1,4-Dioxane is not mutagenic in five in vitro assays and mouse peripheral blood micronucleus assay, but is in mouse liver micronucleus assay.
1,4-Dioxane, an animal carcinogen, was not previously genotoxic in in vitro assays. We reevaluated the compound's genotoxic potential in five in vitro genotoxicity tests in the presence and absence of S9 mix using recommended new protocols. We used the bacterial reverse mutation assay with Salmonella TA and E. coli WP2 strains, including the plate and preincubation methods, the CHO chromosomal aberration assay, including examination of polyploid induction and extended sampling time, the CHO sister-chromatid exchange assay with short and long treatment time, the mouse lymphoma tk assay (microtiter method), including longer treatment time (24 hr), and the CHO micronucleus assay with short and long treatment times. The highest concentration we used was five mg/ml or plate. We also evaluated the genotoxic effect of 1,4-dioxane in vivo by conducting peripheral blood and liver micronucleus assays in the same mice after single oral administration of up to 3,000 mg/kg. All in vitro assays and the peripheral blood micronucleus assay were negative. The mouse liver micronucleus assay, on the other hand, was positive, indicating that 1,4-dioxane might be genotoxic. It is also conceivable that the positive result in mouse liver micronucleus assay was due to a nongenotoxic mechanism, i.e., errors in genetic repair following enhancement of hepatocyte proliferation.
Morita
T
T
Tsukuba Research Laboratories, Nippon Glaxo Ltd., Ibaraki, Japan. tm28417@glaxowellcome.co.uk
Hayashi
M
M
D000818:Animals; D001711:Biotransformation; D016466:CHO Cells; D006224:Cricetinae; D004146:Dioxanes / Q000633:toxicity*; D004926:Escherichia coli / Q000235:genetics; D006498:Hepatectomy; D008099:Liver / Q000648:ultrastructure; D051379:Mice; D015162:Micronucleus Tests / Q000379:methods*; D009152:Mutagenicity Tests; D009153:Mutagens / Q000633:toxicity*; D012475:Salmonella / Q000235:genetics; D012854:Sister Chromatid Exchange
D004146:Dioxanes; D009153:Mutagens; C025223:1,4-dioxane