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Upcoming Events ment, health foundations, charities), the aca- Sponsorship packages are available for
demic research community (universities, re- all sessions, as well as other specialized op-
8th Annual 3Rs Symposium: search institutes), environmental and human tions. Please contact Camila Sgrignoli Janu-
Pandemic-Driven Advances toxicity researchers, the pharmaceutical ario (cjanuar1@jhu.edu) for details.
June 3-4, 2021 (online) and other industries (cosmetics, chemical, Website: https://mpsworldsummit.com
and food industries), medical centers and
The eighth annual joint 3Rs symposium, practitioners, patient associations, and policy
organized by the Johns Hopkins Univer- makers and testing centers – in a series of VIDEO: Thomas Hartung and
sity Center for Alternatives to Animal Test- global annual conferences to create a road- Paul Locke Join Jane Goodall for
ing, USDA’s Animal Welfare Information map for MPS technologies. This will be a first Congressional Panel on Humane
Center, NIH’s Office of Laboratory Animal step in establishing an international MPS Research and Testing Act
Welfare, and the Johns Hopkins Depart- society. 21st Century Innovations in Alternatives
ment of Molecular and Comparative Patho- Additionally, this series of international to Animals in Biomedical Research:
biology, is scheduled for June 3 and 4, 2021. conferences (which include two virtual Congressional Briefing – The Humane
This year’s virtual symposium is titled Pan- events in 2021 in the lead-up to the hybrid Research & Testing Act
demic-Driven Advances. Its goal is to bring event in June 2022) will facilitate stake-
together experts and practitioners to fo- holder communication as well as net- On Wednesday March 10, 2021, Citizens for
cus on the challenges faced during the pan- working among young scientists and MPS Alternatives to Animal Research (CAARE)
demic and the successes in effectively using thought leaders, promoting international hosted a virtual panel discussion, titled “21st
animal models to maximize both biomedi- standardization and harmonization of MPS Century Innovations in Alternatives to An-
cal discovery and the goals of the 3Rs. and serving as a global training environment. imals in Biomedical Research,” recogniz-
Registration closes on June 1, 2021. The May 30, 2022 summit is a hy- ing the importance of the Humane Research
Event website: https://caat.jhsph.edu/ brid event that will host up to 500 in-per- and Testing Act. Scientists discussed the
programs/Refinement/3Rssymposium.html son participants and 500 additional partici- moral imperative to mitigate the use of an-
pants online. It will be co-chaired by Suzie imals in medical research and recent scien-
Fitzpatrick, FDA, Don Ingber, Harvard tific advancements that reduce the need for
Microphysiological Systems Wyss and Thomas Hartung, Johns Hopkins animal testing. Presenters included: Dr Jane
World Summit CAAT. The two preceding virtual meetings Goodall, DBE, founder of the Jane Good-
Virtual Conferences will be held on June 24, 2021 and Decem- all Institute and United Nations Messenger
June 24, 2021: Regulatory Acceptance ber 9, 2021. of Peace; Paul Locke, JD, DrPH, Associate
December 9, 2021: Systems Engineering The 2022 meeting will start on a Mon- Professor at the Johns Hopkins Bloomberg
of Microphysiological Systems day with two pre-meeting workshop ses- School of Public Health and affiliate of the
sions focused on hands-on training and ed- Center for Alternatives to Animal Testing;
Hybrid Conference (In-person and virtual) ucation. The scientific sessions will include Don Ingber MD, PhD, Founding Director of
May 30-June 3, 2022 varying formats: workshops, roundtables, the Wyss Institute for Biologically Inspired
New Orleans, LA plenary sessions, and scientific symposia. Engineering at Harvard University; Azra
In total, we will have four keynotes, up to Raza, MD, Chan Soon-Shiong Professor of
The MPS (Microphysiological Systems) 24 parallel sessions, and three lunch ses- Medicine and Director of the MDS Center
World Summit will bring together a global sions. Lunch and keynotes will be 60-min- at Columbia University; and Thomas Har-
audience, including institutions (govern- ute sessions. tung, MD, PhD, Professor at the Johns Hop-
358 ALTEX 38(2), 2021
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kins Bloomberg School of Public Health need for new animal studies in toxicology. Thomas Hartung and Marcel Leist
and Director of the Center for Alternatives The Next Generation Humane Science Interviewed by Science Blogger
to Animal Testing. Award is available annually to young sci- Stefanie M. Hohenberger
Watch now: https://tinyurl.com/jnbw8rbk entists to acknowledge and encourage re-
searchers who focus on replacing the use Thomas Hartung and Marcel Leist were in-
of animals in experiments. Please join us in terviewed about their lifetime of work in
EBTC in Nature Scientific Reports: congratulating Leah Wehmas! developing and promoting alternatives to
In Vitro Tests Outperform Animal Details about the award may be found animal testing (in German).
