3D cell culture models & their role in enhancing genotoxicity testing approaches for nano- and advanced-materials

• The need to adapt existing OECD TGs for NM testing.
• The limitations of existing in vitro OECD TGs for NMs testing including lack of physiological relevance, and that do not cover all mechanisms of action underpinning genotoxicity.
• Examples of how NAMs have overcome in vitro limitations.
• How NAMs are gaining momentum and better support regulatory risk decision making.

Watch the Recording

Shareen Doak is Professor of Genotoxicology and Cancer in Swansea University Medical School where she co-leads the In Vitro Toxicology Group. Shareen is a UK and EUROTOX Registered Toxicologist.Shareen’s research interests focus on the genotoxic profiles of chemicals and engineered nanomaterials, the mechanisms underlying their DNA damaging potential and subsequent consequences upon human health. Her interests extend to carcinogenicity and the development of advanced 3D culture models and mechanism-based bioassays for safety assessment to reduce the need for animal testing. Shareen sits on the UK Government Committee on Mutagenicity (COM), and the Scientific Advisory Group on Chemical Safety in Consumer Products (SAG-CS) under the Office for Product Safety and Standards (OPSS). She is also the Editor-in-Chief for Mutagenesis. In the past she has acted as an external expert for the European Commission Scientific Committee on Consumer Safety (SCCS) and European Food Standards Agency (EFSA).

Abstract:

Standard in vitro genotoxicity testing approaches have limitations for testing nanomaterials (NMs) and in 2013, an OECD expert panel concluded it was necessary to adapt the in vitro mammalian cell micronucleus test (OECD TG487) to facilitate evaluation of manufactured NMs. An OECD project was initiated, aimed at developing a new OECD Guidance Document detailing the necessary steps to adapt OECD TG487 for NMs, which was subsequently published in Sept 2022 (Series on Testing and Assessment No. 359; ENV/CBC/MONO(2022)15). Whilst ongoing efforts have focused on adapting existing OECD TGs for NMs testing, limitations remain as existing in vitro approaches lack physiological relevance, often do not consider long-term exposure effects, and do not cover all mechanisms of action underpinning genotoxicity. New approach methodologies (NAMs) provide the opportunity to overcome these issues and there have been substantial developments in this area over recent years. For example, co-culture models incorporating epithelial and macrophage cells can detect secondary genotoxicity, a key nanomaterial mode of action only detected in vivo. Additionally, 3D in vitro liver spheroids exhibit higher metabolic capacity, which is important for identifying pro-carcinogens. These models also support longer-term, repeated dosing, which is more representative of nanomaterial human exposure. The broad field of NAMs to better support regulatory risk decision making is therefore gaining momentum, with a variety of promising technologies emerging.

About ScitoVation:

ScitoVation helps clients assess chemical compound safety using innovative science, next-generation technology, and professional expertise. ScitoVation is known for partnership, flexibility, and proven success in its work to develop safer and more effective pharmaceuticals, food ingredients, agricultural chemicals, commodity chemicals and consumer products. A spin-off of the former The CIIT and The Hammer Institutes for Chemical & Drug Safety Sciences, ScitoVation is an industry leader of New Approach Methods (NAMS) for chemical/drug discovery & development in the rapidly evolving global regulatory landscape.