Proposal of an in silico profiler for categorisation of repeat dose toxicity data of hair dyes

Nelms, Mark; Ates, Gamze; Madden, Judith C.; Vinken, Mathieu; Cronin, Mark T.D.; Rogiers, Vera; Enoch, Steven J.

doi:10.1007/s00204-014-1277-8

Cited by 27 publications

(21 citation statements)

References 41 publications

(1 reference statement)

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“…Interest in the application of MOAs and AOPs in predictive toxicology have already begun to appear, including the use of mode of action for aquatic toxicity prediction 36 and the application of the skin sensitization AOP to a risk assessment. 37 MIEs add a new level of understanding to MOAs and AOPs that is gaining attention as basis for work into QSAR development, 38 category formation and read-across, 39 and molecular modelling leading to mechanistic understanding. 40…”

Section: Figurementioning

confidence: 99%

Defining Molecular Initiating Events in the Adverse Outcome Pathway Framework for Risk Assessment

Allen

Goodman

Gutsell

et al. 2014

Chem. Res. Toxicol.

143

102

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Consumer and environmental safety decisions are based on exposure and hazard data, interpreted using risk assessment approaches. The adverse outcome pathway (AOP) conceptual framework has been presented as a logical sequence of events or processes within biological systems which can be used to understand adverse effects and refine current risk assessment practices in ecotoxicology. This framework can also be applied to human toxicology and is explored on the basis of investigating the molecular initiating events (MIEs) of compounds. The precise definition of the MIE has yet to reach general acceptance. In this work we present a unified MIE definition: an MIE is the initial interaction between a molecule and a biomolecule or biosystem that can be causally linked to an outcome via a pathway. Case studies are presented, and issues with current definitions are addressed. With the development of a unified MIE definition, the field can look toward defining, classifying, and characterizing more MIEs and using knowledge of the chemistry of these processes to aid AOP research and toxicity risk assessment. We also present the role of MIE research in the development of in vitro and in silico toxicology and suggest how, by using a combination of biological and chemical approaches, MIEs can be identified and characterized despite a lack of detailed reports, even for some of the most studied molecules in toxicology.

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Section: Figurementioning

confidence: 99%

Defining Molecular Initiating Events in the Adverse Outcome Pathway Framework for Risk Assessment

Allen

Goodman

Gutsell

et al. 2014

Chem. Res. Toxicol.

143

102

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“…Mitochondrial function plays a critical role in the development of disease and chemical toxicity (7,8), as well as the regulation of stem cell pluripotency (9). Mitochondrial dysfunction can occur through direct damage to the respiratory chain, or through secondary mechanisms such as ER stress or lipid accumulation (10).…”

mentioning

confidence: 99%

“…Because cells can adapt to loss of mitochondrial respiration by using anaerobic pathways such as glycolysis and glutaminolysis (Fig. 1A), mitochondrial damage can often go undetected with disastrous clinical and financial consequences (8), which is a particular concern in cultured cells that show an increased reliance on glycolysis and glutaminolysis due to the Warburg effect. Thus, real-time monitoring of these metabolic fluxes could provide critical insight into the development of mitochondrial dysfunction, as well as loss and gain of mitochondrial function in development.…”

mentioning

confidence: 99%

Real-time monitoring of metabolic function in liver-on-chip microdevices tracks the dynamics of mitochondrial dysfunction

Bavli

Prill

Tsur

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

247

277

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Microfluidic organ-on-a-chip technology aims to replace animal toxicity testing, but thus far has demonstrated few advantages over traditional methods. Mitochondrial dysfunction plays a critical role in the development of chemical and pharmaceutical toxicity, as well as pluripotency and disease processes. However, current methods to evaluate mitochondrial activity still rely on end-point assays, resulting in limited kinetic and prognostic information. Here, we present a liveron-chip device capable of maintaining human tissue for over a month in vitro under physiological conditions. Mitochondrial respiration was monitored in real time using two-frequency phase modulation of tissue-embedded phosphorescent microprobes. A computer-controlled microfluidic switchboard allowed contiguous electrochemical measurements of glucose and lactate, providing real-time analysis of minute shifts from oxidative phosphorylation to anaerobic glycolysis, an early indication of mitochondrial stress. We quantify the dynamics of cellular adaptation to mitochondrial damage and the resulting redistribution of ATP production during rotenone-induced mitochondrial dysfunction and troglitazone (Rezulin)-induced mitochondrial stress. We show troglitazone shifts metabolic fluxes at concentrations previously regarded as safe, suggesting a mechanism for its observed idiosyncratic effect. Our microfluidic platform reveals the dynamics and strategies of cellular adaptation to mitochondrial damage, a unique advantage of organ-on-chip technology.microfluidics | liver tissue engineering | toxicology | organ-on-a-chip

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“…As commented in the previous paragraph, the AOP framework assists in the support of biological similarity and category formation by defining MIEs and/or key intermediate events as a measure of similarity . The application of AOPs to support a mechanistic hypothesis in read‐across is an attractive hypothesis but as yet largely unproven, and how to select/validate the large numbers of in vitro HTS data to elucidate the AOP in reality is very difficult…”

Section: Open Issues and Challenges In Read‐acrossmentioning

confidence: 99%

Filling Data Gaps by Read‐across: A Mini Review on its Application, Developments and Challenges

Kovarich

Ceriani

Gatnik

et al. 2019

Molecular Informatics

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Read-across is a non-testing data gap filling technique which provides information for toxicological assessments by inferring from known toxicity data of compound(s) with a "similar" property or chemical profile. The increased usage of read-across was driven by monetary, timing and ethical costs associated with in vivo testing, as well as promoted by regulatory frameworks to minimize new animal testing (e. g., EU-REACH). Several guidance documents have been published by ECHA and OECD providing guidelines on how to perform, assess and docu-ment a read-across study. In parallel, much effort was invested by the scientific community to provide good readacross practices and structured frameworks to enhance validity of read-across justifications. Nevertheless, readacross is an evolving method with several open issues and opportunities. A brief review is here provided on key developments on the use of read-across, regulatory and scientific expectations, practical hurdles and open challenges.

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Proposal of an in silico profiler for categorisation of repeat dose toxicity data of hair dyes

Cited by 27 publications

References 41 publications

Defining Molecular Initiating Events in the Adverse Outcome Pathway Framework for Risk Assessment

Defining Molecular Initiating Events in the Adverse Outcome Pathway Framework for Risk Assessment

Real-time monitoring of metabolic function in liver-on-chip microdevices tracks the dynamics of mitochondrial dysfunction

Filling Data Gaps by Read‐across: A Mini Review on its Application, Developments and Challenges

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