and Human Studies in Predicting here: https://caat.jhsph.edu/programs/ Link: http://wissenschaftsversessen.
Troglitazone-Induced Toxicity awards/HumaneScience.html de/blog/haendel-tierschutzpreis-2020/
The Evidence-based Toxicology Collabo-
ration (EBTC) has published the results of VIDEO: Contemporary Refinement Article in Das Magazin
a systematic review, conducted in collabo- Research, its Application in (German) Features Thomas
ration with the Norwegian Institute of Pub- Practice, and Future Directions Hartung and Marcel Leist
lic Health, Safer Medicines Trust (UK),
and other partners. The review found that On March 11, CAAT’s Beyond Classical Animal testing is still the standard in re-
pre-clinical animal and pre-market hu- Refinement Program hosted a webinar fea- search – although many are imprecise and al-
man trials do not predict a drug’s potential turing four former winners of the CAAT ternatives have long been available. So why
to cause harm, despite being mandatory in Refinement Award, a prize awarded for out- do animals have to continue to suffer? The
safety and efficacy trials. standing research that has the potential to Swiss magazine Das Magazin covers the
The collaboration conducted a compre- significantly improve the lives of laboratory research of Thomas Hartung and Marcel
hensive comparison of the in vivo (ani- animals and/or reduce the number of ani- Leist.
mal and human) and in vitro tests currently mals used. Becca Franks (New York Uni- Link: https://bit.ly/3wEmfQr
available to assess drug safety before mar- versity), Brianna Gaskill (Novartis), Judith
ket authorization and compared their find- de Haan (Utrecht University) and Cathy
ings against “real world data” on adverse Schuppli (University of British Colum- VIDEO: Thomas Hartung and
drug reactions. They focused on two drugs: bia) talked about what they have been up to Tom Luechtefeld IVAMSS Webinar
troglitazone, which was withdrawn from since they received the CAAT Refinement January 29, 2021 (11am EST)
the market due to severe liver toxicity, and Award and where their careers have taken
rosiglitazone, which remains on the market. them. They gave short presentations on On January 29, 2021, the In Vitro and Alter-
No reported biomarker for either drug indi- their recent or ongoing research activities native Methods Specialty Section (IVAM)
cated a strong hazard signal in either pre- and engaged in a conversation on the role of presented a series of webinars focused on
clinical animal studies or human trials. In contemporary refinement research and on the development and application of in vitro
contrast, the in vitro data showed that trogl- how barriers to its implementation in prac- methods and non-animal models for tox-
itazone was active in twice as many in vitro tice can be overcome. icology and product safety. The webinar
assays as rosiglitazone, indicating a strong Watch now on CAAT’s YouTube Chan- with Thomas Hartung and Tom Luechtefeld
signal for off-target effects. The in vitro nel: https://youtu.be/udiGTIM4KMo broke the record for largest IVAMSS webi-
data showed marked differences in the two nar ever, with 536 registrants.
