Abstract:Read-across is one of the most frequently used alternative tools for hazard assessment, in particular for complex endpoints such as repeated dose or developmental and reproductive toxicity. Read-across extrapolates the outcome of a specific toxicological in vivo endpoint from tested (source) compounds to "similar" (target) compound(s). If appropriately applied, a read-across approach can be used instead of de novo animal testing. The read-across approach starts with structural/ physicochemical similarity betwe… Show more
“…Also, the absence of a certain mechanism or effect can be demonstrated, as well as the relatively low potency for a certain testing endpoint. The EU-ToxRisk RAx testing framework demonstrated how NAMs can be integrated into practical RAx procedures (Escher et al 2019 ). Fig.…”
Section: Incorporation Of Nams In Read-across Approachesmentioning
confidence: 99%
“…This entails the implementation of NAM-based safety science into regulatory toxicology (Krebs et al 2020b ). The project initially focused on read-across (RAx) (Escher et al 2019 ; Rovida et al 2020a ) and here we outline key outcomes and general learnings on the use of NAMs for RAx. This collection of outputs will facilitate new efforts in next-generation risk assessment (NGRA) (Dent et al 2018 ; Dearfield et al 2017 ; Cote et al 2016 ; Krewski et al 2014 ) and thus advance the field of safety assessment by more mechanistically driven and animal-free approaches (Suppl.…”
In 2016, the European Commission launched the EU-ToxRisk research project to develop and promote animal-free approaches in toxicology. The 36 partners of this consortium used in vitro and in silico methods in the context of case studies (CSs). These CSs included both compounds with a highly defined target (e.g. mitochondrial respiratory chain inhibitors) as well as compounds with poorly defined molecular initiation events (e.g. short-chain branched carboxylic acids). The initial project focus was on developing a science-based strategy for read-across (RAx) as an animal-free approach in chemical risk assessment. Moreover, seamless incorporation of new approach method (NAM) data into this process (= NAM-enhanced RAx) was explored. Here, the EU-ToxRisk consortium has collated its scientific and regulatory learnings from this particular project objective. For all CSs, a mechanistic hypothesis (in the form of an adverse outcome pathway) guided the safety evaluation. ADME data were generated from NAMs and used for comprehensive physiological-based kinetic modelling. Quality assurance and data management were optimized in parallel. Scientific and Regulatory Advisory Boards played a vital role in assessing the practical applicability of the new approaches. In a next step, external stakeholders evaluated the usefulness of NAMs in the context of RAx CSs for regulatory acceptance. For instance, the CSs were included in the OECD CS portfolio for the Integrated Approach to Testing and Assessment project. Feedback from regulators and other stakeholders was collected at several stages. Future chemical safety science projects can draw from this experience to implement systems toxicology-guided, animal-free next-generation risk assessment.
“…Also, the absence of a certain mechanism or effect can be demonstrated, as well as the relatively low potency for a certain testing endpoint. The EU-ToxRisk RAx testing framework demonstrated how NAMs can be integrated into practical RAx procedures (Escher et al 2019 ). Fig.…”
Section: Incorporation Of Nams In Read-across Approachesmentioning
confidence: 99%
“…This entails the implementation of NAM-based safety science into regulatory toxicology (Krebs et al 2020b ). The project initially focused on read-across (RAx) (Escher et al 2019 ; Rovida et al 2020a ) and here we outline key outcomes and general learnings on the use of NAMs for RAx. This collection of outputs will facilitate new efforts in next-generation risk assessment (NGRA) (Dent et al 2018 ; Dearfield et al 2017 ; Cote et al 2016 ; Krewski et al 2014 ) and thus advance the field of safety assessment by more mechanistically driven and animal-free approaches (Suppl.…”
In 2016, the European Commission launched the EU-ToxRisk research project to develop and promote animal-free approaches in toxicology. The 36 partners of this consortium used in vitro and in silico methods in the context of case studies (CSs). These CSs included both compounds with a highly defined target (e.g. mitochondrial respiratory chain inhibitors) as well as compounds with poorly defined molecular initiation events (e.g. short-chain branched carboxylic acids). The initial project focus was on developing a science-based strategy for read-across (RAx) as an animal-free approach in chemical risk assessment. Moreover, seamless incorporation of new approach method (NAM) data into this process (= NAM-enhanced RAx) was explored. Here, the EU-ToxRisk consortium has collated its scientific and regulatory learnings from this particular project objective. For all CSs, a mechanistic hypothesis (in the form of an adverse outcome pathway) guided the safety evaluation. ADME data were generated from NAMs and used for comprehensive physiological-based kinetic modelling. Quality assurance and data management were optimized in parallel. Scientific and Regulatory Advisory Boards played a vital role in assessing the practical applicability of the new approaches. In a next step, external stakeholders evaluated the usefulness of NAMs in the context of RAx CSs for regulatory acceptance. For instance, the CSs were included in the OECD CS portfolio for the Integrated Approach to Testing and Assessment project. Feedback from regulators and other stakeholders was collected at several stages. Future chemical safety science projects can draw from this experience to implement systems toxicology-guided, animal-free next-generation risk assessment.
