EURL ECVAM strategy for achieving 3Rs impact in the assessment of toxicokinetics and systemic toxicity

Bessems, Jos; Coecke, Sandra; Gouliarmou, Varvara; Whelan, Maurice; Worth, Andrew

doi:10.1016/j.toxlet.2015.08.372

Cited by 21 publications

(36 citation statements)

References 26 publications

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“…1107/2009) and biocides (Regulation (EU) 528/2012). An overview of regulatory provisions on ADME (absorption, distribution, metabolism and excretion) and toxicokinetics is available in the recently published EURL ECVAM (European Reference Laboratory for Alternatives to Animal Testing) strategy for achievement of 3Rs impact in the assessment of toxicokinetics and systemic toxicity (Bessems et al, 2015). However, it becomes more and more evident that animal-derived pharmaco-/toxicokinetic data are not always reliable for extrapolation to human safety assessment due to interspecies differences in physiology as well as in biochemical and metabolic pathways.…”

Section: Ex Vivo Intestine Modelsmentioning

confidence: 99%

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Non-animal models of epithelial barriers (skin, intestine and lung) in research, industrial applications and regulatory toxicology

Gordon

Daneshian

Bouwstra

et al. 2015

ALTEX

124

103

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SummaryModels of the outer epithelia of the human body -namely the skin, the intestine and the lung -have found valid applications in both research and industrial settings as attractive alternatives to animal testing. A variety of approaches to model these barriers are currently employed in such fields, ranging from the utilization of ex vivo tissue to reconstructed in vitro models, and further to chip-based technologies, synthetic membrane systems and, of increasing current interest, in silico modeling approaches. An international group of experts in the field of epithelial barriers was convened from academia, industry and regulatory bodies to present both the current state of the art of non-animal models of the skin, intestinal and pulmonary barriers in their various fields of application, and to discuss research-based, industry-driven and regulatory-relevant future directions for both the development of new models and the refinement of existing test methods. Issues of model relevance and preference, validation and standardization, acceptance, and the need for simplicity versus complexity were focal themes of the discussions. The outcomes of workshop presentations and discussions, in relation to both current status and future directions in the utilization and development of epithelial barrier models, are presented by the attending experts in the current report.

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Section: Ex Vivo Intestine Modelsmentioning

confidence: 99%

“…priority setting (Marquart et al, 2012). It can also serve for risk assessment, such as route-to-route extrapolation, interspecies extrapolation, and internal exposure-based waiving, as outlined in the EURL ECVAM strategy for achieving 3Rs impact in the assessment of toxicokinetics and systemic toxicity (Bessems et al, 2015).…”

Section: In Silico Modelingmentioning

confidence: 99%

Non-animal models of epithelial barriers (skin, intestine and lung) in research, industrial applications and regulatory toxicology

Gordon

Daneshian

Bouwstra

et al. 2015

ALTEX

124

103

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“…The role of internal exposure in predicting effects of chemicals is now well recognised. 37 Models are needed for all ADME endpoints, however, review of the literature demonstrated that there are significant differences in numbers of models available depending on the endpoint in question. This reflects the availability of data on which to build models and the complexity of the processes involved.…”

Section: Discussionmentioning

confidence: 99%

Assessment and Reproducibility of Quantitative Structure–Activity Relationship Models by the Nonexpert

Patel

Chilton

Sartini

et al. 2018

J. Chem. Inf. Model.

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Model reliability is generally assessed and reported as an intrinsic component of quantitative structure-activity relationship (QSAR) publications; it can be evaluated using defined quality criteria such as the Organisation for Economic Cooperation and Development (OECD) principles for the validation of QSARs. However, less emphasis is afforded to the assessment of model reproducibility, particularly by users who may wish to use model outcomes for decision making, but who are not QSAR experts. In this study we identified a range of QSARs in the area of absorption, distribution, metabolism, and elimination (ADME) prediction and assessed their adherence to the OECD principles, as well as investigating their reproducibility by scientists without expertise in QSAR. Here, 85 papers were reviewed, reporting over 80 models for 31 ADME-related endpoints. Of these, 12 models were identified that fulfilled at least 4 of the 5 OECD principles and 3 of these 12 could be readily reproduced. Published QSAR models should aim to meet a standard level of quality and be clearly communicated, ensuring their reproducibility, to progress the uptake of the models in both research and regulatory landscapes. A pragmatic workflow for implementing published QSAR models and recommendations to modellers, for publishing models with greater usability, are presented herein.

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“…the models should also be discussed. 10,11 In this work we have put much emphasis in documenting and evaluating the developed models.…”

Section: ■ Quality and Applicability Of Thementioning

confidence: 99%

“…Presently, significant emphasis is put into developing new in vitro assays and standardizing already available methods in order to provide data on ADME, protein binding, and other relevant biological parameters for use in PBTK based risk assessment. 10, 11,25 Although many PBTK models have been published for pesticides during the past decade, 26−32 only a few of these studies consider cumulative effects due to exposure to more than one chemical. 33−36 PBTK models have been used for many years in the risk assessment of various types of organic chemicals and drugs, mostly for individual compounds.…”

Section: ■ Introductionmentioning

confidence: 99%

Physicologically Based Toxicokinetic Models of Tebuconazole and Application in Human Risk Assessment

Jónsdóttir

Reffstrup

Petersen

et al. 2016

Chem. Res. Toxicol.

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A series of physiologically based toxicokinetic (PBTK) models for tebuconazole were developed in four species, rat, rabbit, rhesus monkey, and human. The developed models were analyzed with respect to the application of the models in higher tier human risk assessment, and the prospect of using such models in risk assessment of cumulative and aggregate exposure is discussed. Relatively simple and biologically sound models were developed using available experimental data as parameters for describing the physiology of the species, as well as the absorption, distribution, metabolism, and elimination (ADME) of tebuconazole. The developed models were validated on in vivo half-life data for rabbit with good results, and on plasma and tissue concentration-time course data of tebuconazole after i.v. administration in rabbit. In most cases, the predicted concentration levels were seen to be within a factor of 2 compared to the experimental data, which is the threshold set for the use of PBTK simulation results in risk assessment. An exception to this was seen for one of the target organs, namely, the liver, for which tebuconazole concentration was significantly underestimated, a trend also seen in model simulations for the liver after other nonoral exposure scenarios. Possible reasons for this are discussed in the article. Realistic dietary and dermal exposure scenarios were derived based on available exposure estimates, and the human version of the PBTK model was used to simulate the internal levels of tebuconazole and metabolites in the human body for these scenarios. By a variant of the models where the R(-)- and S(+)-enantiomers were treated as two components in a binary mixture, it was illustrated that the inhibition between the two tebuconazole enantiomers did not affect the simulation results for these realistic exposure scenarios. The developed models have potential as an important tool in risk assessment.

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EURL ECVAM strategy for achieving 3Rs impact in the assessment of toxicokinetics and systemic toxicity

Cited by 21 publications

References 26 publications

Non-animal models of epithelial barriers (skin, intestine and lung) in research, industrial applications and regulatory toxicology

Non-animal models of epithelial barriers (skin, intestine and lung) in research, industrial applications and regulatory toxicology

Assessment and Reproducibility of Quantitative Structure–Activity Relationship Models by the Nonexpert

Physicologically Based Toxicokinetic Models of Tebuconazole and Application in Human Risk Assessment

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