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ToxSci Advance Access published online on June 4, 2007
Toxicological Sciences, doi:10.1093/toxsci/kfm147
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© The Author 2007. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Why Not Start With a Single Test: A Transformational Alternative to Genotoxicity Hazard and Risk Assessment

Warren W. Ku*,1, Jiri Aubrecht{dagger}, Robert J. Mauthe{dagger}, Robert H. Schiestl{ddagger} and Albert J. Fornace, Jr.§

* Exploratory Medicinal Sciences {dagger} Drug Safety, Pfizer Global Research and Development, Groton, CT {ddagger} Departments of Pathology, Environmental Health and Radiation Oncology, Schools of Medicine and Public Health, University of California, Los Angeles, CA 90095 § Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington DC 20057 and Harvard School of Public Health, Boston, MA 02115

1 To whom correspondence should be addressed. Email: warren.w.ku{at}pfizer.com

Received March 5, 2007; revision received May 29, 2007; accepted May 30, 2007


  Abstract

A transformational alternative for genotoxicity hazard and risk assessment is proposed to the current standard regulatory test battery. In principle, the proposed approach consists of a single in vitro test system with high genomic sequence homology to humans that addresses the relevant principal genetic lesions assessed in the current test battery. The single test system also possesses higher throughput attributes to permit the screening of large numbers of compounds and allow for an initial differentiation of genotoxic mechanisms (i.e. direct vs. indirect mechanisms) by how the hazard endpoint is measured. To differentiate compounds showing positive results, toxicogenomic analysis can be conducted to evaluate genotoxic mechanisms and further support risk assessment. Lastly, the results from the single test system can be followed up with a complementary in vivo assessment to establish mechanistic relevance at potential target tissues. Here, we propose the in vitro (yeast) DNA deletion (DEL) recombination assay as a single test alternative to the current genotoxicity test battery with a mechanistic follow up toxicogenomic analysis of genotoxic stress response as one approach that requires broader evaluation and validation. In this assay, intrachromosomal recombination events between a repeated DNA sequence lead to DNA deletions, which have been shown to be inducible by a variety of carcinogens including those both negative and positive in the standard Salmonella Ames assay. It is hoped that the general framework outlined along with this specific example will provoke broader interest to propose other potential test systems.

Key Words: genotoxicity; carcinogenesis; mechanisms; risk assessment; toxicogenomics.


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