“…Within the EU-funded consortium EU-ToxRisk, a large integrated European in vitro "flagship" toxicology project exploring new alternative-to-animal approaches to chemical safety evaluation (Daneshian et al 2016;Escher et al 2019;Leist et al 2017), one project addresses alternatives to mammalian teratogenicity testing, which, especially from an animal welfare point of view, represents a major challenge. One alternative approach to mammalian testing is based on the use of early developmental stages of lower vertebrates (fish), which are not regarded protected according to current EU animal welfare legislation (EU 2010;Strähle et al 2012).…”
Since teratogenicity testing in mammals is a particular challenge from an animal welfare perspective, there is a great need for the development of alternative test systems. In this context, the zebrafish (Danio rerio) embryo has received increasing attention as a non-protected embryonic vertebrate in vivo model. The predictive power of zebrafish embryos for general vertebrate teratogenicity strongly depends on the correlation between fish and mammals with respect to both overall general toxicity and more specific endpoints indicative of certain modes-of-action. The present study was designed to analyze the correlation between (1) effects of valproic acid and nine of its analogues in zebrafish embryos and (2) their known neurodevelopmental effects in mice. To this end, zebrafish embryos exposed for 120 h in an extended version of the acute fish embryo toxicity test (FET; OECD TG 236) were analyzed with respect to an extended list of sublethal endpoints. Particular care was given to endpoints putatively related to neurodevelopmental toxicity, namely jitter/tremor, deformation of sensory organs (eyes) and craniofacial deformation, which might correlate to neural tube defects caused by valproic acid in mammals. A standard evaluation of lethal (LC according to OECD TG 236) and sublethal toxicity (EC) merely indicated that four out of ten compounds tested in zebrafish correlate with positive results in mouse in vivo studies. A detailed assessment of more specific effects, however, namely, jitter/tremor, small eyes and craniofacial deformation, resulted in a correspondence of 75% with in vivo mouse data. A refinement of endpoint analysis from an integration of all observations into one LCx or ECx data (as foreseen by current ecotoxicology-driven OECD guidelines) to a differential evaluation of endpoints specific of selected modes-of-action thus increases significantly the predictive power of the zebrafish embryo model for mammalian teratogenicity. However, for some of the endpoints observed, e.g., scoliosis, lordosis, pectoral fin deformation and lack of movement, further experiments are required for the identification of underlying modes-of-action and an unambiguous interpretation of their predictive power for mammalian toxicity.
“…One of our most important advances was the template for a comprehensive methods description, and a related database for the methods of this study (Krebs et al 2019b ), and this achievement of the CSY has been used subsequently to document methods in read-across (RAx) case studies (Escher et al 2019 ). The regulators reviewing the case studies found the transparent disclosure of all methods very important, and they suggest the RAx studies to be submitted to the OECD as examples for good practice.…”
Hazard assessment, based on new approach methods (NAM), requires the use of batteries of assays, where individual tests may be contributed by different laboratories. A unified strategy for such collaborative testing is presented. It details all procedures required to allow test information to be usable for integrated hazard assessment, strategic project decisions and/or for regulatory purposes. The EU-ToxRisk project developed a strategy to provide regulatorily valid data, and exemplified this using a panel of > 20 assays (with > 50 individual endpoints), each exposed to 19 well-known test compounds (e.g. rotenone, colchicine, mercury, paracetamol, rifampicine, paraquat, taxol). Examples of strategy implementation are provided for all aspects required to ensure data validity: (i) documentation of test methods in a publicly accessible database; (ii) deposition of standard operating procedures (SOP) at the European Union DB-ALM repository; (iii) test readiness scoring accoding to defined criteria; (iv) disclosure of the pipeline for data processing; (v) link of uncertainty measures and metadata to the data; (vi) definition of test chemicals, their handling and their behavior in test media; (vii) specification of the test purpose and overall evaluation plans. Moreover, data generation was exemplified by providing results from 25 reporter assays. A complete evaluation of the entire test battery will be described elsewhere. A major learning from the retrospective analysis of this large testing project was the need for thorough definitions of the above strategy aspects, ideally in form of a study pre-registration, to allow adequate interpretation of the data and to ensure overall scientific/toxicological validity.
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