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Chemical mixtures

People, animals and the environment can be exposed to multiple chemicals from a variety of sources. EFSA has already developed some approaches for assessing combined exposure to multiple pesticides and contaminants in humans and multiple pesticides in bees. Our scientists are further developing new approaches and tools for harmonising how we assess risks to humans and the environment from combined exposure to multiple chemicals in the food chain: “chemical mixtures” and their effects, sometimes called “cocktail effects”.

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New guidance from EFSA’s Scientific Committee provides a framework for grouping chemicals for human risk assessment of combined exposure to multiple chemicals and methods for identifying low priority chemicals to reduce the number of chemicals in assessments . The framework proposes:

  • To apply hazard-driven criteria for grouping of chemicals, using mechanistic information (how chemicals behave) on toxicity as the gold standard, i.e. common mode of action or adverse outcome pathway, where available.
  • Grouping using a common adverse outcome, e.g. EFSA’s approach to the cumulative risk assessment of pesticides, when mechanistic data are not available.
  • To use toxicokinetic data (what happens to chemicals in an organism) for grouping, particularly of compounds which share common toxicologically relevant metabolites (breakdown products resulting from metabolism).
  • Risk-based approaches for combined or single chemicals, and exposure-driven approaches as prioritisation methods.
  • A structured weight of evidence approach in all cases.

EFSA is grateful to the many experts and scientific advisory organisations who provided feedback and shared their insights during a public consultation on a draft version of this guidance document and during an international workshop. EFSA considers international cooperation on methodologies in this area critical and is committed to maintaining this partnership approach alongside EU risk managers as the guidance is implemented in future scientific assessments.


  1. 2022


    EFSA publishes an assessment of the risks to pregnant women from dietary cumulative exposure to pesticide residues that have acute effects on embryos development. The assessment was conducted for two types of craniofacial malformations: alterations due to abnormal skeletal development, and head soft tissue alterations and brain neural tube defects. The conclusion is that, with varying degrees of certainty, exposure is below the threshold that triggers regulatory action.

  2. 2021


    EFSA holds an international workshop on scientific criteria for grouping chemicals into assessment groups and future challenges in risk assessment of chemical mixtures. Scientific advisory bodies from across the globe take part.

  3. June - September

    EFSA meets French MEPS to clarify the methods and data used to establish the safety of representative formulations of herbicides and pesticides. This follows a letter co-signed by more than 100 political leaders – MEPs, French deputies and French senators – to EFSA concerning its role in considering cumulative effects of substances in pesticide formulations under EU regulations on plant protection products.

  4. May

    EFSA consults publicly on a draft guidance document (‘MixTox 2’) for grouping chemicals across the food safety area and prioritisation of groups of chemicals for human health risk assessment.

  5. February

    The European Commission and EFSA publish an action plan to accelerate development of the methodology for cumulative risk assessment (CRA) of pesticides, with a view to gradually implementing CRA into regulatory practice.

  6. 2020


    EFSA publishes the results of its first two pilot assessments on the risks posed to humans by residues of multiple pesticides in food. The assessments – one considering chronic effects on the thyroid system and the other acute effects on the nervous system – are the culmination of a multi-year collaboration between EFSA and the Dutch National Institute for Public Health and the Environment (RIVM).

    The overall conclusion for both assessments is that consumer risk from dietary cumulative exposure is, with varying degrees of certainty, below the threshold that triggers regulatory action for all the population groups covered.

  7. 2019


    EFSA finalises its ‘MixTox’ guidance document following a public consultation. The guidance equips its scientists with methodologies and tools to assess combined exposure to multiple chemicals. Related advice comes out on how to assess the genotoxicity of substances in chemical mixtures.

    An EFSA research study from 2018 shows that overall in the EU awareness of chemical mixtures among the general public is quite low.

  8. 2018


    EFSA’s partners the Dutch National Institute for Public Health and the Environment (RIVM) and Wageningen University, publish data model for probabilistic cumulative dietary exposure assessments of pesticides.

  9. 2017


    Launch of “OpenFoodTox” database reporting summary chemical hazards information and linking to the OECD eChemPortal. Step-by-step approaches for human and ecological risk assessment of chemical mixtures using OpenFoodTox data provide alternatives to animal testing in toxicological assessments.

  10. 2016


    Public consultation on proposed MixTox guidance scope and objectives.

  11. May

  12. January

    An RIVM-EFSA pilot study tests the Monte Carlo Risk Assessment software tool for carrying out exposure assessments of multiple pesticides.

  13. 2015


    Finalisation of data collection on toxicokinetic and toxicodynamic interactions of chemical mixtures for human risk assessment and combined toxicity of multiple chemicals for animal health and ecological risk assessment.

  14. 2014


  15. 2013


  16. 2008


  17. 2006


EFSA's role

EFSA’s Scientific Committee develops harmonised risk assessment methodologies on cross-cutting scientific matters in EFSA's areas of activities where EU-wide approaches are not already defined. The Scientific Committee considers development of guidance for harmonised methodologies for combined exposure to multiple chemicals a priority for EFSA.

EFSA’s Panel on Plant Protection Products and their Residues is responsible for the general methodology for classifying pesticides into cumulative assessment groups. The methodology developed by the Panel uses broad criteria for inclusion of pesticides in groups to maximise consumer protection.

EFSA undertakes and/or supports research activities to contribute to the implementation of guidance in this area:

  • Data collection and analysis of combined toxicity of multiple chemicals of relevance to EFSA in the area of human, animal and environmental toxicology.
  • Development of tools for modelling (tiered approaches, population dynamics, human variability) for human and ecological risk assessment for single and multiple chemicals.


1. How do scientists assess chemical mixtures?

For a single chemical, scientists review available toxicity data to set a safe level for human health or the environment. They compare this with exposure (for example through food) to predict potential risks. For multiple chemicals, scientists have developed methods which use the same principles. They assess the toxicity of the group of chemicals identifying how these substances are metabolised in the body and how they might express their toxicity, often referred to as “mode of action”. Then, the toxicity information is combined with exposure information to assess potential health risks using assumptions about the combined toxicity. The most common assumptions are dose addition, response addition and interaction.

2. What is dose addition?

Dose addition means that the individual chemicals in the mixture have a similar toxicity and the doses are added up and combined with exposure for the risk assessment.

3. What is response addition?

For response addition, scientists consider the independent toxic effects of each substance in the mixture and include these together when carrying out the risk assessment.

4. What is meant by interactions? What are “synergistic” and “antagonistic” effects?

Interactions are more complex. Some chemicals can become more toxic when combined. This is called “synergism”. On the other hand, other chemicals when combined can be less toxic when combined, which is known as “antagonism”. The mechanisms behind synergism and antagonism are complex. Two important ones are: an increase or decrease in the body’s ability to detoxify and eliminate the compounds, and an increase or decrease in toxicity of the chemical(s). If there is evidence of such interactions, scientists collect the information to take these effects into account in the risk assessment.

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