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NC3Rs: National Centre for the Replacement Refinement & Reduction of Animals in Research

3 Minute 3Rs podcast: May 2022 transcript

Microbrains for neurotoxicity testing, improved experimental design, and post-op severity assessment.

Papers behind the pod:

  1. Wang Q et al. (2022). Assessment of a 3D neural spheroid model to detect pharmaceutical-induced neurotoxicity. ALTEX 39. doi: 10.14573/altex.2112221
  2. Reynolds P (2022). Between two stools: preclinical research, reproducibility, and statistical design of experiments. BMC Research Notes 15(73). doi: 10.1186/s13104-022-05965-w
  3. Tappe-Theodor A et al. (2022). The “WWHow” Concept for Prospective Categorization of Post-operative Severity Assessment in Mice and Rats. Frontiers in Veterinary Science. 9: e841431. doi: 10.3389/fvets.2022.841431


It’s the third Thursday of May, and you’re listening to 3 Minute 3Rs, your monthly recap of efforts to replace, reduce and refine the use of animals in research. This month, we’re bringing you a paper for each R – let’s start with replacement, and how microbrains could provide a non-animal approach for neurotoxicity studies.


Drug-induced neurotoxicity is a leading cause of safety-related failures of drugs in clinical trials. Therefore, there is a need to replace the current poorly predictive models with new technology.

Researchers at Takeda recently published an evaluation of the predictive capabilities of human iPSC-derived neural spheroids. They tested these spheroids with 84 diverse pharmaceuticals with varying degrees of drug-induced neurotoxicity. The models they created from the results could distinguish between neurotoxic and non-neurotoxic molecules with a specificity as high as 93% and sensitivity of 53% which allows for a very low false positive rate.

Ultimately, this assay can be used to detect neurotoxicity in early drug discovery allowing institutions to predict failing compounds and replace these animal studies altogether.

Read the full article in ALTEX.


Next up: could better experimental design training help address the reproducibility crisis and reduce the number of animals wasted in poorly conceived studies? That’s the proposal made in a new commentary by Dr Penny Reynolds, highlighting that animal-based experiments fall “between two stools”; the experimental methods used in clinical trials, and those developed for agricultural and industrial settings.

Despite most animal-based studies having the small sample sizes and multiple factors of interest that characterise agricultural experiments, they are usually analysed as if they were large-scale clinical trials. This leads to poor-quality data which has scientific, economic, as well as ethical implications. The misuse of concepts and terminology suggests that this results from a lack of appropriate statistical training.

To better train researchers and encourage this shift towards more robust study designs, the statisticians that deliver this training or consult with biologists may also need to be more aware of what is required in preclinical research, and focus on the design process rather than mathematical concepts.

Check out the full commentary in BMC Research Notes for further details.

And finally, a refined concept for post-operative severity assessment in rats and mice.


Assessing prospective severity of an animal experiment is essential to determine if an experiment is ethically acceptable. As part of applications to approve procedures, researchers have to estimate the likely harm to the animals caused by each intervention and classify the severity as mild, moderate or severe. Catalogs and guidelines are available for guidance; however, these classifications are often based on established interventions for which the severity is known, and cannot be adapted to novel procedures.

In Frontiers in Veterinary Science, a multidisciplinary and interprofessional group composed of medical professionals, scientists, animal welfare-associated experts and politicians provide a new approach for prospective severity assessment of rodent surgical interventions. The Where-What-How (WWHow) approach integrates intra-operative characteristics from three categories: the surgical site (where), tissue trauma (what) and methodological aspects (how) determine a severity score that predicts the maximum expected severity of an intervention. The WWHow approach is easy to use and can be adapted to new procedures to identify potential refinement strategies.

To learn more about this study, read the full paper online.


That’s it for this month’s episode. 3 Minute 3Rs is brought to you each month by Lab Animal, the North American 3Rs Collaborative, and the NC3Rs. If you’re enjoying the show, why not rate and review it wherever you’re listening? It helps more people find the show and discover new ways to put the 3Rs into practice. Thanks for tuning in, we’ll see you next month for more 3Rs research.

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