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Letter to the Editor, Response to Commentary "Re-Evaluation of the Big Blue® Mouse Assay of Propiconazole Suggests Lack of Mutagenicity"
Citation:
ROSS, J. A. AND S. A. LEAVITT. Letter to the Editor, Response to Commentary "Re-Evaluation of the Big Blue® Mouse Assay of Propiconazole Suggests Lack of Mutagenicity". ENVIRONMENTAL AND MOLECULAR MUTAGENESIS. John Wiley & Sons, Inc, Hoboken, NJ, 53(7):574-577, (2012).
Impact/Purpose:
In their commentary titled "Re-Evaluation of the Big Blue® Mouse Assay of Propiconazole Suggests Lack of Mutagenicity", Shane et 01. present an overview of portions of our previously reported work examining the potential for some conazole fungicides to induce increases in mutant frequency in a transgenic mouse mutation assay (Ross and Leavitt 2010; Ross et al. 2009). Based on several lines of argument, the authors of the commentary conclude that our finding that propiconazole induced an increase in mutations in vivo relative to controls under the assay conditions employed are not supportable. While we agree with some of the statements made by the Commenters, it appears that they have made a number of factual errors and mischaracterizations of our data in their commentary which we wish to take this opportunity to address. These errors and mischaracterizations undermine their conclusions regarding our studies.
Description:
In their commentary titled "Re-Evaluation of the Big Blue® Mouse Assay of Propiconazole Suggests Lack of Mutagenicity", Shane et 01. present an overview of portions of our previously reported work examining the potential for some conazole fungicides to induce increases in mutant frequency in a transgenic mouse mutation assay (Ross and Leavitt 2010; Ross et al. 2009). Based on several lines of argument, the authors of the commentary conclude that our finding that propiconazole induced an increase in mutations in vivo relative to controls under the assayconditions employed are not supportable. While we agree with some of the statements made by the Commenters, it appears that they have made a number of factual errors and mischaracterizations of our data in their commentary which we wish to take this opportunity to address. These errors and mischaracterizations undermine their conclusions regarding our studies The first line of reasoning put forward by the Commenters is that our conclusions are not supportable because propiconazole is not positive in a variety of short term genotoxicity assays. We made this point in our previous publications, and cited a number of those negative assays. We also believe that our current hypothesis for the mechanistic basis for in vivo mutagenesis by propiconazole and triadimefon would not be operant under the conditions of the short term tests. We therefore do not believe that for these chemicals there is any conceptual disagreement between the short term assay negative results and the positive results in the in vivo mutation assay. We agree with the Commenters that propiconazole and triadimefon should not be considered to act via a genotoxic mode of action, and never proposed in our previous manuscripts that they do. The second line of reasoning has to do with a relatively low concurrent control mutant frequency (MF) in the study of myclobutanil and propiconazole, compared to that in the study of triadimefon, and to the control mutant frequencies in some of our previous studies. The Commenters state that "If a significant statistical difference exists among control groups from different experiments (Controls 1 and 2) run by the same researchers in the same laboratory within a short time frame, it adds ambiguity to any conclusions that the small difference between the control and PPZ-treated groups represents a real, chemical-related difference." There are several points of clarification that need to be made. Soon after completion of the triadimefon study, the lab was relocated to a new building in a new research facility. Approximately 1.5 years elapsed between the completion of the triadimefon study and the initiation of the propiconazole and myclobutanil study. Also, the transgenic animals received for the second study were reared in a different barrier facility than those used in the first study. These circumstances do not meet the presupposition of the Commenters that the two studies took place "in the same laboratory within a short time frame". As the controllVlF was lower than in our previous studies, we performed rigorous quality control testing to assure that our ability to detect faint blue phenotype mutants was not impaired in the new setting, relative to our previous detection sensitivity. Using commercially available color controls, as well as previously characterized very pale blue phenotype mutants, we concluded that our detection sensitivity was comparable between the two laboratory settings. Although our mutant frequency was lower in the Control 2 group, is was equally low in the concurrent myclobutanil treatment group, with no indication of increased MF induced by this ** nontumorigenic conzaole.
