Genetic Toxicity Assessment: Employing the Best Science for Human Safety Evaluation
Associate Editor
Associate Editor
Editor in Chief
We are pleased to announce a new initiative for the Forum Section of Toxicological Sciences, which is designed to include discussions and commentaries providing an interface between toxicology and public policy. A series of articles focused on the theme "Genetic Toxicity Assessment: Employing the Best Science for Human Safety Evaluation" has been formulated. Clearly, this is an important and controversial topic. Gene and chromosomal mutations have been implicated in adverse health consequences in humans including cancer and birth defects. Hence, it is incumbent upon the scientific and regulatory community that the best available scientific tools be employed not only to identify the inherent mutagenic hazard but also to mitigate the potential risk posed by such agents to humans.
Currently, genetic toxicology tests are routinely used to predict carcinogenic potential of new chemical entities during the discovery process as well as to screen the chemicals that are already in commerce. These assays are also important measures for determining whether exposure to agent may induce heritable mutations. In general, results from the tests are viewed in simple binary terms, i.e., "yes" or "no" for the induction of the effect being investigated with little consideration for the dose-response or the definition of a no-observed-effect level. A positive result in one or more of the standard genetic toxicology assays may cause a test chemical to be dropped from further development, to be labeled as a mutagen or carcinogen if it is a marketed product in certain geographies, or to be evaluated exclusively with a linear, nonthreshold approach in risk assessment.
The interpretation of the results of genetic toxicity tests is frequently called into question because the assays are usually conducted at high concentrations (up to 10mM) or at excessive cytotoxic levels (e.g., up to 90% inhibition in cell growth) in cell lines that do not have normal DNA repair pathways. Furthermore, data accumulated over the past few decades have shown that the sensitivity and specificity of the widely used genetic toxicology tests, especially the in vitro mammalian cell culture-based assays, to predict animal carcinogens are somewhat disappointing. As a result, there continues to be ongoing dialogue, discussion, and debate over the most appropriate tests for assessing the mutagenic potential of xenobiotics, the best way to interpret positive results obtained in the tests, and the most meaningful way to apply these results to a comprehensive assessment of human risk.
The goal of the Forum Series is to facilitate the communication of ideas and promote discussion and new thinking in order to enhance the scientific basis for evaluating the mutagenic risk that chemicals might pose for people. Over the next several months, an invited article will appear in successive issues of the journal featuring state-of-the-art assessments of mutagenicity test performance, strategies for evaluating and interpreting mutagenicity test results, and perspectives and challenges concerning the best approaches to screening mutagenic potential. Contributors have been selected in order to encompass diverse opinions and experiences. It is also our intention to conclude the series with an Editorial addressing our perspective on the state of the science of genetic toxicology and the impact of the series on identifying important issues for further resolution and refinement. We hope that content of these articles will be informative, provocative, and useful to the broad readership of the journal.
In the future, we would like to have additional series of articles in the Forum Section addressed to different, topical themes. Your suggestions for these are welcome.
NOTES
Editors' Note: In light of the fact that some of the papers in the series will focus on a comparison of the performance of different assays for mutagenic potential, rather than an emphasis on individual chemicals per se, the use of code letters/numbers, rather than chemical names and structures, will be permitted. This is an exception from the journal's policy that requires the use of chemical names/structures for all research papers, but we recognize that this flexibility is necessary in order to obtain the most current, critical assessments of test performance.
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