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

Abstract

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. ARTICLE HISTORY

The Promises and Challenges of Toxico-Epigenomics: Environmental Chemicals and Their Impacts on the Epigenome

“…Cedergreen (2014) defined synergetic mixtures as those which elicited an observed effect that was at least 2-fold greater than the predicted effect, using concentration addition as a reference model. As reviewed extensively by Bopp et al (2019), the challenge in realistically assessing exposure to mixtures is taking into account the target population(s), the timing of exposure, or whether individuals or organisms are exposed to mixtures simultaneously or sequentially (Bopp et al 2019). Kienzler et al (2016) described current and potential future tools for modeling mixture effects but indicated that further guidance, data, and expertise are required before they can be fully applied (Kienzler et al 2016).…”

Critical assessment and integration of separate lines of evidence for risk assessment of chemical mixtures

“…The wholemixture approach is frequently applied for environmental samples, as it has the advantage of assessing the toxicity of mixtures of unknown composition and unknown potential for interactions, and measures directly the combined effect of the complete mixture. Although this approach is increasingly being used in situations of unknown and varying composition, such as chemical pollutants in surface water and wastewater effluents, the whole-mixture effect data are available for a limited number of mixtures and the substances driving the overall response frequently remain unidentified as well as potential interactions amongst mixture components (Bopp et al 2019;Hernández et al 2017). Conversely, the component-based approach requires identification of the chemicals present in the mixture of concern (e.g., concentration, mode of action (MoA) and toxicity of the components of the mixture, which is often lacking) followed by mathematical modeling to predict their joint action based on information from each individual component of the mixture.…”

“…The missing information can be addressed using novel technologies which enable a mechanistic understanding of the combined effects or can be estimated in part using computational models (see "Mechanism-based methodologies for the evaluation of the impact of chemical mixtures on human health"). However, component-based approaches can potentially lead to underestimations of hazard when the composition of a mixture is not fully known, which is usually the case, except for clearly defined, intentionally manufactured products (e.g., pesticide formulations), or chemicals present in foodstuff (e.g., multiple residues of pesticides) (Bopp et al 2019;Hernández et al 2017).…”

“…Models assuming dose addition are the most frequently applied because they provide reliable estimates of combined effects and are appropriate for the risk assessment of chemical mixtures when their individual components share the same molecular mechanism of action. A robust body of experimental evidence indicates that the basic assumption of additivity offers a reasonable expectation of mixture toxicity assuming that the components of the mixture do not interact with each other, which can modify the magnitude and even the nature of the toxic effect (Bopp et al 2019;Hernández et al 2017). The European Food Safety Authority (EFSA) EFSA Panel on Plant Protection Products and their Residues (2013) recommended the use of methodologies derived from dose addition for the assessment of mixtures of pesticides with dissimilar MOA, provided they produce a common adverse outcome as no cumulative risk assessment method has been derived from independent action.…”

“…As some of these concepts describing deviations from additivity are usually a matter of controversy, a proper and unambiguous definition is needed. The three main forms of interactions are (a) potentiation, which occurs when the toxicity of a chemical on a certain tissue or organ system is enhanced when given together with another chemical that alone does not have toxic effects on the same tissue or organ system; (b) synergism, which can result from chemicals acting simultaneously in different molecular or cellular targets from toxicity pathways, thus magnifying their final toxic effect, with deviations from additivity-based predictions being within a factor of four at environmentally realistic concentrations; (c) antagonism, a phenomenon that occurs when two or more chemicals in a mixture have an overall effect that is less than the sum of their individual effects, either as a result of toxicokinetic interactions (one chemical may stimulate the metabolism of a second one or somehow interfere with its absorption or distribution) or toxicodynamic interactions (chemicals elicit the opposite effects by acting on the same or different molecular targets, such as enzymes and receptors) (Boobis et al 2011;Bopp et al 2019;Hernández et al 2013Hernández et al , 2017.…”