drugs’ toxicological profiles, offering a new – Thomas Hartung: A.I. and Big Data –
paradigm for reducing drug attrition and VIDEO: 13th Conference on New Kids on the Toxicology Block
preventing adverse drug reactions. Animal Experimentation of – Thomas Luechtefeld, Insilica LLC:
The open access publication appeared in Swiss Animal Protection STS Smart Chemistry – Algorithms for Chem-
Nature Scientific Reports on March 18 and ical Classification and Clustering
may be viewed here: https://www.nature. Video of the 13th Conference on Animal Watch now: https://www.toxicology.org/
com/articles/s41598-021-85708-2 Experimentation of Swiss Animal Protec- groups/ss/IVSS/Events.asp
tion STS, which was recorded on Novem-
ber 13, 2020, is now available, along with a
Next Generation Humane Science PDF of supplementary material. VIDEO: EBTC Webinar on Application
Award Winner: Leah Wehmas Thomas Hartung: Brauchen wir wirklich of US EPA IRIS Systematic
noch Tierversuche? (video, in German): Review Methods to Health Effects
Leah Wehmas, of Oregon State Univer- https://vimeo.com/522847664 February 2, 2021
sity/US EPA, was awarded CAAT’s Next
Generation Humane Science Award for her Scientists at the US EPA IRIS Program re-
work on recently developed genomics tech- cently finalized a series of systematic re-
nologies to make use of archival tissues views (SR) investigating the human health
from toxicity studies that will minimize the effects of exposure to phthalates. In this
ALTEX 38(2), 2021 359
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EBTC Online Scientific Symposium, the Given the manifold intersectional forms cations for animal health and OneHealth. It
scientists presented the main findings from of oppression, subjugation, and indifference also holds the potential to reduce the use of
their SRs, highlighting novel uses of SR experienced by animals and human people whole animal studies in research.
methods in dose-response modeling and affected by climate change, how can we de- This workshop, held January 19 and 20,
drawing out general lessons learned in the velop a multispecies approach to climate 2021, explored the use of MPS for a range
application of SR methods in chemical justice and to animal and human health? of animal species/strains and for optimizing
assessment. What – if any – arguments are there to in- animal model selection where whole animal
Watch now (YouTube): https://www. clude animals’ voices in the regulation of models are necessary.
youtube.com/watch?v=IgoHiYllBMg climate policy? How does the global Black Thomas Hartung spoke on Multi-organ
Lives Matter movement intersect with and chips and emerging applications for biolog-
shape the future of animal liberation move- ics studies: Integrated multi-organ systems.
Thomas Hartung Profiled in ments? How does this relate to other ques- Link: https://tinyurl.com/yfh8jzv7
De Standaard: “Pope of A.I. tions of global justice, and the oppression
Research in Toxicology” of human groups (e.g., just transitions for
farmers and other workers)? How is this Is Animal Testing Still Needed?
Thomas Hartung and CAAT’s research in interconnected with capitalism? How do (German Article)
toxicology and artificial intelligence was questions of equality play into this?
profiled in the Dutch De Standaard. Watch now: https://animalsclimatehealth. The promise made by their developers: Tiny
Full article (in Dutch): https://www. com/session-6/ models of human organs will in future lead
standaard.be/cnt/dmf20210204_98023736 to less suffering, more knowledge, better
therapies. Thomas Hartung is interviewed.
Animal-Free Drug Safety Testing: Full article from P.M. (German science
VIDEO: EUROTOX In2Tox Challenges and Opportunities magazine, in German):
Followup COVID-19 Webinar https://tinyurl.com/4navwt8t
January 18, 2021 This virtual fireside chat, held January 26,
Introduction: Mathieu Vinken, Chair EU- 2021, invited visionaries who are leading
ROTOX In2TOX Specialty Section the way toward implementing animal-free Thomas Hartung – The Promise of AI
methods that better predict the patient re- in Pandemic Times: Beyond the Hype
“New approach methods as door-open- sponse to new drugs. In an interactive
ers for drugs and vaccines or the other way roundtable, panelists discussed important This ePanel, part of a virtual keystone sym-
around?” by Thomas Hartung (CAAT) scientific questions that all researchers in- posium in collaboration with Frontiers held
Watch now: https://youtube/ volved in drug R&D should consider, espe- January 12, 2021, addressed the promise,
rBxCLx 4cbzM cially as regulatory agencies move to stop and reality, of AI in the context of health.
supporting and funding research using ani- Bringing together AI luminaries with di-
mal models by 2035 or sooner. verse perspectives on AI in medicine and
VIDEO: The Future of Animal Thomas Hartung presented, along with public health, we explored these questions
Politics in the Context of Climate Stephan Platz (AstraZeneca) and Armin in the context of the COVID-19 pandemic,
Change, COVID-19, and Movements Wolf (InSphero). in an effort to drive AI applications towards
Against Racial Capitalism Link: https://newfrontiersin3d.com/ tangible impacts on global public health.
