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GENOTOXICITY AND METABOLISM OF THE SOURCE-WATER CONTAMINANT 1,1-DICHLOROPROPENE: ACTIVATION BY GSTT1-1 AND STRUCTURE-ACTIVITY CONSIDERATIONS
Citation:
Granville, C. A., M. K. Ross, R TORNERO-VELEZ, N. M. Hanley, A. Gold, A M. Richard, K. Funasaka, A H. Tennant, A D. Kligerman, M V. Evans, AND D M. Demarini. GENOTOXICITY AND METABOLISM OF THE SOURCE-WATER CONTAMINANT 1,1-DICHLOROPROPENE: ACTIVATION BY GSTT1-1 AND STRUCTURE-ACTIVITY CONSIDERATIONS. MUTATION RESEARCH. Elsevier Science BV, Amsterdam, Netherlands, 572(1-2):98-112, (2005).
Impact/Purpose:
To perform a hazard characterization of 1,1-DCPe by evaluating its mutagenicity in the Salmonella assay and its DNA damaging (comet assay) and apoptotic (caspase assay) activities in human lymphoblastoid cells
Description:
1, 1 -Dichloropropene (1,1-DCPe) is a contaminant of some source waters used to make drinking water. Because of this and the fact that no toxicological data were available for this compound, which is structurally similar to the rodent carcinogen 1,3-dichloropropene (1,3DCPe), 1,1-DCPe was placed on the Contaminant Candidate List of the US Environmental Protection Agency. Consequently, we have performed a hazard characterization of 1,1-DCPe by evaluating its mutagenicity in the Salmonella assay and its DNA damaging (comet assay) and apoptotic (caspase assay) activities in human lymphoblastoid cells. In Salmonella, 1,1-DCPe was not mutagenic in strains TA98, TA100, TA1535, or TA104 +/-S9 mix. However, it was clearly mutagenic in strain RSJ100, which expresses the rat GSTTI-1 gene. 1,l-DCPe did not induce DNA damage in GSTTI-I-deficient human lymphoblastoid cells, and it induced apoptosis in these cells only at 5 mM. Consistent with its mutagenesis in RSJ100, 1,1-DCPe reacted with glutathione (GSH) in vitro, suggesting an addition-elimination mechanism to account for the detected GSH conjugate. 1,1-DCPe was~5,000 times more mutagenic than its ethene congener 1,1-dichloroethylene (1,1-DCE or vinylidene chloride). Neither 1,1-DCE nor 1,3-DCPe showed enhanced mutagenicity in strain RSJ100, indicating a lack of activation of these congeners by GSTTI-1. Thus, 1, l-DCPe is a base-substitution mutagen requiring activation by GSTTI-1, possibly involving the production of a reactive episulfonium ion. This bioactivation mechanism of 1,1-DCPe is different from that of its congeners l,l-DCE and 1,3DCPe. The presence of 1,1-DCPe in source waters could pose an ecological or human health risk. Occurrence data for 1,l-DCPe in finished drinking water are needed to estimate human exposure to, and possible health risks from, this mutagenic compound.