6.-9. March 2018: Course on computational toxicology and modelling

CAAT-Europe organized a Summer School for European project partners (EU-ToxRisk and other projects, n = 30 participants) in the historical Konzil building on the use of computational toxicology tools such as quantitative in vitro-in vivo extrapolations (qIVIVE), physiology-based pharmacokinetic modelling (PBPK), metabolite predictions, quantitative AOP (qAOP) and Bayesian networks

27. February 2018: Publications

Following a workshop uniting specialists from Europe and the USA on developmental neurotoxicology (DNT) from academia national competence centers and and regulatory agencies, a catalog of Test Readiness Criteria was published. These were put into the context of regulatory application of New Approach Methods (NAM).

https://www.ncbi.nlm.nih.gov/pubmed/29485663

The publication was accompanied by a consensus statement on the state of DNT testing by international stakeholders.

https://www.ncbi.nlm.nih.gov/pubmed/29447839

27. February 2018: German Toxicology Summit

German Toxicology summit (DGPT annual meeting in Göttingen). Talk by M. Leist at Systems Toxicology Symposium on “A human stem cell differentiation system to screen for developmental toxicants”

22. February 2018

Tanja Waldmann receives the ‘best poster price’ at the EU-ToxRisk general assembly. Over 70 posters had been assembled and scored. Tanja’s work referred to a human stem cell based method to characterize developmental toxicants and to rank compounds known to trigger craniofacial malformations according to their hazard potential. The assay has been developed mainly by Nadine Dreser, Stefanie Klima, Nina Balmer and several others over many years, and it is has been used in several collaborative research projects.

Background literature: https://www.ncbi.nlm.nih.gov/pubmed/27188386

20. February 2018

The University submitted the proposals for the Excellence initiative (final evaluation round). We feel that it was an enormous challenge to design and shape a project like ‘ChemLife’. And now we are happy that (i) a really solid and excellent proposal has been assembled, and (ii) that this intense phase of work is over for a while :-).

We all hope for intense project kick-off activities again after the judgement day (end of September).

15. February 2018

We came out as winner of a public procurement process of the European Food Agency (EFSA; http://www.efsa.europa.eu/) in a bid to establish a test battery for developmental neurotoxicity. The Kick-off meeting of this EFSA project was held in Parma. For the next 18 months, we will develop together with the US-EPA, the European Comission JRC (EURL-ECVAM) and the Leibnitz Research institute for Environmental Medicine in Düsseldorf (Prof. E. Fritsche; http://www.iuf-duesseldorf.com/home.html) new tests for DNT

Background literature: https://www.ncbi.nlm.nih.gov/pubmed/29447839 (consensus statement); https://www.ncbi.nlm.nih.gov/pubmed/28407175 (OECD/EFSA workshop)

5. Februar 2018

Publication on ‘Canagliflozin mediated dual inhibition of mitochondrial glutamate dehydrogenase and complex I: an off-target adverse effect’ in Cell Death and Disease (CDDis)

This collaboration with the group of Prof. Daniel Dietrich (Human and Environmental Toxicology, Konstanz) used metabolic analysis and our mitochondrial profiling approach to identify the potential for specific toxicity of an important diabetic drug. https://www.ncbi.nlm.nih.gov/pubmed/29445145

25. Januar 2018

Publication on ‘A high-throughput approach to identify specific neurotoxicants/ developmental toxicants in human neuronal cell function assays’  in ALTEX

In this work, we collaborated with the National Toxicology Program of the USA (NTP), a renowned computational toxicology group in Barcelona (University Pompeu Fabra) and our Department of Computer and Information Science). We performed two screens for specific neurotoxicants and established several new principles on how to use screen assays in modern toxicology. https://www.ncbi.nlm.nih.gov/pubmed/29423527

12. Januar 2018

Publication on ‘Stage-specific metabolic features of differentiating neurons: Implications for toxicant sensitivity’ in Toxicology and Applied Pharmacology (TAAP)

This collaborative work brought together specialists in metabolomics, systems toxicology and metabolic flux analysis. It may at present be the most comprehensive description of a metabolic flux model in human neurons.

It also provides the first evidence for the dependence of toxicant sensitivities of neurons at different developmental stages. https://www.ncbi.nlm.nih.gov/pubmed/29278688

9. Januar 2018

 Participation of Prof. M. Leist as founding member of the Bf3R committee in Berlin. This commission gives advice to the new center for animal protection (Bf3R) at the Federal institute of Risk assessment (BfR).

http://www.bfr.bund.de/en/german_centre_for_the_protection_of_laboratory_animals.html

10. Dezember 2017

Publication on ‘An adverse outcome pathway for parkinsonian motor deficits associated with mitochondrial complex I inhibition’ out in Arch Toxicol.

The large review (42 pages), together with EFSA, Danish EPA and EURL-ECVAM specialists relates toxicants affecting mitochondrial function to the risk of Parkinson’s disease. Here a new approach was pioneered to use structure-activity relationships to identify toxicant mode-of-action:
https://www.ncbi.nlm.nih.gov/pubmed/29209747

7. Dezember 2017

Talk of Marcel Leist at the ethics platform of the BOKU University Vienna on alternatives to animal experimentation: state of the art (available on YouTube)

https://youtu.be/jMYrIQBhV3Q

1. Dezember 2017

Publication on ‘A structure-activity relationship linking non-planar PCBs to functional deficits of neural crest cells: new roles for connexins’ out in Arch Toxicol.

