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.

Key words:

• Cancer
• Chlorination by-products
• Drinking Water
• Halogenated Hydroxyfuranones
• MX
• Risk

Acknowledgments

The views expressed by Dr. McDonald do not necessarily represent those of the Office of Environmental Health Hazard Assessment, the California Environmental Protection Agency or the State of California

The authors would like to thank Jorma Mäki-Paakkanen for his careful technical review of the manuscript.

Notes

^a Mean revertants/L water, Salmonella typhimurium strain TA100 (without exogenous activation).

^b Sampling year not provided in report.

^c Lowland (i.e., downstream): water that often receives industrial and domestic waste effluent. Upland (i.e, upstream): more pristine water.

^a Significantly different from control animals by pair-wise Fisher Exact Test, p ≤ 0.05.

^b Significantly different from control animals by pair-wise Fisher Exact Test, p ≤ 0.01.

^c Significantly different from control animals by pair-wise Fisher Exact Test, p ≤ 0.001.

^d Results of exact trend test [61].

^e Significant by one-sided trend test [62], as used by the original study authors.

^a Significantly different from control animals by pair-wise Fisher exact test, p ≤ 0.05.

^b Significantly different from control animals by pair-wise Fisher exact test, p ≤ 0.01.

^c Significantly different from control animals by pair-wise Fisher exact test, p ≤ 0.001.

^d Results of exact trend test [61].

^e Significant by one-sided trend test [62], as used by the original study authors.

^a Statistically different from controls, p < 0.05.

^a Holme et al. (1999) observed dose-related DNA damage (as measured by alkaline elution method) in the liver and kidney when mice were pretreated with DNA repair enzyme inhibitors, but not without pretreatment.

^b An increased net nuclear grain count was observed three hours after administration of MX, which is usually considered a positive finding. However, the authors did not conclude that this increase represented a positive finding since the effect was not strong and the increase was not observed 16 hours after dosing (see text).

^a Levels of MX in drinking water vary and are shown in Table 1. Data comparing concentrations of CMCF, MCF and MCA to MX (47 ng/l) come from Smeds [6]. Data comparing concentrations of MX to brominated analogues of MX (BMX) come from water samples from three cities, one with a high naturally occurring bromide levels (↓Br⁻) and two with low bromide concentrations (↑ Br⁻) [48].

^b Relative potency in bacteria without exogenous activation: [(revertants/μg CMCF, MCF MCA or BMX)/(revertants/μg MX)] [7, 43, 55, 147].

^c Relative potency in mamalian cells: [(μMlowest MX)/(μMlowest CMCF, MCF or MCA)] [115].

^a YG7119, YG112 and YG7113 are derivatives of Salmonella typhimurium tester strain TA100 which contain different inactivating deletions in the genes encoding the DNA repair enzyme, O ⁶-methylguanine DNA methyltransferase.

^aCancer potency estimates shown for the linearized multistage model shown in the table employed interspecies scaling based on the ¾-power of body weight in order to better compare with the benchmark dose methodology. Use of surface area scaling [20] increases the cancer potency estimates shown here by a factor of 1.29 for females and 1.51 for males.

^bFor all tumor sites, the quantal-linear model was the best fitting model.

^cDerived using Monte Carlo techniques (see text). Since the male and female cancer potency estimates were similar, an average estimate of 4.5 (mg/kg-d)⁻¹ was derived.