New and emerging technologies for genetic toxicity testing

Abstract

The International Life Sciences Institute (ILSI) Health and Environmental Sciences Institute (HESI) Project Committee on the Relevance and Follow-up of Positive Results in In Vitro Genetic Toxicity (IVGT) Testing established an Emerging Technologies and New Strategies Workgroup to review the current State of the Art in genetic toxicology testing. The aim of the workgroup was to identify promising technologies that will improve genotoxicity testing and assessment of in vivo hazard and risk, and that have the potential to help meet the objectives of the IVGT. As part of this initiative, HESI convened a workshop in Washington, DC in May 2008 to discuss mature, maturing, and emerging technologies in genetic toxicology. This article collates the abstracts of the New and Emerging Technologies Workshop together with some additional technologies subsequently considered by the workgroup. Each abstract (available in the online version of the article) includes a section addressed specifically to the strengths, weaknesses, opportunities, and threats associated with the respective technology. Importantly, an overview of the technologies and an indication of how their use might be aligned with the objectives of IVGT are presented. In particular, consideration was given with regard to follow-up testing of positive results in the standard IVGT tests (i.e., Salmonella Ames test, chromosome aberration assay, and mouse lymphoma assay) to add weight of evidence and/or provide mechanism of action for improved genetic toxicity risk assessments in humans.

Outcome of the public consultation on the draft opinion providing clarification of some aspects related to genotoxicity assessment

“…The appropriate in vivo follow up to positive results in in vitro genotoxicity assays has been widely reviewed in the context of developing science, availability of emerging test methods and the introduction of new standardized test guidelines (see for example Aardema 2013;Dearfield et al, 2011;Eastmond et al, 2009;EFSA 2011;Lorge et al, 2007;Lynch et al, 2011;Pfuhler et al, 2007;UKCOM 2011). From these it has become apparent that the in vivo UDS assay is now less favoured in a tiered genotoxicity testing strategy than has historically been the case.…”

Models for Detection of Genotoxicity in vivo: Present and Future

“…DNA fragments will travel faster than the intact parts of the nucleus, and will run in front of the nucleus. When the DNA is stained and observed with a microscope, the fragments form what looks like a comet's tail, and the nucleus forms the comet's head (17,18) (Fig1. direct visualization).…”

“…Liver metabolism can be mimicked in testing paradigms by adding primary hepatocytes, liver slices, or various organ extract fractions to tester cell cultures, or by liver perfusion (15). The standard fraction is known as S9 fraction, which combines microsomes (containing CYPs) and cytosol (enriched for transferases) from the liver of rodents whose metabolism has been activated through xenobiotic pre-treatment (15,16 In the context of drug discovery, in vivo methods are second-line assays performed to support the safety of a compound that is in the pipeline for clinical development (17,18).…”

Construction and evaluation of two biosensors based on yeast transcriptional response to genotoxic chemicals

“…It has now been well-established that diseases like cancer are due to the accumulation of genetic variations that promote uncontrolled cell proliferation (Vineis and Perera, 2007); hence it is not surprising that essentially all genotoxic agents are rodent carcinogens (Granath et al, 1999;Strauss, 1992), making it extremely critical to detect environmental genotoxins that may exist in low abundance and to assess their cancer risk (Lynch et al, 2011).…”