Toxicokinetics as a key to the integrated toxicity risk assessment based primarily on non-animal approaches

Coecke, Sandra; Pelkonen, Olavi; Leite, Sofia Batista; Bernauer, Ulrike; Bessems, Jos; Bois, Frédéric Y.; Gundert‐Remy, Ursula; Loizou, George; Testai, Emanuela; Zaldı́var, J.M.

doi:10.1016/j.tiv.2012.06.012

Cited by 126 publications

(85 citation statements)

References 56 publications

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“…The combination of toxicodynamic and toxicokinetic approaches has been extensively investigated in the EU funded 7th Framework Project Predict-IV. Results obtained support the usefulness of in vitro biokinetic data in the interpretation of in vitro repeated exposure toxicity data (Broeders et al, 2013;Coecke et al, 2013;Parmentier et al, 2013). Overall, despite the limited number of molecules tested, this approach displayed some sensitivity (able to detect true positives) and specificity (able to detect true negatives) for the prediction of PLD and inhibition of Mrp2-mediated transport.…”

Section: Discussionsupporting

confidence: 64%

“…In addition, Table 2 summarizes the results obtained under these experimental conditions compared to preclinical and clinical findings. In order to have a more precise in vitro-in vivo extrapolation, the use of toxicokinetics data as well as physiologically based toxicokinetics modeling (PBTK) is recommended (Coecke et al, 2013). The nominal concentrations applied to the culture systems may deviate from the actual concentration of the compound due to the occurrence of multiple possible events, such as accumulation, evaporation, binding to plastic and/ or medium components, uptake and metabolism (Blaauboer, 2010;Tanneberger et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

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Determination of liver specific toxicities in rat hepatocytes by high content imaging during 2-week multiple treatment

Germano

Uteng

Philippe

et al. 2015

Toxicology in Vitro

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DILI is a major safety issue during drug development and one of the leading causes for market withdrawal. Despite many efforts made in the past, the prediction of DILI using in vitro models remains very unreliable. In the present study, the well-established hepatocyte Collagen I-Matrigel™ sandwich culture was used, mimicking chronic drug treatment after multiple incubations for 14 days. Ten drugs associated with different types of specific preclinical and clinical liver injury were evaluated at non-cytotoxic concentrations. Mrp2-mediated transport, intracellular accumulation of neutral lipids and phospholipids were selected as functional endpoints by using Cellomics™ Arrayscan® technology and assessed at five timepoints (day 1, 3, 7, 10, 14). Liver specific functional impairments after drug treatment were enhanced over time and could be monitored by HCI already after few days and before cytotoxicity. Phospholipidosis-inducing drugs Chlorpromazine and Amiodarone displayed the same response as in vivo. Cyclosporin A, Chlorpromazine, and Troglitazone inhibited Mrp2-mediated biliary transport, correlating with in vivo findings. Steatosis remained difficult to be reproduced under the current in vitro testing conditions, resulting into false negative and positive responses. The present results suggest that the repeated long-term treatment of rat hepatocytes in the Collagen I-Matrigel™ sandwich configuration might be a suitable tool for safety profiling of the potential to induce phospholipidosis and impair Mrp2-mediated transport processes, but not to predict steatosis.

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Section: Discussionsupporting

confidence: 64%

Section: Discussionmentioning

confidence: 99%

Determination of liver specific toxicities in rat hepatocytes by high content imaging during 2-week multiple treatment

Germano

Uteng

Philippe

et al. 2015

Toxicology in Vitro

View full text Add to dashboard Cite

show abstract

“…Ideally, these parameters also are derived from non-animal studies (Adler et al, 2011;Basketter et al, 2012;Coecke et al, 2012). For a recent review of these "Quantitative In Vitro-In Vivo Extrapolations," (QIVIVE) we refer to Yoon et al (2012).…”

Section: Biokinetic 2 Considerationsmentioning

confidence: 99%

“…Because biokinetic considerations are critical to accurately interpreting in vitro data (Blaauboer, 2010;Adler et al, 2011;Coecke et al, 2012) the use of physiologically-based biokinetic (PBBK) models has become critical in translating the concentration-effect relationships found in relevant in vitro models to dose-effect relationships in vivo. In essence, the kinetic models are used to estimate the external exposure that would result in effective concentrations at relevant targets.…”

Section: Adversity Versus Adaptationmentioning

confidence: 99%

The use of biomarkers of toxicity for integrating in vitro hazard estimates into risk assessment for humans

Blaauboer

Boekelheide

Clewell

et al. 2012

ALTEX

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SummaryThe role that in vitro systems can play in toxicological risk assessment is determined by the appropriateness of the chosen methods, with respect to the way in which in vitro data can be extrapolated to the in vivo situation. This report presents the results of a workshop aimed at better defining the use of in vitro-derived biomarkers of toxicity (BoT) and determining the place these data can have in human risk assessment. As a result, a conceptual framework is presented for the incorporation of in vitro-derived toxicity data into the risk assessment process. The selection of BoT takes into account that they need to distinguish adverse and adaptive changes in cells. The framework defines the place of in vitro systems in the context of data on exposure, structural and physico-chemical properties, and toxicodynamic and biokinetic modeling. It outlines the determination of a proper point-of-departure (PoD) for in vitro-in vivo extrapolation, allowing implementation in risk assessment procedures. A BoT will need to take into account both the dynamics and the kinetics of the compound in the in vitro systems. For the implementation of the proposed framework it will be necessary to collect and collate data from existing literature and new in vitro test systems, as well as to categorize biomarkers of toxicity and their relation to pathways-of-toxicity. Moreover, data selection and integration need to be driven by their usefulness in a quantitative in vitro-in vivo extrapolation (QIVIVE). Keywords: biomarker of toxicity, integrated testing strategies, quantitative in vitro-in vivo extrapolations

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“…the latter often will require information on transport processes of the compound across different membranes. to perform an in vitro-in vivo extrapolation (IVIVe), the real concentration of a compound has to be determined (Coecke et al, 2012). Some compounds may bind to plastic or to proteins or they may evaporate; others react quickly or become metabolized.…”

Section: In Vitro Based Risk Evaluation Approachmentioning

confidence: 99%

Novel technologies and an overall strategy to allow hazard assessment and risk prediction of chemicals, cosmetics, and drugs with animal-free methods

Leist

Lidbury

Yang

et al. 2012

ALTEX

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Summary Several alternative methods to replace animal experiments have been accepted by legal bodies. An even larger number of tests are under development or already in use for non-regulatory applications or for the generation of information stored in proprietary knowledge bases. The next step for the use of the different in vitro methods is their combination into integrated testing strategies (ITS) to get closer to the overall goal of predictive "in vitro-based risk evaluation processes." We introduce here a conceptual framework as the basis for future ITS and their use for risk evaluation without animal experiments. The framework allows incorporation of both individual tests and already integrated approaches. Illustrative examples for elements to be incorporated are drawn from the session "

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Toxicokinetics as a key to the integrated toxicity risk assessment based primarily on non-animal approaches

Cited by 126 publications

References 56 publications

Determination of liver specific toxicities in rat hepatocytes by high content imaging during 2-week multiple treatment

Determination of liver specific toxicities in rat hepatocytes by high content imaging during 2-week multiple treatment

The use of biomarkers of toxicity for integrating in vitro hazard estimates into risk assessment for humans

Novel technologies and an overall strategy to allow hazard assessment and risk prediction of chemicals, cosmetics, and drugs with animal-free methods

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