Deliverable D2.4 - Report on the integrated use of QSAR and TTC approaches to prioritise chemicals for further risk assessment in the context of mixtures
Creators: name: Rorije, Emiel
name: Cotterill, Jane
name: Eberini, Ivano
name: Peijnenburg, Ad
Publisher: name: Zenodo
Year: 2020

description: This deliverable describes the overall workflow followed in EuroMix Work Package 2. This workflow, which is proposed to be used as a first tier <em>in-silico </em>risk assessment of chemical mixtures in general, consists of four steps: 1) The first step is the identification of chemicals in food or feed that are of interest for combined exposures. A list of 1598 substances has been identified specifically for the purpose of EuroMix, and is described in D2.1 “Report describing cumulative assessment groups for a broad range of chemicals, based on information extracted from (literature) databases” . This list – the EuroMix Chemical Inventory – is subsequently completed with the results from the <em>in-silico</em> tools and calculations performed in EuroMix Work Package 2, described in detail in Deliverables 2.2, 2.3 and this deliverable (see next steps). 2) Determining the probability that a chemical belongs to a certain Cumulative Assessment Group (CAG). The level at which CAGs need to be determined for mixture risk assessment (level 1, organ toxicity, level 2: organ effect phenotype, level 3: mode of action, i.e. cellular processes, and level 4: mechanism of action, or molecular initiating events) is not established yet, as indications for this should come from the experimental work packages in EuroMix. The present deliverable D2.4 outlines the work-flows using existing QSAR models described in EuroMix D2.2 (Report on the use of in‐silico methods for the prioritisation of substances and mixtures thereof), in combination with the results from detailed molecular docking calculations performed as new research in the EuroMix project and described in D2.3. 3) Assignment of a relative potency factor to each chemical that was considered in the previous step to be part of the CAG of interest. These relative potencies are used to scale the exposures of all mixture components. RPF derivation using Threshold of Toxicological Concern (TTC) concepts, and Molecular Docking results were described in D2.3. Additionally a proposal for the use of read across based on chemical similarity is given in this deliverable. Interpretation of molecular docking based RPFs, as well as the interpretation of <em>in vitro</em> modelling results from WP3 in EuroMix, requires In Vitro to In Vivo Extrapolation. A first (QSAR based) tier to IVIVE is presented in section 6 of this deliverable. 4) Finally the mixture risk is determined by adding up all the scaled exposures of the mixture components that are predicted to be part of the Cumulative Assessment Group. As exposure considerations are not taken into account at all at this stage – for a large part of the EuroMix Inventory no exposure data will be available – the final risk assessment calculations are not part of this Deliverable. This workflow and all the data obtained with the tools and model predictions will be implemented in the EuroMix software tool as part of the EuroMix Work Package 6. The individual tools used in the mixture risk assessment workflow can be used to do prioritizations and rankings, i.e. to find the (predicted) most potent substances for a specific CAG. In section 5 of this Deliverable, these prioritizations have been performed to generate lists of potentially interesting substances - based on their predicted effect / mechanism of action and potency – for further testing in the <em>in-vitro</em> toolbox (EuroMix work package 3).