included e.g. encouraging policymakers to look into the opportunities of establishing clear legal mandates for mixture risk assessment within EU chemicals and environmental legislation and across the regulatory silos. It was also suggested that “protection goals” should be established for human health, applying the idea and concept from the Water Framework Directive which requires good chemical and ecological status for European water bodies. For humans, similar type of “protection goals” could be set for good chemical and health status. Furthermore, it was raised that there is a need for developing uniform principles and harmonised approaches for performing human and environmental mixture risk assessments. In practice, also procedures should be piloted and put in place to enable more holistic and systematic mixture risk assessments, across regulatory bodies and sectors. It was concluded that interdisciplinary and international collaboration as well as dialogue between scientists, regulators and policy-makers are essential to make progress in the mixture efforts.

The workshop outcome and future research needs will be published later in 2018.

JRC has published recently a news item on chemical mixtures and safety of combined exposures: https://ec.europa.eu/jrc/en/news/chemical-mixtures-safety

JRC has also published a related Policy Brief: “Something from nothing? Ensuring the safety of chemical mixtures”:
https://ec.europa.eu/jrc/en/publication/something-nothing-ensuring-safety-chemical-mixtures


The EHESP School of Public Health and the IRSET Research institute for environmental and occupational health organized the 5th European Doctoral College on Environment and Health (EDCEH) in Rennes, France, 4-6 June 2018.

EDC-MixRisk was represented in the meeting by Dr. Anastasia Repouskou from the School of Health Sciences, National and Kapodistrian University of Athens. She presented in the meeting their recent study on the effects of gestational exposure to a mixture of four phthalates (mixture S) on the reproductive health of mice. Mouse is one of the experimental models used in EDC-MixRisk to study the health effects of chemical mixtures.

Phthalates are repeatedly detected in humans, raising thus significant concerns due to the constant exposure and their endocrine disruptive properties. They are widely used as plasticizers in the manufacture of hundreds of commercial products.

The results of the study indicated that in utero exposure of experimental animals (mice) to a mixture of phthalates administered at epidemiologically-defined concentrations and simulating real-life human exposure levels, leads to long-term reproductive defects, particularly of male offspring. The title of Dr. Reposkou’s abstract was “Reproductive impact of gestational exposure to an epidemiologically-defined phthalate mixture in prepubertal and adult mice”.

The meeting offered a great opportunity for networking and insight into important topics regarding endocrine disruptors (EDs), such as definition of EDs within the regulatory context, emerging approaches for assessing the exposure to EDs, models and (non-)standard tests for endocrine disruption and innovative methods and predictive tools to investigate endocrine disruption.

Click here for more information about the meeting.