program/ #animal-free The event concluded with a live audience
The webinar series is designed to bring to- Q&A, where the field leaders were asked
gether a diverse audience of people inter- burning questions and shaped the discus-
ested in animal studies, critical animal stud- National Academies of Sciences, sion around new frontiers at the intersection
ies, animal ethics, animal politics, animal Engineering, and Medicine Webinar of AI and medicine.
law, environmental studies, environmental Microphysiological Systems: Thomas Hartung shared his insights from
law, migration studies, as well as climate Bridging Human and Animal a scientific, policy and societal perspective
law/studies. Research – A Workshop in a talk entitled “The Promise of A.I. in
This sixth and final session, held on Pandemic Times: Beyond the Hype”.
January 21, 2021, reflected on the insights Microphysiological systems (MPS) are in Preview: https://youtu.be/ttfhQ5gz7Mg
from the previous sessions and identified vitro platforms (such as tissues/organs on
ways of moving forward in theory and chips) that mimic the biochemical, electri-
practice. Specifically, we looked to as- cal, and mechanical properties of organ or Thomas Hartung on
semble scholars to map future areas of re- tissue function. They hold promise for ad- Reconstruction Podcast
search at the juncture of animal studies, vancing understanding of the mechanisms
climate change, racial injustice and global of disease and accelerating drug develop- The speed with which our scientific com-
health: What areas deserve our attention ment. To date, MPS has been focused on munity has identified the coronavirus and
going forward? human health but could have many appli- developed these vaccines is unprecedented.
360 ALTEX 38(2), 2021
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Never before have researchers been able to New Publications R., Kleensang, A. et al. (2021). Organo-
conduct thousands of tests in such a short phosphorus flame retardants are devel-
period of time. In fact, it may be that the Anderson, W. A., Bosak, A., Hogberg, H. opmental neurotoxicants in a rat primary
biggest impact over the long term will be T. et al. (2021). Advances in 3D neuro- BrainSphere in vitro model. Arch Tox-
the revolution in research science that made nal microphysiological systems: Towards icol 95, 207-228. doi:10.1007/s00204-
this unprecedented speed possible. a functional nervous system on a chip. In 020-02903
Thomas Hartung was interviewed. Vitro Cell Dev Biol Anim 57, 191-206. Loser, D., Schaefer, J., Danker, T. et al.
Listen now: https://tinyurl.com/ doi:10.1007/s11626-020-00532-8 (2021). Human neuronal signaling and
shxmbc6c Aschner, M., Paoliello, M. M. B., Tsatsakis, communication assays to assess func-
A. et al. (2021). Social injustice in envi- tional neurotoxicity. Arch Toxicol 95, 229-
ronmental health: A call for fortitude. En- 252. doi:10.1007/s00204-020-02956-3
CAAT Paper on Paroxetine and viron Res 194, 110675. doi:10.1016/j. Meisig, J., Dreser, N., Kapitza, M. et al.
Developmental Neurotoxicity envres.2020.110675 (2020). Kinetic modeling of stem cell
Published in New Frontiers Ebook Calina, D., Hartung, T., Mardare, I. et al. transcriptome dynamics to identify regu-
(2021). COVID-19 pandemic and al- latory modules of normal and disturbed
Research on the antidepressant paroxetine cohol consumption: Impacts and inter- neuroectodermal differentiation. Nucleic
and developmental neurotoxicity, utilizing connections. Toxicol Rep 8, 529-535. Acids Res 48, 12577-12592. doi:10.1093/
CAAT’s “mini-brain” models and originally doi:10.1016/j.toxrep.2021.03.005 nar/gkaa1089
published in February 2020, has been incor- Farsalinos, K., Poulas, K., Kouretas, D. Pamies, D., Zurich, M.-G. and Hartung, T.
