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.


The conference entitled ”Aiming for a Safe Chemical Environment: New Frontiers in the Comprehension of Endocrine Disrupting Chemicals Exposure, Effects and Specific Risk Assessment Requirements” took place in Les Diablerets, June 3-8, 2018. It was the 11th Gordon Research Conference on Environmental Endocrine Disruptors.

EDC-MixRisk was represented in the meeting by Prof. Carl-Gustaf Bornehag from Karlstad University who gave a presentation in the meeting about a novel approach, a proof-of-concept, which has been developed within the project for the risk assessment of chemical mixtures. The title of his presentation was “A novel approach for risk assessment of chemical mixtures – Linking data from population based epidemiology and experimental toxicology in the EDC-MixRisk study

Also several other EDC-MixRisk researchers were present at the meeting to discuss the topical aspects and latest scientific advances in research of Environmental Endocrine Disruptors (EEDs).

The meeting provided an overview of:

  • EED effects in wildlife and laboratory animal models and life-span effects in the context of human exposure
  • review of our current understanding of EED effects and mechanisms of action, including at low-doses
  • updated state of the science and discussion on specific issues, such as mixture effects, perinatal imprinting and novel paradigms e.g. on microbiome’s role and trans-generational effects
  • key issues related to incorporating the results of laboratory, field and human studies in the process of EED risk assessment.

For more information about the conference:
https://www.grc.org/environmental-endocrine-disruptors-conference/2018/


To express concern and raise awareness on hazardous chemical mixtures and combined exposure, the Coordinators and representatives of several EC funded research projects, EDC-MixRisk, EuroMix, EU-ToxRisk, HBM4EU, SOLUTIONS, have sent a position paper (17 April 2018) to Director‐Generals of DG Environment, DG Research and Innovation and DG Health and Food Safety.

The position paper entitled “Preventing risks for people and environment from hazardous chemical mixtures” calls for action, taking benefit from the stepwise translation of the science i.e., employment of already existing  as well as development of new approaches, methodologies and tools. It proposes 12 key actions and recommendations to help better address combined effects and overcome remaining gaps in chemical mixture research and policy making. It also provides some feedback and ideas from research projects’ perspective to the preparations of the next Framework Programme, Horizon Europe.

 

Researchers and stakeholders agreeing with the key messages have the opportunity to support the initiative and co-sign the position paper (until 31 May 2018).

Link to the Position Paper: Position paper 180417 for the EC

Link to the co-signing form: https://goo.gl/forms/aORWa3FtxgpGth3o2


Five EC 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 mixtures on human health and the environment, including also research activities at the European Food Safety Authority (EFSA) and the Joint Research Centre (JRC). Through this collaboration, synergies, knowledge exchange and the ability to exchange and use methods and data will be promoted.

A joint workshop ‘Advancing the Assessment of Chemical Mixtures and their Risks for Human Health and the Environment’ will be held 29-30 May 2018 at the Joint Research Centre in Ispra, Italy. The aim is to discuss the current state of knowledge as well as further elaborate and prioritise areas for future policy and research needs. The active participation of experts from EFSA, JRC, the European Environment Agency and Directorate General Environment, as well as Directorate General for Research and Innovation will ensure policy relevance of the discussions.

The topics of the workshop include hazard and exposure assessment, data and tools, and risk analysis and governance. The meeting will focus on setting the scene in terms of governance and policy frameworks as well as on advancement in research, knowledge and identification of gaps. Further research and policy needs in the field will be discussed and elaborated together with the workshop participants. Also, there will be an opportunity to learn about the international approaches from U.S., Japan and OECD work. The intention is to publish the outcome of this workshop in a scientific journal. The ultimate aim of the collaboration is to maximise the impact of the work on mixtures and to enhance chemical safety.