1,4-Dioxane is a widely used synthetic industrial chemical and its contamination of
drinking water and food is a potential health concern. It induces liver
tumors when administered in the
drinking water to rats and mice. However, the mode of action (MOA) of the hepatocarcinogenicity of
1,4-dioxane remains unclear. Importantly, it is unknown if
1,4-dioxane is genotoxic, a key consideration for risk assessment. To determine the in vivo mutagenicity of
1,4-dioxane, gpt delta transgenic F344 rats were administered
1,4-dioxane at various doses in the
drinking water for 16 weeks. The overall mutation frequency (MF) and A:T- to -G:C transitions and A:T- to -T:A transversions in the gpt transgene were significantly increased by administration of 5000 ppm
1,4-dioxane. A:T- to -T:A transversions were also significantly increased by administration of 1000 ppm
1,4-dioxane. Furthermore, the
DNA repair enzyme MGMT was significantly induced at 5000 ppm
1,4-dioxane, implying that extensive genetic damage exceeded the repair capacity of the cells in the liver and consequently led to liver
carcinogenesis. No evidence supporting other MOAs, including induction of oxidative stress, cytotoxicity, or
nuclear receptor activation, that could contribute to the carcinogenic effects of
1,4-dioxane were found. These findings demonstrate that
1,4-dioxane is a genotoxic hepatocarcinogen and induces hepatocarcinogenesis through a mutagenic MOA in rats. Because our data indicate that
1,4-dioxane is a genotoxic
carcinogen, we estimated the point of departure of the mutagenicity and carcinogenicity of
1,4-dioxane using the no-observed effect-level approach and the Benchmark dose approach to characterize its dose-response relationship at low doses.