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Analysis of the mutations inducedd by conazole fungicides in vivo
ROSS, J. A. AND S. A. LEAVITT. Analysis of the mutations inducedd by conazole fungicides in vivo. MUTAGENESIS. Oxford University Press, Cary, NC, 10-doi(mutage/gep068):1093, (2010).
The mouse liver tumorigenic conazo1e fungicides triadimefon and propiconazo1e have previously been shown to be in vivo mouse liver mutagens in the Big Blue" transgenic mutation assay when administered in feed at tumorigenic doses, whereas the nontumorigenic conazo1e myc1obutani1 was not mutagenic. DNA sequencing ofthe mutants recovered from each treatment group as well as from animals receiving control diet was conducted to gain additional insight into the mode of action by which tumorigenic conazo1es induce mutations. Relative dinucleotide mutabilities (RDM) were calculated for each possible dinucleotide in each treatment group, and then examined by multivariate statistical analysis techniques. Unsupervised hierarchical clustering analysis ofRDM values segregated two independent control groups together, along with the nontumorigen myclobutanil. The two tumorigenic conazo1es clustered together in a distinct grouping. Partitioning around mediods of RDM values into two clusters also groups the triadimefon and propiconazo1e together in one cluster, and the two control groups and myclobutani1 together in a second cluster. Principal component analysis ofthese results identifies two components that account for 88.3% of the variability in the points. Taken together, these results are consistent with the hypothesis that propiconazo1e and triadimefon induced mutations do not represent clonal expansion of background mutations, and support the hypothesis that they arise from the accumulation of reactive e1ectrophi1ic metabolic intermediates within the liver in vivo.
This study was undertaken as a part of a larger multi-investigator study to identify mode(s) of action for tumorigenic conazoles, initiated in consultation with OPP. Elucidation of MOA is needed to support reassessment of currently registered conazoles human cancer risk, and to provide information to support evaluations ofnew conazoles. What is the impact to the field and the Agency
Record Details:Record Type: DOCUMENT (JOURNAL/PEER REVIEWED JOURNAL)
Organization:U.S. ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF RESEARCH AND DEVELOPMENT
NATIONAL HEALTH AND ENVIRONMENTAL EFFECTS RESEARCH LAB
INTEGRATED SYSTEMS TOXICOLOGY DIVISION