Genetic toxicity assessment: employing the best science for human safety evaluation Part VII: Why not start with a single test: a transformational alternative to genotoxicity hazard and risk assessment.
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 end point 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.
Ku
Warren W
WW
Exploratory Medicinal Sciences, Pfizer Global Research and Development, Groton, CT 06340, USA. warren.w.ku@pfizer.com
Aubrecht
Jiri
J
Mauthe
Robert J
RJ
Schiestl
Robert H
RH
Fornace
Albert J
AJ
D000826:Animal Testing Alternatives; D000818:Animals; D006801:Humans; D066298:In Vitro Techniques; D009152:Mutagenicity Tests / Q000379:methods* / Q000639:trends; D009153:Mutagens / Q000145:classification / Q000633:toxicity*; D018570:Risk Assessment; D043922:Toxicogenetics
D009153:Mutagens