A prospective whole-mixture approach to assess risk of the food and chemical exposome

Reply to the opinion paper “The EU chemicals strategy for sustainability: an opportunity to develop new approaches for hazard assessment” by Scholz et al.

“…Already in previous years, BfR has addressed this issue in a number of completed projects contributing constructive, scientific proposals to address complex issues such as mixture toxicity (Tralau et al 2021 ) or engaging in the promotion of new approach methodologies (NAMs) (Escher et al 2019 ; Moné et al 2020 ; Rovida et al 2020 , 2021 ). Currently, we are active in a number of complex EU research projects with exactly this goal, e.g., with respect to the implementation of New Approach Methodologies and Next Generation Risk Assessment ( https://www.risk-hunt3r.eu/ ), mixture toxicity ( https://panoramix-h2020.eu/ , together with UFZ), and will strongly engage in the partnership for the assessment of risk from chemicals (PARC, https://www.anses.fr/en/content/european-partnership-assessment-risks-chemicals-parc ).…”

“…With regard to human health, these boundary conditions for mixtures to become a toxicologically relevant problem are scientifically well defined as is the potential chemical space for which this might indeed be of regulatory relevance. The available data indicate that this space is confined to a limited number of substances that could become relevant in regulatory terms only in scenarios where single substance-based assessment of the main mixture risk drivers leaves a significant regulatory gap (Herzler et al 2021 ; Tralau et al 2021 ). To some extent, mixture toxicity also has been in the focus of “classical” and regulatory toxicology already, particularly at the BfR.…”

An approach for mixture testing and prioritization based on common kinetic groups

“…It is for this reason that incidences of known mixture toxicity are generally low and that single substance assessments are in most cases considered sufficiently conservative (Herzler et al 2021 ). Yet, the ever-increasing use of and exposure to chemicals have led to regained regulatory awareness of potential mixture effects (Tralau et al 2021 ). This is particularly the case for chemical substances regulated under REACH (EU legislation on the Registration, Evaluation and Authorization of Chemicals), but has also stimulated conceptual debates for those regulatory domains where potential mixture effects already are already considered to some extent, such as pesticides.…”

“…However, with about 22,000 compounds currently registered as industrial chemicals under REACH, the number of chemical combinations available for exposure is almost infinite. Add to this some 470 and 150 active substances approved for use in plant protection products and biocides in the EU, and there is unarguably a need to develop strategies for the identification and prioritization of potentially critical mixtures even in the absence of an immediate concern (Tralau et al 2021 ). Given the large chemical space, any wider regulatory strategy on mixture toxicity will in the end have to settle for a two-tier system.…”

“…First, there needs to be a filtering step to narrow down and define the number of substance combinations to be looked at. Ideally, this should be done with a strong focus on exposure, which can, if needed, be complemented by considerations regarding hazard potential (Herzler et al 2021 ; Tralau et al 2021 ). The actual assessment then follows in a second step that will strongly rely on the toxicological evaluation of the potential effects and in that context grouping and prioritization.…”