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

Abstract

In light of an ever-increasing exposure to chemicals, the topic of potential mixture toxicity has gained increased attention, particularly as the toxicological toolbox to address such questions has vastly improved. Routinely toxicological risk assessments will rely on the analysis of individual compounds with mixture effects being considered only in those specific cases where co-exposure is foreseeable, for example for pesticides or food contact materials. In the field of pesticides, active substances are summarized in so-called cumulative assessment groups (CAG) which are primarily based on their toxicodynamic properties, that is, respective target organs and mode of action (MoA). In this context, compounds causing toxicity by a similar MoA are assumed to follow a model of dose/concentration addition (DACA). However, the respective approach inherently falls short of addressing cases where there are dissimilar or independent MoAs resulting in wider toxicokinetic effects. Yet, the latter are often the underlying cause when effects deviate from the DACA model. In the present manuscript, we therefore suggest additionally to consider toxicokinetic effects (especially related to xenobiotic metabolism and transporter interaction) for the grouping of substances to predict mixture toxicity. In line with the concept of MoA-based CAGs, we propose common kinetics groups (CKGs) as an additional tool for grouping of chemicals and mixture prioritization. Fundamentals of the CKG concept are discussed, along with challenges for its implementation, and methodological approaches and examples are explored.

Lessons Learned from the Grouping of Chemicals to Assess Risks to Human Health

“…For pesticides, active substances with common target organ toxicity and toxicity mechanisms are summarized in so‐called cumulative assessment groups (CAG). Bräuning and co‐workers [134] proposed to additionally consider toxicokinetic effects for the grouping of substances to predict mixture toxicity. The proposed common kinetics groups (CKG) are defined using inhibition and induction of xenobiotic‐metabolizing enzymes and transporter proteins as criteria.…”

Basic concepts of mixture toxicity and relevance for risk evaluation and regulation

“…As explained above for OTA and ATB, disrupting the metabolic clearance of a toxic substance may increase its concentration in target tissues and consequently its adverse effects. In addition, the inhibition of active efflux or the induction of active uptake transporters may also affect the toxicity of a substance (Braeuning et al 2022 ). In substance-based risk assessment and threshold derivation, such modes of interaction are not considered and remain a data gap in mixture toxicity.…”

Lehren aus dem Gruppieren von Chemikalien zur Bewertung der Risiken für die Gesundheit des Menschen

“…Für Pestizide werden Wirkstoffe mit gleicher Zielorgan-Toxizität und Toxizitätsmechanismen in so genannten kumulativen Bewertungsgruppen (Cumulative Assessment Groups, CAG) zusammengefasst. Bräuning et al [134] schlugen vor, zusätzlich toxikokinetische Effekte bei der Gruppierung von Stoffen zu berücksichtigen, um die Toxizität von Gemischen vorherzusagen. Die vorgeschlagenen Gruppen übereinstimmender Biokinetik (common kinetic groups, CKG) werden anhand der Hemmung und Induktion von Transporterproteinen und von Xenobiotika metabolisierenden Enzymen als Kriterien definiert.…”

“…Für Pestizide werden Wirkstoffe mit gleicher Zielorgan‐Toxizität und Toxizitätsmechanismen in so genannten kumulativen Bewertungsgruppen (Cumulative Assessment Groups, CAG) zusammengefasst. Bräuning et al [134] . schlugen vor, zusätzlich toxikokinetische Effekte bei der Gruppierung von Stoffen zu berücksichtigen, um die Toxizität von Gemischen vorherzusagen.…”