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© 2020 Elsevier Ltd Risk assessment of chemicals occurring in our diet is commonly performed for single chemicals without considering exposure to other chemicals. We performed a case study on risk assessment of combined dietary exposure to chemicals from different regulatory silos, i.e. pesticides (PPRs), persistent organic pollutants (POPs) and food additives (FAs). Chemicals were grouped into the cumulative assessment group (CAG) liver steatosis using a component-based approach. Based on literature, the CAG included 144 PPRs, 49 POPS and 7 FAs for which concentration data were available. For each silo, chronic combined dietary exposure was assessed for adults and children of nine European countries following the most commonly used exposure methodologies in Europe and by using a relative potency factor approach. For risk characterization, a Margin of Exposure (MOE) was calculated. To overarch the risk across silos, a normalised combined margin of exposure (nMOET) approach was proposed. This case study demonstrated that risk assessment of combined exposure to chemicals can be performed within regulatory silos. It also highlighted important differences in the conservatism of exposure scenarios, the derivation of point of departures and the subsequent acceptable MOEs between the silos. To overarch the risk despite these differences, a nMOET approach can be used.

The number of anthropogenic chemicals, manufactured, by-products, metabolites and abiotically formed transformation products, counts to hundreds of thousands, at present. Thus, humans and wildlife are exposed to complex mixtures, never one chemical at a time and rarely with only one dominating effect. Hence there is an urgent need to develop strategies on how exposure to multiple hazardous chemicals and the combination of their effects can be assessed. A workshop, “Advancing the Assessment of Chemical Mixtures and their Risks for Human Health and the Environment” was organized in May 2018 together with Joint Research Center in Ispra, EU-funded research projects and Commission Services and relevant EU agencies. This forum for researchers and policy-makers was created to discuss and identify gaps in risk assessment and governance of chemical mixtures as well as to discuss state of the art science and future research needs. Based on the presentations and discussions at this workshop we want to bring forward the following Key Messages:•We are at a turning point: multiple exposures and their combined effects require better management to protect public health and the environment from hazardous chemical mixtures.•Regulatory initiatives should be launched to investigate the opportunities for all relevant regulatory frameworks to include prospective mixture risk assessment and consider combined exposures to (real-life) chemical mixtures to humans and wildlife, across sectors.•Precautionary approaches and intermediate measures (e.g. Mixture Assessment Factor) can already be applied, although, definitive mixture risk assessments cannot be routinely conducted due to significant knowledge and data gaps.•A European strategy needs to be set, through stakeholder engagement, for the governance of combined exposure to multiple chemicals and mixtures. The strategy would include research aimed at scientific advancement in mechanistic understanding and modelling techniques, as well as r

Humans and wildlife are exposed to an intractably large number of different combinations of chemicals via food, water, air, consumer products, and other media and sources. This raises concerns about their impact on public and environmental health. The risk assessment of chemicals for regulatory purposes mainly relies on the assessment of individual chemicals. If exposure to multiple chemicals is considered in a legislative framework, it is usually limited to chemicals falling within this framework and co-exposure to chemicals that are covered by a different regulatory framework is often neglected. Methodologies and guidance for assessing risks from combined exposure to multiple chemicals have been developed for different regulatory sectors, however, a harmonised, consistent approach for performing mixture risk assessments and management across different regulatory sectors is lacking. At the time of this publication, several EU research projects are running, funded by the current European Research and Innovation Programme Horizon 2020 or the Seventh Framework Programme. They aim at addressing knowledge gaps and developing methodologies to better assess chemical mixtures, by generating and making available internal and external exposure data, developing models for exposure assessment, developing tools for in silico and in vitro effect assessment to be applied in a tiered framework and for grouping of chemicals, as well as developing joint epidemiological-toxicological approaches for mixture risk assessment and for prioritising mixtures of concern. The projects EDC-MixRisk, EuroMix, EUToxRisk, HBM4EU and SOLUTIONS have started an exchange between the consortia, European Commission Services and EU Agencies, in order to identify where new methodologies have become available and where remaining gaps need to be further addressed. This paper maps how the different projects contribute to the data needs and assessment methodologies and identifies remaining challenges to be fu

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.

RIVM rapport:Het gebruik van steviol glycosiden (extracten van de Stevia plant) als zoetstof in voedingsmiddelen is recent goedgekeurd door de Europese Commissie. De marktintroductie van deze producten zal waarschijnlijk niet leiden tot een gezondheidsprobleem in Nederland. Echter, extreme gebruikers van producten die gezoet worden met steviol glycosides zouden de ADI kunnen overschrijden. De potentiële toekomstige blootstelling van Nederlandse kinderen aan steviol glycosides is bekeken met behulp van scenarios. Hiervoor zijn consumptiedata uit de VCP-jonge kinderen (van 2 tot 6 jaar), de EC lijst met maximaal toegestane hoeveelheden en de producten waarin stevia is toegestaan gebruikt. Naast een 'worst case' scenario zijn ook scenarios met marktaandelen berekend. Bij het 10% marktaandeel scenario was de blootstelling van kinderen aan steviol glycosiden 1.7 mg/kg lichaamsgewicht per dag op het 95e percentiel en de ADI van 4 mg/kg lichaamsgewicht per dag werd overschreden door 0.3% van de kinderen. Limonades en frisdranken droegen het meest bij aan de blootstelling. Uit een literatuurstudie naar de gezondheidseffecten van steviol glycosiden werd geconcludeerd dat er weinig informatie beschikbaar is over effecten die optreden in combinatie met andere zoetstoffen. Echter, op basis van de aanwezige informatie worden geen nadelige effecten verwacht. Monitoring van de blootstelling aan zoetstoffen wordt geadviseerd, zodat potentiële problemen in de toekomst tijdig gesignaleerd en voorkomen kunnen worden., Market introduction of products sweetened with steviol glycosides (extracts from the Stevia plant), as recently authorized by the European Committee, is not likely to create a serious health problem in the Netherlands. However, extreme consumers of products sweetened with steviol glycosides may exceed the acceptable daily intake (ADI). The potential future exposure of children in the Netherlands to steviol glycosides is explored by means of scenarios. These comprised observational intake data from the DNFCS-young children (aged 2 to 6 years), the EC list of food products that are authorized to contain steviol glycosides and the maximum permitted levels for these products. Besides a worst case scenario, a 10% market share scenario was calculated. In this scenario, dietary exposure to steviol glycosides in children aged 2 to 6 years was 1.7 mg/kg bodyweight per day at the 95th percentile (expressed as steviol equivalents) and the ADI (4 mg/kg bodyweight per day) was exceeded by 0.3% of the children. The most important contributors to exposure to steviol glycosides in children were water-based flavoured drinks. From a literature study on health effects it was concluded that little data exist on interactive effects of sweeteners, but from what is available interactive adverse effects are not expected. It is advised to monitor exposure to all sweeteners, so that potential problems in the future can be foreseen and acted upon.