Abstract
Organs-on-chip (OC) have gained much interest as animal-free toxicity testing methods due to their closer resemblance to human tissues and longer culture viability than conventional in vitro methods. The current paper discusses where and how OCs may take a role in the transition to a more predictive, animal-free safety assessment for regulatory purposes. From a preliminary analysis of a repeated dose toxicity database, ten organs of priority for OC development for regulatory use have been identified. For a number of these organs (lung, skin, liver, kidney, heart, and intestine), OCs are already at rather advanced stages of development, such that involvement of regulators becomes of value in the optimization towards fitness-for-purpose of these methods. For organs such as testis, spleen, brain, and stomach, OCs are much more premature, if existing at all. Therefore, developmental work on OCs for these latter organs is expected to stay in the academic arena for the coming time. A number of technical recommendations and some challenges to reaching final implementation are discussed. We recommend that the development of OCs goes forward together with the development of adverse outcome pathways (AOP) and that they are combined with other methods into integrated testing strategies. Overall, opportunities exist, but much still needs to be done. In our view, regular interactions in multi-stakeholder workshops on the application of animal-free innovations such as OCs will be beneficial.
Highlights
Much of the data needed for the regulatory safety assessment of chemical substances and pharmaceuticals comes from experimental animal studies
OCs may play a role in the future regulatory safety assessment of chemical and pharmaceutical substances, especially in the assessment of complex, systemic toxicity
OCs offer novel possibilities, such as longer exposure durations and inclusion of multiple cell types, which might eventually allow the prediction of complex, systemic adverse outcome (AO) for which no non-animal approaches currently exist
Summary
Much of the data needed for the regulatory safety assessment of chemical substances and pharmaceuticals comes from experimental animal studies. From a regulatory point of view, the transition to a more predictive safety assessment of chemical and pharmaceutical substances requires the development of novel models and methods that reflect complex human physiology and biology in vitro. In this respect, one of the fastest-growing, most promising innovative technologies is the organ-on-chip (OC) technology (Marx et al, 2016). The revolutionary approach represents a more radical change in safety assessment, starting with the identification of crucial mechanisms and biochemical events in clinical toxicity observations that are relevant for humans These mechanisms and events should be the basis for the development of a set of animal-free assays that together predict these toxicities. We outline the expected challenges to implementation of this innovative technology for regulatory safety assessment purposes
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