From the article: "To enable selection of novel chemicals for new processes, there is a recognized need for alternative toxicity screening assays to assess potential risks to man and the environment. For human health hazard assessment these screening assays need to be translational to humans, have high throughput capability, and from an animal welfare perspective be harmonized with the principles of the 3Rs (Reduction, Refinement, Replacement). In the area of toxicology a number of cell culture systems are available but while these have some predictive value, they are not ideally suited for the prediction of developmental and reproductive toxicology (DART). This is because they often lack biotransformation capacity, multicellular or multi- organ complexity, for example, the hypothalamus pituitary gonad (HPG) axis and the complete life cycle of whole organisms. To try to overcome some of these limitations in this study, we have used Caenorhabditis elegans (nematode) and Danio rerio embryos (zebrafish) as alternative assays for DART hazard assessment of some candidate chemicals being considered for a new commercial application. Nematodes exposed to Piperazine and one of the analogs tested showed a slight delay in development compared to untreated animals but only at high concentrations and with Piperazine as the most sensitive compound. Total brood size of the nematodes was also reduced primarily by Piperazine and one of the analogs. In zebrafish Piperazine and analogs showed developmental delays. Malformations and mortality in individual fish were also scored. Significant malformations were most sensitively identified with Piperazine, significant mortality was only observed in Piperazine and only at the higest dose. Thus, Piperazine seemed the most toxic compound for both nematodes and zebrafish. The results of the nematode and zebrafish studies were in alignment with data obtained from conventional mammalian toxicity studies indicating that these have potential as developmental toxicity screening systems. The results of these studies also provided reassurance that none of the Piperazines tested are likely to have any significant developmental and/or reproductive toxicity issues to humans when used in their commercial applications."
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Summary: Xpaths is a collection of algorithms that allow for the prediction of compound-induced molecular mechanisms of action by integrating phenotypic endpoints of different species; and proposes follow-up tests for model organisms to validate these pathway predictions. The Xpaths algorithms are applied to predict developmental and reproductive toxicity (DART) and implemented into an in silico platform, called DARTpaths.
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Implementation of reliable methodologies allowing Reduction, Refinement, and Replacement (3Rs) of animal testing is a process that takes several decades and is still not complete. Reliable methods are essential for regulatory hazard assessment of chemicals where differences in test protocol can influence the test outcomes and thus affect the confidence in the predictive value of the organisms used as an alternative for mammals. Although test guidelines are common for mammalian studies, they are scarce for non-vertebrate organisms that would allow for the 3Rs of animal testing. Here, we present a set of 30 reporting criteria as the basis for such a guideline for Developmental and Reproductive Toxicology (DART) testing in the nematode Caenorhabditis elegans. Small organisms like C. elegans are upcoming in new approach methodologies for hazard assessment; thus, reliable and robust test protocols are urgently needed. A literature assessment of the fulfilment of the reporting criteria demonstrates that although studies describe methodological details, essential information such as compound purity and lot/batch number or type of container is often not reported. The formulated set of reporting criteria for C. elegans testing can be used by (i) researchers to describe essential experimental details (ii) data scientists that aggregate information to assess data quality and include data in aggregated databases (iii) regulators to assess study data for inclusion in regulatory hazard assessment of chemicals.
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Bespreking van onderzoek van Rychard Bouwens in ‘Waar wij trots op zijn. De ontdekkingen van 2011’ van de Universiteit Leiden Faculteit der Wiskunde & Natuurwetenschappen. Het valt goed te begrijpen voor iedereen met een basale kennis van klassieke fotografie: bij weinig licht neem je een lange sluitertijd. En dat is wat Rychard Bouwens deed. Om naar de zogenaamde Dark Ages van het heelal te kijken, hield hij de Hubble-ruimtetelescoop maar liefst 87 uur lang op een plek gericht.
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Bespreking van onderzoek van Anton Akhmerov in ‘Waar wij trots op zijn. De ontdekkingen van 2011’ van de Universiteit Leiden Faculteit der Wiskunde & Natuurwetenschappen. De Leidse theoretisch natuurkundige Anton Akhmerov promoveerde in mei op een onderzoek naar functionele toepassingen van grafeen, een eenlaags koolstofmateriaal dat de afgelopen jaren volop in de belangstelling staat. Daarnaast werkte hij ook nog aan quantumcomputers, omdat hij tijd over had in zijn onderzoek.
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Bespreking van onderzoek van Erik Danen in ‘Waar wij trots op zijn. De ontdekkingen van 2011’ van de Universiteit Leiden Faculteit der Wiskunde & Natuurwetenschappen. Celbioloog Erik Danen doet onderzoek naar de verwoestende – maar in evolutionaire termen ook wonderlijke – strategieën van de kankercel. Met welke trucs verspreiden kankercellen zich door het lichaam? Hoe overleven ze een aanval van een chemokuur? En hoe wrang is het dat de één procent cellen die de therapie overleeft vervolgens dubbelhard terugslaat.
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Bespreking van onderzoek van Todor Stefanov in ‘Waar wij trots op zijn. De ontdekkingen van 2011’ van de Universiteit Leiden Faculteit der Wiskunde & Natuurwetenschappen. De Bulgaar Todor Stefanov onderzoekt methoden en middelen voor het ontwerpen en programmeren van multiprocessorsystemen die zijn geïntegreerd in een enkele chip. Dit om de verwerking van signalen en beelden in bijvoorbeeld smartphones te verbeteren. En dat moet snel, want ieder jaar komt er wel weer een nieuwe generatie op de markt.
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