March 7, 2019 by Kate Roylance & Grace Panter


In January (22nd – 23rd) Kate and Grace attended the Regulatory Science Associates (rsa) Conference on The Toxicology of Mixtures and Application of Cumulative Risk Assessment, Cranage Hall, UK. Pesticide mixtures and the risk assessment of pesticide residues are “hot topics” on agendas both in Europe and the US. The US assessment has been described as an “inclusion approach”, whereas the European described as an “exclusion approach”.

The conference was opened by a series of talks from Alan Boobis (Imperial College London), Andreas Kortenkamp (Brunel University) and Gary Roberts (rsa), highlighting some of the factors to consider when thinking about cumulative assessment groups (common effect versus critical effect), cumulative risk assessment (mixture effects at low exposures, mode of action) and residue assessment of dietary risk assessment (use of quantitative structure activity relationship for which an alternative approach was recently developed by the European Crop Protection Association [ECPA] and commented on).

Jean Lou Dorne (European Food Safety Authority, EFSA) gave an update on the EFSA guidance on “Harmonised methodologies for human health, animal health and ecological risk assessment of combined exposure to multiple chemicals"1. This was expected to be adopted in February 2019 and published in March 2019. The guidance is designed to provide a harmonised approach for all relevant areas within EFSA yet contain the flexibility to be fit for purpose.

The framework is based on the risk assessment steps (problem formulation; exposure assessment; hazard identification and characterisation, and risk characterisation including uncertainty analysis), with tiered and stepwise approaches for both whole mixture and component-based approaches. Specific considerations are given to component-based approaches including the classifying of pesticides into Cumulative Assessment Groups (CAGs). CAGs have been proposed for several target organs. Further case studies are being developed to illustrate the use of the guidance and EFSA are building toxicokinetic, dynamic energy budget and physiologically based toxicokinetic models to support single compound and mixture assessments.

With regards to the US, Charles Wood (Boehringer Ingelheim Pharmaceuticals, Inc) gave an overview of cumulative risk assessment at the US EPA2, which cuts across several federal states (e.g. water, air, drinking water, food quality acts) and the use of adverse outcome pathways as an organising concept in cumulative risk assessment. The approach taken by the US EPA focuses on identifying Common Mechanism Groups (CMGs) within cumulative risk assessments, rather than CAGs. This includes identifying a common Mode of Action (MoA) between chemicals within the same CMG. Due to the lack of experimental data on MoA information, this approach has been criticised for being too specific. Douglas Wolf (Syngenta), discussed the use of RISK213 Framework, as a feasible, transparent and common-sense tool for structing data required to inform a cumulative risk assessment.

Stephanie Melching-Kollmuss (BASF, representing ECPA) went into the draft EFSA guidance in more detail and gave the European perspective (ECPA) on cumulative risk assessment of residues and the use of CAGs. ECPA are proposing that groupings are based on full hazard assessment characterisation and the number of CAGs could be reduced for many target organs. This latter point was further elaborated on further in the talks by Giovanna Semino-Beinel (Bayer, representing ECPA), Wolfgang Dekant (University of Würzburg) and Mary Moxon (Independent consultant). Using the thyroid, the liver and reproduction as examples, respectively, they highlighted the complexity, ambiguity and time-consuming nature of assigning chemicals to the EFSA CAGs and that several of these groups were redundant and could be reduced.

In other talks Frank Laporte (Bayer, representing ECPA) discussed the cumulative risk assessment of pesticides using PRIMo and European monitoring. Using CAGs for motor division and the nervous system as examples, there are several uncertainties due to the handling of residues <LOQ (limit of quantification) and the use of moiety methods that do not allow to distinguish between individual substances.

The final talk of the conference was by Christian Strupp (Gowan Crop Protection), who introduced the prospects for cumulative assessment and mixtures and again reiterated the need to reduce the number of CAGs to a manageable size and evolve the mechanistic understanding of toxicity (toxicological mode of action and realistic exposure need to be integrated).

wca has experienced toxicologists and ecotoxicologists who have been conducting chemical risk assessments for human and veterinary medicines and industrial chemicals, for regulatory submissions, for many years. Our expertise also extends to evidence-based training, adverse outcome pathways and environmental risk assessments. Please contact us if you would like more information on our services in this area or support with the development of approaches to the assessment of mixtures.


  1. Draft guidance on harmonised methodologies for human health, animal health and ecological risk assessment of combined exposure to multiple chemicals.
  2. Concepts, methods and data sources for cumulative health risk assessment of multiple chemicals, exposure effects: A resource document.
  3. HESI®– RISK21® Roadmap.