porated into a new, free ebook: Brain Or- et al. (2021). Improved strategies to (2020). Organotypic models to study hu-
ganoids: Modeling in Neuroscience. counter the COVID-19 pandemic: Lock- man glioblastoma – Studying the beast
Get the Free Ebook (PDF and Epub): downs vs. primary and community health- in its ecosystem. iScience 23, 101633.
https://www.frontiersin.org/research- care. Toxicol Rep 8, 1-9. doi:10.1016/j. doi:10.1016/j.isci.2020.101633
topics/9488/brain-organoids-modeling-in- toxrep.2020.12.001 van der Stel, W., Carta, G., Eakins, J. et al.
neuroscience Golden, E., Maertens, M., Hartung, T. et al. (2020). Multiparametric assessment of
(2020). Mapping chemical respiratory mitochondrial respiratory inhibition in
Zhong, X., Harris, G., Smirnova, L. et al. sensitization: How useful are our current HepG2 and RPTEC/TERT1 cells using
(2020). Antidepressant paroxetine ex- tools? Chem Res Toxicol 34, 473-482. a panel of mitochondrial targeting agro-
erts developmental neurotoxicity in an doi:10.1021/acs.chemrestox.0c00320 chemicals. Arch Toxicol 94, 2707-2729.
iPSC-Derived 3D human brain model. Gupta, R., Schrooders, Y., Hauser, D. et doi:10.1007/s00204-020-02792-5
Front Cell Neurosci 14, 25. doi:10.3389/ al. (2020). Comparing in vitro human Wang, T., Liu, H., Itoh, K. et al. (2021).
fncel.2020.00025 liver models to in vivo human liver us- C9orf72 regulates energy homeostasis by
ing RNA-Seq. Arch Toxicol 95, 573-589. stabilizing mitochondrial complex I as-
doi:10.1007/s00204-020-02937-6 sembly. Cell Metab 33, 531-546.e9. doi:
Hogberg, H. T., de Cássia da Silveira e Sá, 10.1016/j.cmet.2021.01.005
Global beauty brand rial and individual ingredients, for any cases produce products not tested on animals, will
Garnier goes cruelty free of animal testing. Garnier and Cruelty Free now feature on all of Garnier’s products,
International worked together for many and it is hoped that other L’Oréal Group
On March 5, 2021, Cruelty Free Interna- months to secure this evidence from more brands will soon follow.
tional announced that cosmetics and hair- than 500 suppliers, who source over 3,000 Since 2017, there has been a 190% in-
care giant Garnier has been approved under different ingredients for the brand, from crease in brands enquiring about Leaping
the Leaping Bunny programme. across the world. Bunny status, showing that consumer de-
Leaping Bunny certification requires The Leaping Bunny logo, which is the mand for cruelty free products across the
brands to forensically investigate their en- best visible and independent assurance for globe can have an impact on how cosmetics
tire supply chain, including all raw mate- consumers of a company’s commitment to brands operate.
ALTEX 38(2), 2021 361
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Appeal success at ECHA to prevent First Geoffrey Deckers Award York, where a revised bill will soon be rein-
conduct of unnecessary animal tests goes to EcoVegAnimals, EVA troduced. After the Covid-19 pandemic cut
many state legislatures short last year, work
Two cases against animal testing decisions On the day of Geoffrey Decker’s birthday, on these state bills was delayed; however
made by the EU Chemicals Agency (ECHA) January 13, Cruelty Free Europe announced progress has come quickly in 2021.
have been decided, sparing thousands of an- the recipients of the first Geoffrey Deckers In Virginia, after a whirlwind legislative
imals from unnecessary tests. Cruelty Free Award, EcoVegAnimals, EVA, from Bosnia session, Senate bill 1379 and House bill
Europe intervened in both cases. and Herzegovina. 2250 passed the Virginia legislature with
In a case heard by the European Court EcoVeg Animals is a young animal pro- bipartisan support and was signed into law
of Justice, Esso Raffinage (a division of tection organisation working to improve on March 11, 2021, making Virginia the 4th
ExxonMobil) was challenging a demand by animal welfare in Bosnia and Herzegov- state to pass legislation prohibiting the sale
ECHA to conduct a developmental toxicity ina and beyond. Last year they successfully of new animal-tested cosmetics. The new
study. After receiving a final decision, Esso helped to end the use of live animals in the law will prohibit the sale of any cosmetic
decided that the test could still be avoided education programme at the Faculty of Vet- product that has been tested on animals after
by demonstrating the safety of its chemi- erinary Medicine at the University of Sara- January 1, 2022.
