The OSIRIS Weight of Evidence approach: ITS for the endpoints repeated-dose toxicity (RepDose ITS)

Tluczkiewicz, Inga; Kroese, Dinant; Buist, Harrie; Aldenberg, Tom; Pauné, Eduard; Grimm, Helvi; Kühne, Ralph; Schüürmann, Gerrit; Mangelsdorf, Inge; Escher, Sylvia

doi:10.1016/j.yrtph.2013.02.004

Cited by 20 publications

(20 citation statements)

References 34 publications

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“…In the method proposed by Tluczkiewicz et al . () four criteria were included as ’knock‐out criteria‘, which should be used to exclude inadequate studies from the risk assessment. In contrast, the intention of the two‐tiered method proposed here is not to disqualify studies based on strict criteria for reliability but, as already mentioned, to improve transparency and facilitate the use of different types of studies for risk assessment purposes.…”

Section: Discussionmentioning

confidence: 99%

“…() and Tluczkiewicz et al . (). In our opinion a qualitative approach is more appropriate than attributing a numerical value to describe the quality of a study and its adequacy for health risk assessment, which might imply a level of scientific certainty that may be misleading.…”

Section: Discussionmentioning

confidence: 99%

“…that key parameters are adequately covered and that the data are adequate for the purpose of classification and labeling (EC, 2006), whereas studies that include standardized methods and are conducted according to the GLP principles 'are per se considered adequate for regulatory use' (ECHA, 2011a). At the same time, old data, unlikely to fulfill the conditions described above, are sometimes used in REACH registration dossiers (Tluczkiewicz et al, 2013). For example, data published over 100 years ago have been found in registration dossiers (Westerholm and Schenk, 2014).…”

Section: Introductionmentioning

confidence: 99%

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Facilitating the use of non-standardin vivostudies in health risk assessment of chemicals: a proposal to improve evaluation criteria and reporting

et al. 2014

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To improve data availability in health risk assessment of chemicals and fill information gaps there is a need to facilitate the use of non-standard toxicity studies, i.e. studies not conducted according to any standardized toxicity test guidelines. The purpose of this work was to propose criteria and guidance for the evaluation of reliability and relevance of non-standard in vivo studies, which could be used to facilitate systematic and transparent evaluation of such studies for health risk assessment. Another aim was to propose user friendly guidance for reporting of non-standard studies intended to promote an improvement in reporting of studies that could be of use in risk assessment. Requirements and recommendations for the design and execution of in vivo toxicity studies were identified from The Organisation for Economic Co-operation and Development (OECD) test guidelines, and served as basis for the data evaluation criteria and reporting guidelines. Feedback was also collected from experts within the field of toxicity testing and risk assessment and used to construct a two-tiered framework for study evaluation, as well as refine the reporting guidelines. The proposed framework emphasizes the importance of study relevance and an important aspect is to not completely dismiss studies from health risk assessment based on very strict criteria for reliability. The suggested reporting guidelines provide researchers with a tool to fulfill reporting requirements as stated by regulatory agencies. Together, these resources provide an approach to include all relevant data that may fill information gaps and reduce scientific uncertainty in health risk assessment conclusions, and subsequently also in chemical policy decisions.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Facilitating the use of non-standardin vivostudies in health risk assessment of chemicals: a proposal to improve evaluation criteria and reporting

et al. 2014

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“…[108–110] The NO(A)EL and LO(A)EL are assessed by means of in vivo studies that can be based on various protocols accounting for different exposure period, animal model (rodent or non‐rodent species), exposure route (oral, inhalation or dermal), [111] number of experimental doses and size of the intervals between doses. Both NOAEL and LOAEL are not calculated on the basis of dose‐response curves and, thus, it is impossible to give an accurate estimate of the real minimal dose at which an adverse effect occours . On the other hand, repeated dose toxicity assessment is explicitly required by several regulatory contexts, such as REACH the Cosmetic Product Directive, Chemical Safety Assessment (CSA) and regulation concerning the safety assessment of food additives and food flavourings.…”

Section: Human Health Endpointsmentioning

confidence: 99%

Mind the Gap! A Journey towards Computational Toxicology

Mangiatordi

Alberga

Altomare

et al. 2016

Molecular Informatics

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Computational methods have advanced toxicology towards the development of target-specific models based on a clear cause-effect rationale. However, the predictive potential of these models presents strengths and weaknesses. On the good side, in silico models are valuable cheap alternatives to in vitro and in vivo experiments. On the other, the unconscious use of in silico methods can mislead end-users with elusive results. The focus of this review is on the basic scientific and regulatory recommendations in the derivation and application of computational models. Attention is paid to examine the interplay between computational toxicology and drug discovery and development. Avoiding the easy temptation of an overoptimistic future, we report our view on what can, or cannot, realistically be done. Indeed, studies of safety/toxicity represent a key element of chemical prioritization programs carried out by chemical industries, and primarily by pharmaceutical companies.

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“…Based on this assumption, many different public and private initiatives (e.g. DSSTox,3 ACToR,4 AcuteTox,5 EPA’s ToxCast,6,7 Tox21,8 OpenTox,9 ISSTOX,10 RepDose,11 Safe‐T12) are currently working in this direction, gathering information and knowledge with the final aim of increasing the reliability of toxicity prediction. Among these the Innovative Medicines Initiative (IMI) eTOX project “Integrating bioinformatics and chemoinformatics approaches for the development of expert systems allowing the in silico prediction of toxicities” (2010–2016)13 is a public‐private partnering between 11 academic groups, 6 small‐medium enterprises and 13 pharmaceutical companies.…”

Section: Introductionmentioning

confidence: 99%

Integrative Modeling Strategies for Predicting Drug Toxicities at the eTOX Project

Sanz

Carrió

López

et al. 2015

Molecular Informatics

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Early prediction of safety issues in drug development is at the same time highly desirable and highly challenging. Recent advances emphasize the importance of understanding the whole chain of causal events leading to observable toxic outcomes. Here we describe an integrative modeling strategy based on these ideas that guided the design of eTOXsys, the prediction system used by the eTOX project. Essentially, eTOXsys consists of a central server that marshals requests to a collection of independent prediction models and offers a single user interface to the whole system. Every of such model lives in a self-contained virtual machine easy to maintain and install. All models produce toxicity-relevant predictions on their own but the results of some can be further integrated and upgrade its scale, yielding in vivo toxicity predictions. Technical aspects related with model implementation, maintenance and documentation are also discussed here. Finally, the kind of models currently implemented in eTOXsys is illustrated presenting three example models making use of diverse methodology (3D-QSAR and decision trees, Molecular Dynamics simulations and Linear Interaction Energy theory, and fingerprint-based QSAR).

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The OSIRIS Weight of Evidence approach: ITS for the endpoints repeated-dose toxicity (RepDose ITS)

Cited by 20 publications

References 34 publications

Facilitating the use of non-standardin vivostudies in health risk assessment of chemicals: a proposal to improve evaluation criteria and reporting

Facilitating the use of non-standardin vivostudies in health risk assessment of chemicals: a proposal to improve evaluation criteria and reporting

Mind the Gap! A Journey towards Computational Toxicology

Integrative Modeling Strategies for Predicting Drug Toxicities at the eTOX Project

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