Carcinogenicity of the chlorination disinfection by-product MX

3-Chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone, better known by its historical name 'mutagen X' or MX, is a chlorination disinfection byproduct that forms from the reaction of chlorine and humic acids in raw water. MX has been measured in drinking water samples in several countries at levels that ranged from non-detectable to 310 ng/L. Although the concentration of MX in drinking water is typically 100- to 1000-fold lower than other common chlorinated by-products of concern (e.g., trihalomethanes), some have hypothesized that MX might play a role in the increased cancer risks that have been associated with the consumption of chlorinated water. This hypothesis is based on observations that MX, in some test systems, is extremely potent relative to trihalomethanes in inducing DNA damage and altering pathways involved in cell growth, and that in some epidemiological studies increased cancer rates are associated with the bacterial mutagenicity of disinfected water of which MX contributes a significant portion. MX also appears to be more potent than other chlorination by-products in causing cancer in animals. This article reviews the available evidence on the carcinogenicity of MX. MX induced cancer at multiple sites in male and female rats, acted as a tumor initiator and promoter, enhanced tumor yields in genetically modified rodents, induced a myriad of genotoxic effects in numerous in vitro and in vivo test systems, and was a potent inhibitor of gap junction intercellular communication. Although the precise mechanism of MX-induced DNA damage is not known, MX is able to cause DNA damage through an unusual mechanism of ionizing DNA bases due to its extremely high reductive potential. MX may also cause mutations through DNA adduction. This article develops a mean cancer potency estimate for MX of 2.3 (mg/kg-d)(-1) and an upper 95% percentile estimate of 4.5 (mg/kg-d)(-1), and examines the potential health risks posed by this chlorination contaminant in drinking water. A discussion of additional data that would be desirable to better characterize the risks posed by MX and other halogenated hydroxyfuranones follows.