cal using evidence from other sources, but jevo. The organisation plans to use the funds In Maryland, SB 282 passed all commit-
ECHA refused this option. The court ruled from the award to encourage other faculties tee hearings and legislative floor votes in-
that ECHA has a duty to consider alterna- at the university to follow suit. They also cluding unanimous votes in the Senate. The
tives put forward by companies even after a plan to outreach to companies and consum- bills are now on the desk of Maryland Gov-
final decision has been made. This has pos- ers on the importance of bringing animal ernor Larry Hogan, awaiting his signature
itive implications for the use of alternative testing for cosmetics to an end. or default passage into law. Like the Vir-
approaches under REACH. The award honours Geoffrey Deck- ginia law, it will prohibit the sale of any cos-
In another Board of Appeal case, the ers, the much respected and loved former metic product that has been tested on ani-
ZDDP group of companies challenged Chair of the European Coalition to End An- mals after January 1, 2022.
ECHA’s decision requiring them to con- imal Experiments and Cruelty Free Europe, The Hawaii, Cruelty Free Cosmetics Act
duct 90-day repeat dose toxicity studies who passed away in June 2020. The €6,000 SB345 and HB 1088 have now successfully
and prenatal developmental studies on 13 award will be made annually on his birth- passed all committee hearings in their op-
similar substances used in hydraulic fluids. day to groups demonstrating a commitment posite chambers. The bills are now headed
Tests on all 13 substances would have used to ending animal tests and projects likely to for final floor votes and will then go to con-
thousands of animals. ZDDP argued that it make the most efficient and effective use of ference committee to work out small differ-
was possible to avoid at least some of these funds towards this goal. ences in the bills and an effective date be-
tests using read-across. The Board of Ap- fore being sent to Governor David Ige.
peal ruled that ECHA should have given all These important bills not only create
the registrants of the chemicals an oppor- Progress with state-level cruelty change at the state-level but create momen-
tunity to argue for the read-across, not just free cosmetics legislation in the US tum for national change. State efforts on this
the lead registrants. The ZDDP group will issue have already helped inform a way for-
now have another opportunity to argue in This year Cruelty Free International wel- ward for the national approach as the agree-
favour of using data from similar substances comed the re-introduction of cruelty free ments reached on state legislation were ad-
to avoid some of the animal tests demanded cosmetics legislation in Virginia, Maryland opted into the federal Humane Cosmetics
by ECHA. and Hawaii and also resumed work in New Act, which will be reintroduced this year.
362 ALTEX 38(2), 2021Corners
EUSAAT Virtual Seminar Series The Series kicked off on April 15, 2021 If you would like to attend, please regis-
started on 15.4.2021 at 5 p.m. CEST with two presentations and ter via: eusaatvirtualseminarseries2021@
will take place every second week. gmail.com by providing your name, e-mail,
We are very pleased to announce the EU- We have decided to provide a platform affiliation and career stage.
SAAT Virtual Seminar Series 2021. As we for younger researchers, so one young re-
have postponed the EUSAAT Congress searcher and one distinguished researcher We wish many interesting presentations
from this year to 2022 in order not to com- will present per session. The topics will and discussions, and especially good health
pete with WC11, we have decided to offer cover current 3R topics typically dealt to all of you and your loved ones.
our members and the European 3R commu- with in EUSAAT conferences including
nity a replacement with our Virtual Seminar regulatory, ethical, educational, 3Rs cen- Yours sincerely,
Series 2021. ter and scientific news, discussions and EUSAAT, your European 3Rs society
developments.
