IS THE IN VIVO UNSCHEDULED DNA SYNTHESIS (UDS) ASSAY AT THE END OF THE LINE?
IS THE IN VIVO UNSCHEDULED DNA SYNTHESIS (UDS) ASSAY AT THE END OF THE LINE?
IS THE IN VIVO UNSCHEDULED DNA SYNTHESIS (UDS) ASSAY AT THE END OF THE LINE?
In risk evaluation, determining if a substance is genotoxic is important because it decides if the substance can be classified as a threshold or non-threshold toxin. The OECD Test Guidelines (TGs) on genetic toxicology are the “gold standard” on how to perform the preferred studies, with industry sectors suggesting particular tests, or combinations of tests, to meet regulatory criteria on this endpoint.
Concerns have been posed in recent years about OECD TG 486, the in vivo unscheduled DNA synthesis assay (UDS assay). A major drawback is that it is only fully applicable to substances that cause DNA damage in the liver that is repaired by nucleotide excision (i.e. bulky adducts); since the assay does not detect DNA damage that is repaired by other mechanisms or is not repaired at all, it could result in a false negative response. Furthermore, if a positive response is obtained, there is no indication of the fidelity of the DNA repair, implying that the assay offers little to no information on the possibility of mutagenic activity arising from mis-repair or mis-replication. Indeed, the ICH (2014) and ECHA (2017) have imposed restrictions on its use as a follow-up for in vitro positive effects, and the OECD has determined that it meets the requirements for removal from its guidelines (OECD, 2016). It’s no surprise, then, that the UDS assay was recently scrutinized by the European Food Safety Authority (EFSA).
EFSA used the newly created EURL ECVAM database (which contains genotoxicity and carcinogenicity data on over 700 substances that gave positive results in the (Ames) bacterial reverse mutation test, OECD TG 471) to assess the UDS assay’s limitations. The UDS assay was found to have a sensitivity of about 60% for predicting (genotoxic) carcinogenicity, compared to 88 percent for the transgenic rodent gene mutation assay (TGR, OECD TG 488) and 91 percent for the in vivo mammalian comet assay (OECD TG 489). Furthermore, the UDS assay missed about 40% of Ames-positive compounds that had previously tested positive in other in vivo genotoxicity experiments.
EFSA concluded that the UDS assay is no longer suitable as a follow-up to positive in vitro studies for new material dossiers, in accordance with the ICH and ECHA. Only positive responses are considered sufficient to determine genotoxic potential in drug re-evaluations that already have UDS assay data; for negative responses, the reliability and relevance of the findings must be assessed using a weight-of-evidence method (taking into account the type of DNA damage, metabolism, toxicokinetics etc.). Additional tests, such as the TGR or the in vivo comet assay, would almost certainly be needed for certain substances before a final conclusion can be reached.
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