On October 5th 2021, an online autumn symposium with the title “Mixture Toxicity” was organized. The meeting was attended by approximately 100 participants. On the program were 5 speakers. Harry Buist from the Risk Assessment Section chaired the meeting.

Theo Vermeire – General introduction (presentation)

Theo provided an introduction to mixture toxicity, hazard and risk assessment, explaining definitions and currently ongoing initiatives worldwide. Theo provided further information on the different available risk assessment approaches, as e.g. the assessment approaches of SCHEER and US-EPA and the WHO framework for risk assessment of mixtures. Attention was paid to the problem formulation with regard to both exposure and hazard assessment. In a recent publication of Herzler (2021) further information is provided on which mixtures should be considered, e.g. substance which act together, individual substances of high concern, as not all mixtures will be considered for mixture risk assessment and risk management approaches.

Bruno Dujardin (EFSA) - Combined exposure to multiple chemicals - EFSA’s recent achievements and future perspectives (presentation)

Bruno spoke about ongoing initiatives and activities on mixture toxicity within EFSA, especially for non-intentional exposure to mixtures. Initially, the focus was at pesticides, with the Cumulative Assessment Groups (CAGs) for thyroid and CNS effects. In parallel, a guidance on risk assessment of combined exposure to multiple compounds was also issued.

Cumulative risk assessments were performed (2019-2020) retrospectively with focus on acute and chronic exposure to CNS and chronic exposure to thyroid. It included a hazard part (identification, characterization, cumulative risk assessment groups), an exposure part, based on market sampling (120.000 samples) which were combined with consumption data (20.000 subjects), and resulted in a risk assessment part with an uncertainty analysis. Main findings were: 1) the outcome is driven by a limited number of compounds 2) highest exposure was often due to 1 pesticide, 3) model estimations are very conservative, leading to an overall conclusion that the cumulative exposure to pesticides that have chronic/acute thyroid/CNS effects does not exceed the thresholds of regulatory consideration.

Future actions on the cumulative risk assessment of pesticides are scheduled by EFSA, in cooperation with DG Santé, e.g. prioritization of new CAGs. Furthermore, by 2030 EFSA and partners should be equipped for implementation for risk assessment of multiple chemicals, with a focus on dietary and non-dietary exposure for human health, with a stepwise implementation for dietary and aggregate exposure to pesticides and chemical in general, and with further development of methods (harmonized grouping criteria, OMICs data, aggregate exposure) and tools (open source).

An EFSA guidance document, on hazard driven criteria and prioritization methods, is to be expected to be finalized by December 2021.

Stephanie Melching – Kollmuss (BASF) - Experiences with cumulative risk assessments in the agrochemical industry and views (presentation)

Stephanie shared the experience of Croplife on the cumulative risk assessment addressing different compounds (within the group of pesticides), products and applications. As an introduction into the EU approach, initially work was started with establishment of CAGs to cover all relevant target organs, together with performing probabilistic exposure and risk assessments. As also presented by Bruno, from the retrospective cumulative risk assessments, the thresholds for regulatory consideration were not reached, after hazard and exposure-based refinements. However, future work is required, as is indicated in the EFSA/DG Santé action plan. This would also include prioritization with regard to hazard assessment (relevance CAGs, number of compounds in CAGs, dose at which the effect occurs, excluding compounds with low individual hazard quotients) and exposure assessment (realistic retrospective exposure, focus on major crops and uses). Croplife looked at specific groups, e.g. liver (with a focus on primary lesion, rather than the secondary lesions) or the reproduction/developmental CAGs. In addition, prioritization based on exposure is required. In order to avoid extensive refinements in mixture risk assessment, it is proposed to refine upfront by e.g. apply more stringent criteria to substance for inclusion into CAGs, consider only compounds for which the common toxic effect is very close to effect driving the reference value, use realistic exposure scenarios (e.g. maximum market share), monitoring background exposure, etc. Future challenges are aggregate exposures, availability of open data bases and risk management.

Lonneke van Leeuwen (RIVM, bureau REACH) – The EU Chemicals Strategy for sustainability towards a toxic-free environment: A Mixture Assessment Factor under REACH (presentation)

Lonneke presented on the EU Chemical Strategy for Sustainability (CSS) and recent ongoing work on the Mixture Assessment Factor (MAF) with a focus on the environment.

2009 is taken as a starting point with the Kortenkamp ‘State of the art report on mixture toxicity’. It concludes an assessment can be done, but should it also be regulated? In 2016 the RIVM published a thought starter on this topic. This report introduced a data driven mixture assessment factor (MAF) for the environment, and indicated that further work was needed to quantify a MAF. In 2020 the EU CSS was published describing a route to a toxic free environment with the goal to better protect human health and the environment and boost innovation. One of the strategic priorities to achieve this is to build a stronger EU legal framework to deal with mixtures. The focus is on unintentional mixtures.

In 2021 the RIVM has a publication in preparation that uses monitoring data for EU surface waters to identify trends in number of chemicals responsible for toxic pressure due to cumulative (environmental) exposure.

The first outcomes show time-place combination where in most situations 1 or 2 chemicals are present. There are only 376 time-place locations with more than 25 substances present. Further, it was observed that a large portion of the toxic pressure on freshwater bodies (> 90%), is caused by 20% of the chemicals. The chemicals that cause the issues are different between the monitoring locations. The current monitoring data shows that not all surface waters in the EU are properly protected. A general reduction of the RCR for single substances to 0.33 leads to an large improvement of the protection of EU surface waters.

RIVM will further investigate whether the same observations can be made based on a wider set of freshwater modelling data.

Annette Wilschut (DSM) – Mixed feelings (presentation)

Annette gave us a warming up for the discussion on the proposal for a MAF. Industry is recognizing the issue of combined exposure, however, is questioning whether the MAF is the right solution. How to balance the aim and the impact of the measure? Will the MAF solve the issue (e.g., legacy chemicals)? Is it proportional & targeted (e.g., via other targeted frameworks/permits)? What is the scientific basis (i.e., more insight in environmental compared to human risk)? How will it be implemented (e.g., prioritization, one-fits- all solution)? According to Annette, the complexity of the situation does not warrant a generic MAF. A set of targeted science-based solutions is the best way forward.


There was a lively discussion from all areas of the playing field with experts highlighting the pros and cons of a generic MAF:

  • Risk management has been trying to handle this for 30 years. When does the precautionary principle take over from science-based solutions?
  • Only a few chemicals determine the effects, the balance does not seem right in this respect.
  • Is there really an issue? Let’s target the active substances.
  • Would the focus on better exposure and mechanistic data (and making this data publicly available) give us the opportunity for a more targeted approach to come to the critical scenarios and protect human health and the environment?

Diverging opinions were expressed. In the end it is up to policy makers to decide on the best approach in the coming years. Will this be a more general precautionary approach or a science based data driven approach in the end … The future will show us!