The last year of the project has taken a meeting report by Rovida et al. (2021) de- icotinoid pesticides can interfere with hu-
highly visible start with the fourth EU-Tox- scribes how more than a hundred people man neuronal signaling and may therefore
Risk Open Symposium, the yearly appoint- actively participated in the discussion on pose a DNT risk. A broad range of in vitro
ment for discussion and active interaction that occasion, bringing together diverse and in silico approaches was used (molec-
between EU-ToxRisk and international ex- viewpoints across academia, regulators, ular docking to the nicotinic acetylcholine
perts. The meeting took place virtually on and industry. A consensus was reached that receptor (nAChR), physiology-based tox-
February 23-24, 2021, hosting more than NAMs can improve confidence in RAx, in icokinetic modelling, cell-based signaling
300 participants from all over the world. particular in defining category boundaries studies), and the outcome was that a sub-
The scientific program focused on the as well as characterizing the similarities/ group of neonicotinoids triggers neuronal
critical assessment of general and specific dissimilarities between source and target signaling via the nAChR in the low micro-
learnings of the EU-ToxRisk project to pro- substances. molar range, a concentration that may be of
vide a foundation for its legacy. As one of The 4th EU-ToxRisk Open Symposium human toxicological relevance.
the key project deliverables, the “Advi- also hosted a successful session on the cur- Finally, the Open Symposium accom-
sory document on Novel Approach Method rently running 2nd generation case studies modated an exciting discussion on the up-
(NAM)-enhanced read-across (RAx)”, was (CS). These studies address new challeng- coming new frameworks, projects, and part-
the first topic addressed. Its content and ap- ing regulatory and scientific questions, such nerships, including a platform to jump-start
plication were reported, including the feed- as testing of chemicals with little or no ob- new efforts in next-generation risk assess-
back and endorsements from the Regula- served adverse effects, with multi-target ment. The session also included an interest-
tory Advisory Board, the OECD IATA Case organ toxicity that undergo metabolism, ing debate on validation and trust in NAM
Studies Project, and several international or needing ab-initio risk assessment. One to address specific regulatory information
regulatory toxicologists. The approach de- of those is the case study on the develop- requirements or decision-making needs.
scribed in the advisory document had al- mental neurotoxicological (DNT) effects An important conclusion was that trans-
ready been discussed previously at sev- of neonicotinoid pesticides. Results from parency and a close understanding of NAM
eral events. Most notable of these was the this CS were recently published by Loser et will lead to their increased acceptance for
EU-ToxRisk workshop held in Espoo, Fin- al. (2021). In this multi-disciplinary study, regulatory use.
land (May 2019). The recently published the question was addressed whether neon-
ALTEX 38(2), 2021 363Corners
EU-ToxRisk publications proaches (multi-electrode arrays). The de- References
veloped model may fill an important gap in Capinha, L., Jennings, P., Commandeur,
The EU-ToxRisk research has indeed the panel of test systems available to char- S. et al. (2021). Bioactivation of trichlo-
strongly focused on detailed characteriza- acterize the effects of chemicals on neu- roethylene to three regioisomeric gluta-
tion and description of the developed test rotransmitter receptors. thione conjugates by liver fractions and
systems. The better a method and its applica- Knowing your cell system well is crucial recombinant human glutathione trans-
bility domain are characterized, the more ap- for its correct implementation in a toxico- ferases: Species differences and impli-
propriate regulatory questions can be asked. logical test method. However, this is not suf- cations for human risk assessment. Tox-
Here are some examples of this approach ficient. Knowing your tested chemical and icol Lett 341, 94-106. doi:10.1016/j.
described in recent project publications and its correct handling well are also important. toxlet.2021.01.021
addressing different toxicological areas. Handling of chemicals is an often-neglected Klima, S., Brüll, M., Spreng, A. S. et al.
Ter Braak et al. (2021) describe how var- area of test descriptions. In Leist (2021), an (2021). A human stem cell-derived test
ious adaptive cellular stress response path- overview is given on the need for more ac- system for agents modifying neuronal
ways are critical in the pathophysiology of tive involvement of all test developers and N-methyl-D-aspartate-type glutamate
liver disease and drug-induced liver injury. performers with this issue. The publication receptor Ca2+-signalling. Arch Toxi-
The authors systematically compared the gives guidance and examples on how to dis- col. Online ahead of print. doi:10.1007/
transcriptomic profiles upon chemical acti- close transparent information concerning s00204-021-03024-0
vation in (hiPSC)-derived hepatocyte-like the preparation and use of test and control Leist, M. (2021). Identifying, naming
cells (HLCs), hiPSC, primary human he- chemical solutions. and documenting of test and tool com-
patocytes (PHH), and HepG2 liver can- This crucial issue also was addressed by pound stocks. ALTEX 38, 177-182.
