EUROTOX 2018 ControlCenter

Online Program Overview Session: CEC1

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Exposure, hazard and risk assessment of mixtures of pesticides / chemicals in food using the tools developed in the EuroMix project

Session chair: Hubert Dirven Norway; Jacob van Klaveren The Netherlands
Shortcut: CEC1
Date: Sunday, 2 September, 2018, 10:30
Room: Meeting Studio 311
Session type: CEC



Risk assessment of chemical mixtures – Regulatory requirements and current scientific approaches (#104)

R. Solecki1

1 German Federal Institute for Risk Assessment, Department Pesticide Safety, Berlin, Berlin, Germany

Hazard and risk assessment of human exposure to mixtures of chemicals is a big challenge within the regulatory frameworks and for the harmonisation of scientific approaches.  Current legislative frameworks highlight the need to assess potential combined effects from exposure to multiple chemicals. However, substantial differences were identified in the legal requirements for cumulative risk assessment and its implementation between the EU and non-European countries. Risk assessment under different regulatory frameworks should be based on similar principles in order to avoid significant discrepancies between regulatory silos or countries. Thus, harmonized and clearly structured frameworks, which lead risk assessors through the process of a cumulative risk assessment, are required.

While the current scientific approaches represent a broad application of knowledge and integrated methods to address the challenges of mixture risk assessment, additional guidance and harmonised method development could increase transparency and structure, as well as improve confidence in risk assessment conclusions. An integrated test strategy using in vitro and in silico tests verified for chemical mixtures and more appropriate data on potential cumulative effects should be combined in a scientific based weight of evidence approach to account for complexity and to improve risk assessment.


OECD and EFSA identified the development of harmonised methodologies for combined exposure to multiple chemicals as a key priority area and initiated a number of activities. Recently, EFSA works on a guidance document addressing a harmonised application of risk assessment methods for combined exposure to multiple chemicals to all relevant areas within EFSA’s remit. Contributing to the further development of internationally harmonised approaches for risk assessment of combined exposures to multiple chemicals is also the overall goal of the Horizon 2020 project ‘EuroMix’.

Keywords: Horizon 2020, Regulatory, Risk assessment

Opportunities and Pitfalls in Risk Assessment of Coexposures (#351)

H. M. Hollnagel1, J. Mehta2, R. Budinsky3, N. Vallotton1

1 Dow Europe GmbH, TERC, Horgen, Switzerland
2 Dow AgroSciences Ldt, HHA, Milton Park, United Kingdom
3 The Dow Chemical Company, TERC, Midland, United States of America

Humans and environmental receptors are exposed to a variable ‘cocktail’ of manmade and natural substances daily and throughout life. However, our risk assessments and regulatory frameworks approach this situation in a simplistic manner via individual substances. As a result, tools for risk assessment of coexposures need to be advanced and applied to investigate if real-life exposures pose a potential risk and, if so, which exposure situations and which substance classes may be of concern. At the current state of the science, the lack of individual exposure information paired with incomplete data on hazard and mode of action have to be handled pragmatically to enable risk assessments. This applies especially for substance classes with less comprehensive regulatory data submissions when compared to pesticides, e.g. food and personal care ingredients and industrial chemicals. Pragmatic screening approaches to coexposure risk assessment inherently cumulate conservative assumptions in lieu of accurate information, and typically result in extremely conservative risk assessment outcomes. Within pesticide coexposure risk assessments, pragmatic approaches to refine cumulative assessment groups are necessary, and the suitability of methods developed for pesticides for other chemicals will be reviewed. On the exposure assessment side, temporal and spatial variation are challenging to include in models, starting with the question how to handle non-detects in databases. Beyond dietary residue assessment, considerations of use types and exposure scenarios for different product types will be discussed as opportunities to prioritise substances for coexposure risk assessment. Communication of assumptions applied, variability and (un)certainty will be addressed as tool to foster appropriate interpretation of risk assessment outcomes by different stakeholders.

Keywords: coexposure, risk assessment, mixture

Case-study: Real-life dietary exposures to pesticide and the need for an approach overarching regulatory sectors. (#469)

J. van Klaveren1

1 RIVM, VPZ, Bilthoven, Netherlands

This training session will focus on dietary exposure to multiple pesticides. The assumptions made, the data quality and availability for performing such a combined assessment will be discussed. This includes; 1) examples on the uncertainties of relative potency factors (RPFs) used to combine the exposures of individual pesticides, 2) how to reassure/refine the assumption made on dose-addition and 3) the impact of mode of action information on grouping pesticides into cumulative assessment groups.

A hands-on training based on the dietary intake module of the Monte Carlo Risk Assessment (MCRA) software will be given. Monitoring data of pesticides acting via different mode/mechanism of action, but potential causing the same adverse outcome, will be used. Participants of the course will be trained on how to judge for the quality of the input data and how to interpret the exposure assessment results in terms of a margin of exposure (MoE). In case the MoE is considered to be too low and the assessment is done based on conservative data or assumptions, further testing might be needed and MCRA can be used to set test priorities.

AOP wise testing might provide information on mode of action and better estimations of RPFs based on benchmark dose modelling. Apart from pesticides, other chemicals might share an AOP. The need and possibilities of a combined exposure assessment overarching chemical classes regulated via different EU Directives will be discussed.

