This Guidance document describes harmonised risk assessment methodologies for combined exposure to multiple chemicals for all relevant areas within EFSA's remit, i.e. human health, animal health and ecological areas. First, a short review of the key terms, scientific basis for combined exposure risk assessment and approaches to assessing (eco)toxicology is given, including existing frameworks for these risk assessments. This background was evaluated, resulting in a harmonised framework for risk assessment of combined exposure to multiple chemicals. 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 approaches and component-based approaches. Specific considerations are given to component-based approaches including the grouping of chemicals into common assessment groups, the use of dose addition as a default assumption, approaches to integrate evidence of interactions and the refinement of assessment groups. Case studies are annexed in this guidance document to explore the feasibility and spectrum of applications of the proposed methods and approaches for human and animal health and ecological risk assessment. The Scientific Committee considers that this Guidance is fit for purpose for risk assessments of combined exposure to multiple chemicals and should be applied in all relevant areas of EFSA's work. Future work and research are recommended.

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Guidance on harmonised methodologies for human health, animal health and ecological risk assessment of combined exposure to multiple chemicals

http://uu.diva-portal.org/smash/get/diva2:1384687/FULLTEXT01

Statement on advancing the assessment of chemical mixtures and their risks for human health and the environment.

This paper summarizes current challenges, the potential use of novel scientific methodologies, and ways forward in the risk assessment and risk management of mixtures. Generally, methodologies to address mixtures have been agreed; however, there are still several data and methodological gaps to be addressed. New approach methodologies can support the filling of knowledge gaps on the toxicity and mode(s) of action of individual chemicals. (Bio)Monitoring, modeling, and better data sharing will support the derivation of more realistic co-exposure scenarios. As knowledge and data gaps often hamper an in-depth assessment of specific chemical mixtures, the option of taking account of possible mixture effects in single substance risk assessments is briefly discussed. To allow risk managers to take informed decisions, transparent documentation of assumptions and related uncertainties is recommended indicating the potential impact on the assessment. Considering the large number of possible combinations of chemicals in mixtures, prioritization is needed, so that actions first address mixtures of highest concern and chemicals that drive the mixture risk. As chemicals with different applications and regulated separately might lead to similar toxicological effects, it is important to consider chemical mixtures across legislative sectors.

https://tandfonline.com/doi/pdf/10.1080/10408444.2019.1579169

Regulatory assessment and risk management of chemical mixtures: challenges and ways forward.

A hazard quotient (HQ) for a single chemical and the hazard index (HI) for a mixture of chemicals were first described as approaches for risk characterisation by the EPA. HQ is defined as the ratio of exposure to an appropriate reference dose such as the ADI. HI is the sum of the HQs of the chemicals in a mixture. HQ and HI have been used to characterise risk after various exposure scenarios. However, both approaches have a significant limitation in the way they are used. The accurate use of HQ or HI requires estimation of aggregate exposure, that is, exposure to a given chemical(s) from all possible relevant sources. In many studies, risk is assessed assuming exposure from a specific source such as, consumption of water or a specific food item, in which chemical(s) concentration(s) have been measured. In this case the classic HQ/HI approach can result in significant underestimation of risk. For this purpose, we developed an alternative approach, named as Source Related HQ (HQs) where HQS is the ratio of the exposure from the specific source of interest to the respected reference values. According to our approach the HQS, before being compared to the reference dose, should be adjusted by a correction factor, in order to simulate aggregated exposure. A correction factor can be calculated based on the permitted exposure contribution from the specific source to the permitted aggregated exposure. Another important limitation specific to the HI approach is the use of chemical specific ADIs that do not correspond to the same critical effect. In this study, we present an analysis based on the individual critical effects, in order to derive the critical effect and an adversity specific Hazard Index (HIA) and risk characterisation for the whole mixture.

Proposing new approaches for the risk characterisation of single chemicals and chemical mixtures: The source related Hazard Quotient (HQS) and Hazard Index (HIS) and the adversity specific Hazard Index (HIA).

This article reviews the current legislative requirements for risk assessment of combined exposure to multiple chemicals via multiple exposure routes, focusing on human health and particularly on food-related chemicals. The aim is to identify regulatory needs and current approaches for this type of risk assessment as well as challenges of the implementation of appropriate and harmonized guidance at international level. It provides an overview of the current legal requirements in the European Union (EU), the United States and Canada. Substantial differences were identified in the legal requirements for risk assessment of combined exposure to multiple chemicals and its implementation between EU and non-EU countries and across several regulatory sectors. Frameworks currently proposed and in use for assessing risks from combined exposure to multiple chemicals via multiple routes and different durations of exposure are summarized. In order to avoid significant discrepancies between regulatory sectors or countries, the approach for assessing risks of combined exposure should be based on similar principles for all types of chemicals. OECD and EFSA identified the development of harmonized methodologies for combined exposure to multiple chemicals as a key priority area. The Horizon 2020 project "EuroMix" aims to contribute to the further development of internationally harmonized approaches for such risk assessments by the development of an integrated test strategy using in vitro and in silico tests verified for chemical mixtures based on more appropriate data on potential combined effects. These approaches and testing strategies should be integrated in a scientifically based weight of evidence approach to account for complexity and uncertainty, to improve risk assessment.

Overview on legislation and scientific approaches for risk assessment of combined exposure to multiple chemicals: the potential EuroMix contribution.

https://bura.brunel.ac.uk/bitstream/2438/17467/1/FullText.pdf

Paula E. Drakvik

Papers

Current EU research activities on combined exposure to multiple chemicals