A new paradigm for toxicity and safety testing? Non-animal approaches

An engaging forum on the efforts being taken to develop non-animal approaches to toxicity, safety and efficacy testing held at Matrix, Biopolis, Singapore on the 25th January 2016.

Is animal testing reliable? Can safety in animal render a chemical 100% safe in humans? If not, why are animals still being predominantly used in pre-clinical testing models? When will there be a replacement of these animal testing methods with non-animal approaches.

A*STAR entered into a partnership with the US EPA to lead the efforts into co-development of alternative non-animal approaches in toxicity, efficacy testing and equally importantly safety assessments of chemicals more robustly.

This collaboration gave rise to an interactive symposium on ‘Non-animal approaches to predict safety and efficacy’ that was inaugurated by Dr Kenneth Lee, Senior Director, Biomedical Research Council, A*STAR with the announcement of the collaboration between A*STAR and US EPA. International speakers included Dr Russell Thomas (Director, National Centre for Computational Toxicology, US EPA), Prof Melvin Andersen (Senior Scientist, ScitoVation) and Dr Karen Blackburn (Research Fellow, Central Product Safety, P&G).

Russell Thomas discussed the focus of the computational toxicology centre of the US EPA is in the drive for extensive chemical characterization (development of a database of more than a million compounds to accurately correlate their structure) which is followed by competent and robust model development, dose and systems modelling, adverse outcomes pathway modelling, population and exposure data modelling, thorough risk and safety assessments which are being performed at very high throughput levels. Currently there are no regulatory mandate at least in the US for exposure (meaning repeated doses or multiple exposures). So he highlighted that high throughput modeling for risk assessment and exposure data are key areas of focus. He also emphasized on the need for more collaborative research on endocrine disruptors, need for developing technologies to address metabolic competence that allows screening of parent chemicals and identification of potential bioactive metabolites.

Karen Blackburn cited the examples of reconstructed skin models (for skin penetration and irritation studies) which are not accepted by regulatory authorities as they are more easily penetrable than what is seen in normal physiology. She then emphasized the integration of various approaches into an unified model that is robust across various chemicals. Such an unified model leading to the convergence of alternative non-animal approaches into a predictive paradigm will garner support across the various players in the industry, academia and government research organizations with the potential to further convince the regulatory authorities towards acceptance and approval of non-animal testing approaches in the pharmaceutical, food & nutrition and the consumer care sectors. She also indicated that more research is required in the fields of repeated dose testing, developmental toxicity testing and reproductive toxicity testing.

The A*STAR scientists who are part of the collaboration gave snippets of their technologies that will be used in this collaborative research with US EPA. Prof Hanry Yu from IBN, A*STAR touched upon the 3D Cellulosponge and HepatoCue technologies alongside other microfluidic-based approaches to address acute and sub-acute liver toxicity testing in vitro. He highlighted that there is no single assay that does everything but it will be a culmination of readouts and safety assessments that will enable the development of sound alternative methods.

Dr. Daniele Zink, IBN A*STAR and Dr Lit-Hsin Loo, BII A*STAR elaborated on their predictive proximal tubule model for kidney toxicity and imaging-based phenotypic profiling for organ-specific toxicity studies respectively. They emphasized on the importance of using large number of compounds (at least more than 10 compounds that are known to be toxic to that specific organ) and also the used of known non-toxic compounds as negative controls to test and validate the robust nature of a predictive screening model.

Finally, Dr Florent Ginhoux, SIgN A*STAR elucidated his expertise in developing a robust method for generation of human fetal macrophages which play an important role in blood brain barrier development and thus can be useful tools in the creation of a screening model for developmental toxicity.

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Discussion forum involving A*STAR scientists (L to R) Prof Hanry Yu, Dr Florent Ginhoux, Dr Daniele Zink, Dr Lit-Hsin Loo moderated by Dr Frank Eisenhaber (far left)

When science is getting more and more complicated where are these efforts in non-animal approach or 3R animal approach (Reduction, replacement, refinement) that began in 1959 headed to?

Key points of contention that arose out of the discussion forums are outlined below. These are questions that are routinely raised for as long as alternative methods have been researched upon and whose answers are always evolving with time and new knowledge

  • Individual cells are studied in isolation in such alternative models. This is not physiological nor is their response to drug in isolation simulating a real in vivo environment. So how do we study the systemic response or systemic toxicity in an in vitro assay that aims to eventually replace in vivo screening
  • Are 3D models better than 2D models in their effort to simulate the in vivo environment? Is it organ-specific?
  • What can Singapore’s research community do to achieve the challenging questions in this field?
  • How to strike a viable balance between the innovators and industry/investors?

There is a constant comparison between innovators who tend to be risk-taking versus industry/investors who are largely risk averse. The innovators tend to be risk-taking as they see it to be essential trait in the development of novel innovations. But for the industry partners, they tend to be more risk averse as they constantly need to face the regulatory authorities who are more concerned with the safety and risk assessment profiles of the novel innovations.

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Moderated poster session showcasing research efforts within Singapore

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Industry panel discussion with (L to R) Michael McMillian (Invitrocue), JE van der Harst (Danone), Mark Phong (L’Oreal), Karen Blackburn (P&G)

A good way forward as suggested by Karen was the need for further collaborative environment between the industry, academia and research organizations to culminate the research efforts in a unified approach which can convince the regulatory authorities to obtain an approval.

She also suggested that the Singaporean research community needs to have stronger associations with trade unions and other larger regulatory bodies in the US, EU and Asia, more participation in global ‘alternative methods’ meetings to accrue better exposure, recognition and acknowledgement of the high quality research happening within Singapore by the larger global community.

If you are wondering the answer to the question posed in the title of the article. Is ‘the alternative methods’ approach a new paradigm for toxicity and safety testing? Not yet, but the intense collective research efforts underway across multiple sectors seems to have the potential to realize the ideal of 3R approach beginning with preliminary toxicity assessments and high throughput safety assessments.

All photographs are copyright of biotechin.asia.

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