Here a new approach was pioneered to use structure-activity relationships to identify toxicant mode-of-action: https://www.ncbi.nlm.nih.gov/pubmed/29164306

21.-23. November 2017

Invited talk of Johannes Delp at OpenTox workshop "Collaboration and integration: Toxicology and risk assessment in the time of dynamic data". The conference is to be held in Basel November 21-23

http://www.opentox.net/events/opentox-euro-2017

21. November 2017

Generation shift: PhD exam of Johanna Prüfung (now post-doc at the environmental protection agency of the USA (EPA), and start of the new students Ilinca Suciu, Christopher Scholz and Anna-Katharina Ückert: welcome!

6. November 2017

Today, one year ago, the prestigious LUSH prize was awarded for research in our group. See a video informing on the scientific concept of model developoment and systems toxicology:

https://vimeo.com/205706519

21. October 2017

Marcel Leist receives the 2017 world-wide recognition award of the aaalac international

https://aaalac.org/news/Global-3Rs-Award-Winners.cfm

15. October 2017

Leist et al. (2017) Adverse outcome pathways: opportunities, limitations and open questions. Arch Toxicol, in press

https://www.ncbi.nlm.nih.gov/pubmed/29051992

Collaborative work with > 30 co-authors on strengths, weaknesses and opportunities of the adverse outcome pathway (AOP) concept promoted by the OECD.

31. September 2017

Results of the first evaluation round for research clusters of the excellence initiative: The ChemLife project proposal was selected for the second round. Our projects and systems toxicology play an important role.

21. - 25. September 2017

Tanja Waldmann and Johanna Nyffeler are invited to a workshop of the US national toxicology program (NTP) to present data generated from the University of Konstanz (UKN) test methods for developmental neurotoxicity (DNT). Twenty researchers from around the world were assembled by personal invitation to work out new test strategies.

Background on NTP: https://ntp.niehs.nih.gov/results/areas/index.html

1. September 2017

Our alumni Johanna Nyffeler joins the US environmental protection agency (EPA) to work on new systems toxicology approaches of toxicity assessment within the Tox21 program.

Info on the program: www.epa.gov/chemical-research/toxicology-testing-21st-century-tox21

11. August 2017

Production of a document on good in vitro practices in collaboration with the European Commission and the OECD.
The document went into the second public consultation round:

http://www.oecd.org/env/ehs/testing/OECD%20Draft%20GIVIMP_v05%20-%20clean.pdf

http://www.oecd.org/env/ehs/testing/draft-guidance-review-documents-monographs.htm

Background information: There is a scientific policy and regulatory desire for validated and internationally accepted in vitro methods (e.g. OECD test guidelines or ISO standards). To accommodate the needs of regulatory authorities, a number of in vitro methods, often based on the use of human cells and tissues, have been submitted to international validation bodies during the last two decennia. However, the experience gained during these validations revealed that many in vitro methods need significant improvements in design, robustness and reliability before they can be successfully implemented in a routine laboratory environment to generate data sets, which can be used to support regulatory decisions. GIVIMP specifies these improvements.

15. May 2017

Workshop on ‘developmental and reproductive toxicity (DART) test methods’

The workshop was held in collaboration with BASF and CAAT-Europe in the historical concilium building. International experts worked on a roadmap for improved DART testing to support development of new compounds, reduce the use of animals, and increase safety of the population

5. May 2017

Publication of our first screening paper to identify unknown toxicants together with the National Toxicology Program, USA (NTP) and the Computational Toxicology unit at University of Pompeu Fabra (Barcelona). We define strategies for ‘hit’ (= positive screen result) confirmation and hit follow-up in the field of toxicology.

(http://link.springer.com/article/10.1007/s00204-017-1977-y)

https://www.ncbi.nlm.nih.gov/pubmed/28477266

Nyffeler J, Dolde X, Krebs A, Pinto-Gil K, Pastor M, Behl M, Waldmann T, Leist M. (2017) Combination of multiple neural crest migration assay to identify environmental toxicants from a proof-of-concept chemical library. Arch Toxicol, 10.1007/s00204-017-1977-y

29. April 2017

Publication of a large systems toxicology-oriented review on the MPTP Parkinson’s disease model, together with leading experts involved in the initial discovery of the underlying toxicant (D. DiMonte, DZNE, Bonn), and  in contemporary landmark discoveries concerning new mechanisms (K. Tieu, Miami).

 (http://www.sciencedirect.com/science/article/pii/S0165614717300780)

 Schildknecht S, Di Monte DA, Pape R, Tieu K, Leist M (2017) Tipping points and endogenous determinants of nigrostriatal degeneration by MPTP. Trends Pharmacol Sci, in press doi: 10.1016/j.tips.2017.03.010

27. April 2017

Workshop on ‘Data management and data processing in large European projects’ with 28 international participants in the Concilium location in Konstanz. Co-Organised by CAAT-Europe (M. Daneshian), Douglas Connect (Basel) and the European Bioinfomatics Institute (EBI, Cambridge)

5. April 2017

Our new paper on interferon developmental hazard is out 

 https://www.ncbi.nlm.nih.gov/pubmed/28365849

Pallocca G, Nyffeler J, Dolde X, Grinberg M, Gstraunthaler G, Waldmann T, Rahnenführer J, Sachinidis A, Leist M. Impairment of human neural crest cell migration by prolonged exposure to interferon-beta. Arch Toxicol. 2017

16. March 2017

 The EFSA opinion ‘A new path to toxicity assessment’ is officially published

 http://www.efsa.europa.eu/en/press/news/170316

We worked hard on this, and on the embedded adverse outcome pathway (AOP) examining a relevant link of pesticides and Parkinson’s disease (link)

 https://aopwiki.org/aops/3

7.March 2017

M. Leist receives the ‘GT-toxicology award’ at the German Toxicology Summit in Heidelberg for excellent publications in the previous year