Keywords: mixtures, cumulative risk assessment, AOP, dose-response

Case-study: Combining dietary and non-dietary pesticide exposure (hands-on training) (#78)

M. Kennedy1

1 Fera, York, United Kingdom

The Euromix project has developed efficient methods for exposure and risk assessment for chemical mixtures, able to handle many compounds and prioritise a relatively small number for testing. The resulting toolkit is implemented in the Monte Carlo Risk Assessment (MCRA) software that is freely available online ( An important feature is the ability to estimate the distribution of aggregate exposures within a population. Aggregate exposure combines dietary and non-dietary exposure sources per-individual and may include chemical mixtures from each source.

This training session will introduce the methods used to perform the aggregate calculations in the MCRA software. The practical steps required to generate results will be shown based on 2 worked examples. Pre-calculated non-dietary exposures, that were generated from external software BROWSE and BREAM2, will be used. These represent probabilistic exposure estimates for residents living adjacent to arable or orchard crops sprayed with pesticides. UK scenarios are used in these examples. The data formats required for non-dietary exposures in general will be explained, so that the methods can be applied more generally.

An example will be included in which uncertainty is quantified within the non-dietary exposure source.

For each example, the range of results provided by MCRA will be explored and interpreted.

Keywords: Aggregate exposure, bystander, resident

Aggregate and cumulative exposure of bisphenols from food and personal care products: A hands-on training (#91)

C. Karrer1, C. Delmaar2, B. Bokkers2, K. Hungerbühler1, N. von Goetz1, 3

1 Swiss Federal Institute of Technology (ETH), Institute for Chemical and Bioengineering, Zurich, Switzerland
2 National Institute for Public Health and the Environment (RIVM), Bilthoven, Netherlands
3 Swiss Federal Office of Public Health, Bern, Switzerland

One goal of the EuroMix project is the provision of exposure models for different sources in an exposure model toolbox. Among the models that can be combined for an aggregate assessment are the Monte Carlo Risk Assessment model (MCRA) for dietary exposure and the Probabilistic Aggregate Consumer Exposure Model (PACEM) for exposure to personal care products (PCPs).

PACEM has been programmed in R to derive aggregate consumer exposure to PCPs in a person-oriented way. Within the EuroMix project, we have developed a user-friendly interface. PACEM and its interface are available to exposure assessors upon request. In the new interface, results can be interpreted in a dynamic way. Exposures estimates can be easily exported in a format that is compatible to the models within the EuroMix model toolbox.

In this training session, we will use PACEM to model exposure to two bisphenols from PCPs. We will explore input possibilities for concentration data and exposure fractions. It will be shown what kind of results can be generated and how their display can be modified. As a last step within PACEM, we will export the exposure estimates for further use into the EuroMix model toolbox.

In the next part of the training, we will work with MCRA and the EuroMix model toolbox. Dietary concentration and consumption data will be used to model dietary exposure to the two bisphenols within MCRA. The dietary exposure and the pre-calculated external exposure from PCPs will be integrated with absorption fractions to yield aggregate internal exposure estimates. Subsequently, relative potency factors for the two bisphenols will be applied to estimate the cumulative internal exposure and the related risk. We will explore model possibilities and results obtained within MCRA and the EuroMix toolbox. In the end, an outlook will be given how the assessment could be further refined.

Keywords: Exposure modeling, aggregate exposure, exposure models, cumulative risk, bisphenols

Case study: Exposure to mixtures of chemicals in a human study and verification of aggregated exposure models with real-life data (#173)

H. Dirven1, M. Andreassen1, C. Karrer3, N. von Goetz4, A. K. Sakhi2, T. Husøy1

1 NIPH, Toxicology and Risk Assessment, Oslo, Norway
2 NIPH, Environmental Exposure and Epidemiology, Oslo, Norway
3 ETH, Institute for Chemical and Bioengineering, Zurich, Switzerland
4 Swiss Federal Office of Public Health, Bern, Switzerland

Exposure of humans to bisphenols is assumed to be widespread since these chemicals are used in a number of consumer products, and exposure occurs from a vast number of sources and via several routes. Detailed data on food consumption together with the use of personal care products (PCPs) and cosmetics is thus essential for properly assessing the aggregated exposure of the bisphenols.


To provide a verification platform for aggregated exposure assessments in the EuroMix project, a biomonitoring study was performed to obtain real-life human data on food consumption and the use of PCPs. Adult volunteers (n=144) in Norway gave detailed reports on food consumption (weight, time point, type/brand, packaging material) and the PCPs used (type/brand of product, time and number of applications and number of hand washes and showers) during two 24-hour study periods separated by 2-3 weeks. In parallel, 24h urine was collected and urinary levels of phenolic compounds (including BPA, BPS, BPF, oxobenzone and triclosan) were analysed simultaneously using on-line column switching ultra-high performance liquid chromatography and tandem mass spectrometry (UPLC-MS-MS). Concentrations of bisphenols in foods and PCPs were taken from existing literature. Exposure estimates will be correlated with concentrations of bisphenols in urine to verify the aggregated exposure models developed in EuroMix.


This training session will include a detailed description of the design and data collection in the human biomonitoring study. Furthermore, exposure to mixtures based on data of the analytical work performed in urine samples will be presented, as well as the implementation of data in the web-based tools MCRA and PACEM and how these are used for exposure estimation of bisphenols from dietary and non-dietary sources respectively, and in aggregated exposure estimates.

Keywords: bispenols, aggregated exposure