Mixture prioritization and testing: the importance of toxicokinetics

Braeuning, Albert; Marx‐Stoelting, Philip

doi:10.1007/s00204-021-03026-y

Cited by 8 publications

(6 citation statements)

References 5 publications

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“…This is different in respective regulations related to pharmaceuticals (ICH 1994). The development of a grouping approach based on toxicokinetic properties could hence be a way forward (Braeuning and Marx-Stoelting 2021). Concomitantly, with regard to hazard assessment based on the CLP calculation method, it should be critically assessed under which conditions the assumption of additivity is appropriate and when one would have to consider over-additivity due to toxicokinetic interactions (Hernandez et al 2013;Kurth et al 2019).…”

Section: Discussionmentioning

confidence: 99%

Effects of co-formulants on the absorption and secretion of active substances in plant protection products in vitro

et al. 2021

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Currently, the authorisation process for plant protection products (PPPs) relies on the testing of acute and topological toxicity only. Contrastingly, the evaluation of active substances includes a more comprehensive set of toxicity studies. Nevertheless, mixture effects of active ingredients and co-formulants may result in increased toxicity. Therefore, we investigated effects of surface active co-formulants on the toxicity of two PPPs focussing on qualitative and quantitative toxicokinetic effects on absorption and secretion. The respective products are based on the active substances abamectin and fluroxypyr-meptyl and were tested for cytotoxicity in the presence or absence of the corresponding surfactants and co-formulants using Caco-2 cells. In addition, the effect of co-formulants on increased cellular permeation was quantified using LC–MS/MS, while potential kinetic mixture effects were addressed by fluorescence anisotropy measurements and ATPase assays. The results show that surface active co-formulants significantly increase the cytotoxicity of the investigated PPPs, leading to more than additive mixture effects. Moreover, analytical investigations show higher efflux ratios of both active substances and the metabolite fluroxypyr upon combination with certain concentrations of the surfactants. The results further point to a significant and concentration-dependent inhibition of Pgp transporters by most of the surfactants as well as to increased membrane fluidity. Altogether, these findings strongly support the hypothesis that surfactants contribute to increased cytotoxicity of PPPs and do so by increasing the bioavailability of the respective active substances.

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Section: Discussionmentioning

confidence: 99%

Effects of co-formulants on the absorption and secretion of active substances in plant protection products in vitro

et al. 2021

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“…Table 2 shows that various triazole-class fungicides are inducers of CYP3A4 activity, which is mechanistically based on pregnane-X-receptor (PXR) and constitutive androstane receptor (CAR) activation by the compounds, followed by subsequent transcriptional activation of the CYP3A4 gene (Braeuning and Marx-Stoelting 2021 ). Fludioxonil, by contrast, inhibits CYP3A4 activity.…”

Section: Examples For Ckgs: Cyp3a4/5 and Abcc2mentioning

confidence: 99%

“…Respective data should cover the induction and inhibition of key enzymes for phase I and phase II metabolism, as well as interferences related to transport processes. We therefore recently proposed developing a novel grouping system based on common kinetic groups (Braeuning and Marx-Stoelting 2021 ). A schematic overview of respective AOP/CAG- and CKG-based strategies is presented in Fig.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2022

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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.

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“…Integrity of the metabolic barrier can be of high relevance, as alterations in hepatic and intestinal CYP expression and activity caused by foreign compounds are a frequent cause for interindividual variations in drug susceptibility (Zanger and Schwab 2013 ), as well as for drug-drug interactions (Almond et al 2009 ; Galetin et al 2010 ; Nettleton and Einolf 2011 ). Moreover, interference of foreign compounds with CYP activities may also be the underlying cause of non-additive mixture effects of different toxic compounds (Braeuning et al 2022 ; Braeuning and Marx-Stoelting 2021 ; Lasch et al 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Effects of marine biotoxins on drug-metabolizing cytochrome P450 enzymes and their regulation in mammalian cells

Würger,

Alarcan,

Braeuning

2024

Arch Toxicol

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Marine biotoxins are a heterogenous group of natural toxins, which are able to trigger different types of toxicological responses in animals and humans. Health effects arising from exposure to marine biotoxins are ranging, for example, from gastrointestinal symptoms to neurological effects, depending on the individual toxin(s) ingested. Recent research has shown that the marine biotoxin okadaic acid (OA) can strongly diminish the expression of drug-metabolizing cytochrome P450 (CYP) enzymes in human liver cells by a mechanism involving proinflammatory signaling. By doing so, OA may interfere with the metabolic barrier function of liver and intestine, and thus alter the toxico- or pharmacokinetic properties of other compounds. Such effects of marine biotoxins on drug and xenobiotic metabolism have, however, not been much in the focus of research yet. In this review, we present the current knowledge on the effects of marine biotoxins on CYP enzymes in mammalian cells. In addition, the role of CYP-regulating nuclear receptors as well as inflammatory signaling in the regulation of CYPs by marine biotoxins is discussed. Strong evidence is available for effects of OA on CYP enzymes, along with information about possible molecular mechanisms. For other marine biotoxins, knowledge on effects on drug metabolism, however, is scarce.

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Mixture prioritization and testing: the importance of toxicokinetics

Cited by 8 publications

References 5 publications

Effects of co-formulants on the absorption and secretion of active substances in plant protection products in vitro

Effects of co-formulants on the absorption and secretion of active substances in plant protection products in vitro

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

Effects of marine biotoxins on drug-metabolizing cytochrome P450 enzymes and their regulation in mammalian cells

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