Critical review of the current and future challenges associated with advanced in vitro systems towards the study of nanoparticle (secondary) genotoxicity.

Stephen J Evans,Michael Burgum,Martin J D Clift,John W Wills,Gareth J S Jenkins,Jefferson De Oliveira Mallia,Thomas S Wilkinson,Neenu Singh,Shareen H Doak

doi:10.1093/mutage/gew054

Stephen J Evans, Michael Burgum + Show 7 more

Open Access

https://doi.org/10.1093/mutage/gew054

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Abstract

With the need to understand the potential biological impact of the plethora of nanoparticles (NPs) being manufactured for a wide range of potential human applications, due to their inevitable human exposure, research activities in the field of NP toxicology has grown exponentially over the last decade. Whilst such increased research efforts have elucidated an increasingly significant knowledge base pertaining to the potential human health hazard posed by NPs, understanding regarding the possibility for NPs to elicit genotoxicity is limited. In vivo models are unable to adequately discriminate between the specific modes of action associated with the onset of genotoxicity. Additionally, in line with the recent European directives, there is an inherent need to move away from invasive animal testing strategies. Thus, in vitro systems are an important tool for expanding our mechanistic insight into NP genotoxicity. Yet uncertainty remains concerning their validity and specificity for this purpose due to the unique challenges presented when correlating NP behaviour in vitro and in vivo. This review therefore highlights the current state of the art in advanced in vitro systems and their specific advantages and disadvantages from a NP genotoxicity testing perspective. Key indicators will be given related to how these systems might be used or improved to enhance understanding of NP genotoxicity.

Highlights

Due to their unique physical and chemical characteristics, nanoparticles (NPs) exhibit distinctly different properties to their bulk counterparts, which can directly contribute to their alternative biological interaction and subsequent impact [1]
A number of different, advanced in vitro models, as described in Table 1, have been developed varying in their degree of complexity and highlighting the progression of in vitro systems potentially available for nanogenotoxicity testing strategies. The purpose of these advanced models is to create representation of specific organs of the body, beyond that of monoculture systems [29]. Such complex in vitro models are being increasingly applied in the field of nanotoxicology, but to date, their use has been limited in assessing the genotoxic potential of NPs, and they likely require some adaptation to support the evaluation of DNA damage endpoints [41]
Commercial InspheroTM liver microtissues have been utilised in the genotoxic assessment of a panel of NPs including zinc oxide (ZnO), multiwalled CNTs (MWCNTs) and TiO2 NPs

Summary

Introduction

Due to their unique physical and chemical characteristics, nanoparticles (NPs) exhibit distinctly different properties to their bulk counterparts, which can directly contribute to their alternative biological interaction and subsequent impact [1]. Such complex in vitro models are being increasingly applied in the field of nanotoxicology, but to date, their use has been limited in assessing the genotoxic potential of NPs, and they likely require some adaptation to support the evaluation of DNA damage endpoints [41].

Results

Conclusion