Evaluation of an alternative in vitro test battery for detecting reproductive toxicants in a grouping context

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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“…1 (Fig. 1) et al, 2013) and with a test battery for reproductive toxicity including Zet (Kroese et al, 2014).…”

Section: Negative Read-acrossmentioning

confidence: 99%

Read-across approaches - misconceptions, promises and challenges ahead

Patlewicz

2014

ALTEX

108

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“…None of these assays, however, alone can cover the whole mammalian reproductive cycle, because of its inherent complexity (Kroese et al. ). Therefore, recent studies have attempted to combine these alternative methods into a test battery to accurately predict developmental toxicity in humans (Sogorb et al.…”

Section: Introductionmentioning

confidence: 99%

“…Substantial efforts have been undertaken to develop alternative methods for the assessment of developmental toxicity, including the mouse embryonic stem cell test, the rat whole embryo culture assay, and zebrafish toxicology testing (de Jong et al 2011a). None of these assays, however, alone can cover the whole mammalian reproductive cycle, because of its inherent complexity (Kroese et al 2015). Therefore, recent studies have attempted to combine these alternative methods into a test battery to accurately predict developmental toxicity in humans (Sogorb et al 2014; Kroese et al 2015) (reviewed in Sipes et al 2011).…”

Section: Introductionmentioning

confidence: 99%

Using zebrafish in systems toxicology for developmental toxicity testing

Nishimura

Inoue

Sasagawa

et al. 2016

Congenital Anomalies

162

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With the high cost and the long-term assessment of developmental toxicity testing in mammals, the vertebrate zebrafish has become a useful alternative model organism for high-throughput developmental toxicity testing. Zebrafish is also very favorable for the 3R perspective in toxicology; however, the methodologies used by research groups vary greatly, posing considerable challenges to integrative analysis. In this review, we discuss zebrafish developmental toxicity testing, focusing on the methods of chemical exposure, the assessment of morphological abnormalities, housing conditions and their effects on the production of healthy embryos, and future directions. Zebrafish as a systems toxicology model has the potential to elucidate developmental toxicity pathways, and to provide a sound basis for human health risk assessments.

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“…This work confirms and extends the earlier finding of the FP6 ReProTect project [7] that a relatively simple battery of tests can be used successfully to predict reproductive toxicity of chemicalssee Table 1. Significant advances have been made particularly in the further simplification of the test battery, while still being able to identify reproductive toxic chemicals efficiently, either in isolation [25], or in a grouping context [41,43]. We found that even with a relatively small number of tests, either apical tests combined with mechanistic tests or an relatively small number of mechanistic tests predictivities ranging from 74 to 94% can be reached [20,25], which is comparable to that obtained with much larger ToxCast screening panels [21], the ReProTect battery [7], or the zebrafish ELS tests [49], a human embryonic stem cell test [50].…”

Section: Discussionmentioning

confidence: 99%

“…This study showed that the battery was able to make this distinction using three different chemical classes as an example. This provides important opportunities for applications under REACH where read-across procedures are being considered as an important element of integrated testing to avoid or reduce animal experimentation [43]. Here the weight of evidence of available repeated dose toxicity data for both source and query chemical, their structural similarity, as well as their battery results could be used to justify waiving an in vivo study [42].…”

Section: Validationmentioning

confidence: 99%

The ChemScreen project to design a pragmatic alternative approach to predict reproductive toxicity of chemicals

Burg

Wedebye

Dietrich

et al. 2015

Reproductive Toxicology

Self Cite

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a b s t r a c tThere is a great need for rapid testing strategies for reproductive toxicity testing, avoiding animal use. The EU Framework program 7 project ChemScreen aimed to fill this gap in a pragmatic manner preferably using validated existing tools and place them in an innovative alternative testing strategy. In our approach we combined knowledge on critical processes affected by reproductive toxicants with knowledge on the mechanistic basis of such effects. We used in silico methods for prescreening chemicals for relevant toxic effects aiming at reduced testing needs. For those chemicals that need testing we have set up an in vitro screening panel that includes mechanistic high throughput methods and lower throughput assays that measure more integrative endpoints. In silico pharmacokinetic modules were developed for rapid exposure predictions via diverse exposure routes. These modules to match in vitro and in vivo exposure levels greatly improved predictivity of the in vitro tests. As a further step, we have generated examples how to predict reproductive toxicity of chemicals using available data. We have executed formal validations of panel constituents and also used more innovative manners to validate the test panel using mechanistic approaches. We are actively engaged in promoting regulatory acceptance of the tools developed as an essential step towards practical application, including case studies for read-across purposes. With this approach, a significant saving in animal use and associated costs seems very feasible.

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Evaluation of an alternative in vitro test battery for detecting reproductive toxicants in a grouping context

Cited by 38 publications

References 51 publications

Read-across approaches - misconceptions, promises and challenges ahead

Read-across approaches - misconceptions, promises and challenges ahead

Using zebrafish in systems toxicology for developmental toxicity testing

The ChemScreen project to design a pragmatic alternative approach to predict reproductive toxicity of chemicals

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