A framework for using structural, reactivity, metabolic and physicochemical similarity to evaluate the suitability of analogs for SAR-based toxicological assessments

Wu, Shengde; Blackburn, Karen; Amburgey, Jack; Jaworska, Joanna; Federle, Thomas W.

doi:10.1016/j.yrtph.2009.09.006

Cited by 143 publications

(101 citation statements)

References 46 publications

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“…This is a technique based on grouping and comparison of chemicals. It uses existing toxicological information on a group of chemicals to make a prediction of the toxicity of an uncharacterized structure (OECD, 2011;Patlewicz et al, 2014;Schilter et al, 2013;Wu et al, 2010). Obviously, for the prediction to be relevant, chemicals used for read-across must exhibit sufficient analogy with the chemical under investigation.…”

Section: Discussionmentioning

confidence: 99%

“…In this context, the technique of chemical grouping and read-across has been promoted as a most promising and pragmatic alternative approach. It consists of identifying analogs of the chemical under investigation (grouping) and extrapolating its toxic properties using the available toxicological data to the analogs (read-across) (Patlewicz et al, 2014;Schilter et al, 2013;Wu et al, 2010). Finding adequate analogs is not straightforward and has to be based on a number of structural and biological features (OECD, 2011;Patlewicz et al, 2014;Schilter et al, 2013;Wu et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

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Hazard assessment through hybrid in vitro / in silico approach: The case of zearalenone

Ehrlich

2015

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SummaryWithin the framework of reduction, refinement and replacement of animal experiments, new approaches for identification and characterization of chemical hazards have been developed. Grouping and read-across has been promoted as a most promising alternative approach. It uses existing toxicological information on a group of chemicals to make predictions on the toxicity of uncharacterized ones. In the present work, the feasibility of applying in vitro and in silico techniques to group chemicals for read-across was studied using the food mycotoxin zearalenone (ZEN) and metabolites as a case study. ZEN and its reduced metabolites are known to act through activation of the estrogen receptor α (ERα). The ranking of their estrogenic potencies appeared highly conserved across test systems including binding, in vitro and in vivo assays. This data suggests that activation of ERα may play a role in the molecular initiating event (MIE) and be predictive of adverse effects, and it provides the rationale to model receptor-binding for hazard identification. The investigation of receptor-ligand interactions through docking simulation proved to accurately rank estrogenic potencies of ZEN and reduced metabolites, showing the suitability of the model to address estrogenic potency for this group of compounds. Therefore, the model was further applied to biologically uncharacterized, commercially unavailable, oxidized ZEN metabolites (6α-, 6β-, 8α-, 8β-, 13-and 15-OH-ZEN). Except for 15-OH-ZEN, the data indicate that in general, the oxidized metabolites would be considered of lower estrogenic concern than ZEN and reduced metabolites.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Hazard assessment through hybrid in vitro / in silico approach: The case of zearalenone

Ehrlich

2015

ALTEX

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“…An alternative is to consult the initial considerations made to evaluate the suitability of a source analogue for inclusion in an analogue/category approach. Indeed, Wu et al (2010) devised an approach for determining analogue suitability, which was tested in a series of different case studies by Blackburn et al (2011). the overarching hypothesis will typically factor in structural similarity; this, however, is only one aspect of many.…”

Section: Boxmentioning

confidence: 99%

Read-across approaches - misconceptions, promises and challenges ahead

Patlewicz

2014

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108

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Summary Read-across is a data gap filling technique used within category and analogue approaches. It has been utilized as an alternative approach to address information requirements under various past and present regulatory programs such as the OECD High Production Volume Programme as well as the EU's Registration, Evaluation, Authorisation and restriction of CHemicals (REACH) regulation. Although read-across raises a number of expectations, many misconceptions still remain around what it truly represents; how to address its associated justification in a robust and scientifically credible manner; what challenges/issues exist in terms of its application and acceptance; and what future efforts are needed to resolve them. In terms of future enhancements, read-across is likely to embrace more biologicallyorientated approaches consistent with the Toxicity in the 21 st Century vision (Tox-21c). This Food forThought article, which is notably not a consensus report, aims to discuss a number of these aspects and, in doing so, to raise awareness of the ongoing efforts and activities to enhance read-across. It also intends to set the agenda for a CAAT read-across initiative in 2014CAAT read-across initiative in -2015 to facilitate the proper use of this technique.

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“…There is no available metabolic and toxicological data for other fatty acid esters of EGAE. However, the difference in saturated alkyl chain should not have significant impact on chemical reactivity and metabolic hydrolysis (Wu et al, 2010). Hence, series of EGAE esters with different straight saturated fatty chain may yield hemolytic effects via similar metabolic pathway.…”

Section: Discussionmentioning

confidence: 99%

“…Several attempts have recently been made to form categories (Fabjan et al, 2006;Sakuratani et al, 2008) and for data gap filling by read-across (Wu et al, 2010;Blackburn et al, 2011) for complicated toxicity endpoints.…”

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confidence: 99%

A category approach to predicting the hemolytic effects of ethylene glycol alkyl ethers in repeated-dose toxicity

et al. 2012

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A framework for using structural, reactivity, metabolic and physicochemical similarity to evaluate the suitability of analogs for SAR-based toxicological assessments

Cited by 143 publications

References 46 publications

Hazard assessment through hybrid in vitro / in silico approach: The case of zearalenone

Hazard assessment through hybrid in vitro / in silico approach: The case of zearalenone

Read-across approaches - misconceptions, promises and challenges ahead

A category approach to predicting the hemolytic effects of ethylene glycol alkyl ethers in repeated-dose toxicity

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