cer cells. Using targeted RNA-sequencing, Proença et al. (2021). Nominal effect con- doi:10.14573/altex.2012311
benchmark concentration transcriptional re- centrations from in vitro toxicity assays Loser, D., Hinojosa, M. G., Blum, J. et al.
sponse was mapped for the various stress re- may lead to inaccurate estimations of in vivo (2021). Functional alterations by a sub-
sponses in the different test systems. This toxic doses because the nominal concentra- group of neonicotinoid pesticides in hu-
study contributes to a better understanding tion poorly reflects the concentration at the man dopaminergic neurons. Arch Toxi-
of how HLCs can contribute to the assess- molecular target in cells in vitro, which is col. Online ahead of print. doi:10.1007/
ment of cell physiological stress response responsible for initiating effects and can be s00204-021-03031-1
activation to predict hepatotoxic events. referred to as the biologically effective dose. Proença, S., Escher, B. I., Fischer, F. C. et
In the publication by Capinha et al. Chemicals can differentially distribute be- al (2021). Effective exposure of chemi-
(2021), the question was addressed how to tween in vitro assay compartments, includ- cals in in vitro cell systems: A review of
choose the most relevant test model for re- ing serum constituents in exposure medium, chemical distribution models. Toxicol In
nal toxicity. In the publication, the authors plate plastic, headspace, and extracellular Vitro 73, 105133. Online ahead of print.
highlight how enzymatic bioactivation pro- matrices. This paper reviews the mecha- doi:10.1016/j.tiv.2021.105133
cesses can vary among species. The au- nisms by which test chemicals distribute be- Rovida, C., Escher, S. E., Herzler, M. et
thors focused on the enzymatic conjugation tween in vitro assay compartments and also al. (2021). NAM-supported read-across:
of glutathione (GSH) to trichloroethylene lists the physicochemical properties driving From case studies to regulatory guidance
(TCE) followed by catabolism to the cor- the extent of this distribution. It helps define in safety assessment. ALTEX 38, 140-
responding cysteine-conjugate, S-(dichlor- chemical and biological applicability do- 150. doi:10.14573/altex.2010062
ovinyl)-L-cysteine (DCVC) and subsequent mains of individual models, as well as pro- Ter Braak, B., Niemeijer, M., Boon, R. et al.
bioactivation by renal cysteine conjugate vide a perspective on how to improve model (2021). Systematic transcriptome-based
beta-lyases, considered to play an import- predictivity and quantitative in vitro-in vivo comparison of cellular adaptive stress
ant role in the nephrotoxic effects of TCE. extrapolations. response activation networks in hepatic
The results suggest that humans are at much stem cell-derived progeny and primary
lower risk for TCE-associated nephrotoxic human hepatocytes. Toxicol In Vitro 73,
effects than rats. Outlook 105107. doi:10.1016/j.tiv.2021.105107
Finally, the EU-ToxRisk researchers ad-
dressed the area of DNT. Currently avail- The consortium is finalizing the organiza-
able human-based test systems for neuro- tion of its last year of dissemination activ- This project has received funding from the
science research or toxicological assays do ities. More information will be available European Union’s Horizon 2020 research
not well represent crucial receptors, such soon, but all interested readers can already and innovation programme under grant
as the ionotropic glutamate receptors (con- save the dates November 3-4, 2021 (The agreement no 681002.
sidered essential, e.g., for memory forma- Square, Brussels) when the consortium and
tion). Klima et al. (2021) describe the es- its stakeholders will have their last meet-
tablishment and characterization of stem ing at the EU-ToxRisk Final Symposium. Giorgia Pallocca and Marcel Leist
cell-derived neurons that show pronounced On this occasion, the project legacy will be
NMDA signaling, measured either by cal- summarized and the next phase of toxico-
cium imaging or by electrophysiological ap- logical research kicked-off.
364 ALTEX 38(2), 2021You can also read
