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EDITORIALS
Water Chlorination, 3-Chloro-4-(dichloromethyl)-5hydroxy-2(5H)-furanone (MX),
and Potential Cancer Risk
Ronald L. Melnick, Gary A. Boorman, Vicki Dellarco*
The article by Komulainen et al. (1) in this issue of the
Journal reports results of a study that raises potential public
health concerns. The authors administered 3-chloro-4(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX) in drinking
water to rats for 2 years and found carcinogenic effects at multiple sites in both sexes. In particular, there were high incidences
of thyroid gland tumors and liver tumors (cholangiomas, which
are epithelial cell tumors of the bile duct) in treated animals.
This study is important because MX is a potent mutagenic
chemical formed as a byproduct of water chlorination. The significance of these findings needs to be considered in the context
of potential exposure to MX.
Water chlorination is one of the major disease prevention
achievements of the 20th century. Chlorine was first introduced
into urban water supplies in the United States in the early 1900s
to reduce bacterial counts. Disinfection of drinking water by
chlorination has become the principal means of effectively reducing water-borne enteric diseases, such as typhoid fever, cholera, and dysentery. However, chlorine may react with humic
substances in water, producing large numbers of halogenated
organic byproducts. These byproducts include the chlorinated
and brominated trihalomethanes (e.g., chloroform or bromodichloromethane) and haloacetic acids, which are the most frequently and abundantly found disinfection byproducts, as well as
MX, which has been measured at much lower concentrations.
What is the appropriate response to the findings that MX
causes cancer in experimental animals? Certainly, we expect our
drinking water to be clean and safe for public consumption.
Stopping water chlorination in the absence of an equally effective disinfection program is not a sensible choice. This approach
was unfortunately tried in Peru with devastating results (2); a
cholera epidemic involving 300 000 cases occurred as a consequence of inadequate or no disinfection of drinking water supplies. At the other extreme, ignoring the findings of Komulainen
et al. is also not prudent. Animal studies have frequently identified chemicals that have later been shown to be human carcinogens.
A more reasonable consideration may be possible by exploring the potential health risks imposed by MX in comparison to
the health risks of other disinfection byproducts. MX is not the
first chlorination disinfection byproduct shown to cause cancer
in laboratory animals. The trihalomethanes have also been
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EDITORIALS
shown to be carcinogenic in rats and mice (3). In 1979, the U.S.
Environmental Protection Agency (EPA) (4) set a maximum
contaminant level (MCL) for trihalomethanes in drinking water
in the United States at 100 parts per billion (ppb). In 1994, the
EPA proposed an MCL of 80 ppb for trihalomethanes and an
MCL of 60 ppb for five haloacetic acids (5). There are other
disinfectants used in the United States, including chlorine dioxide, chloramines, and ozone, that result in a different spectrum of
disinfection byproducts. Before changing one disinfectant process for another, it should be demonstrated that the alternative
process is equally or more effective in reducing pathogenic organisms and that any risks associated with byproducts of the new
process are lower than those of the current process under the
given water source conditions.
The potential risk from MX in drinking water, as well as the
potential risks of water disinfection byproducts that are considered in EPA’s drinking water regulations, must be weighed
against the benefits of chlorination as a proven disease prevention strategy. It is informative to compare MX with chloroform,
a drinking water disinfection byproduct that has been shown to
be carcinogenic in rodents. Estimates of human risks by use of
animal data are based on estimates of cancer potency, extrapolation models, and estimates of human exposure. One of the
most pronounced carcinogenic effects reported in the MX study
was the induction of cholangiomas in the liver of female rats.
These tumor incidences were fit to a linearized, multistage
model to provide a preliminary estimate of the cancer potency of
MX; estimates with the use of the thyroid tumor data were not
performed because combined incidences of follicular cell adenomas and carcinomas were not provided. A similar low-dose
extrapolation model had been used to estimate cancer potencies
of chloroform and other trihalomethanes. The upper-bound cancer risk per unit dose for lifetime exposure to MX based on
induction of cholangiomas was estimated to be 100% per mg
MX per kg body weight per day, whereas the estimated drinking
*Affiliations of authors: R. L. Melnick, G. A. Boorman, National Institute of
Environmental Health Sciences, Research Triangle Park, NC; V. Dellarco, Office of Water, U.S. Environmental Protection Agency, Washington, DC.
Correspondence to: Ronald L. Melnick, Ph.D., P.O. Box 12233, National
Institute of Environmental Health Sciences, Research Triangle Park, NC 27709.
See ‘‘Note’’ following ‘‘References.’’
© Oxford University Press
Journal of the National Cancer Institute, Vol. 89, No. 12, June 18, 1997
water upper-bound unit cancer risk for chloroform based on
induction of kidney tumors in rats is 0.6% per mg/kg per day,
and the upper-bound unit cancer risk for bromodichloromethane
based on induction of kidney tumors in mice is 6% per mg/kg
per day. Thus, it would appear that the cancer potency of MX is
approximately 170 times greater than that of chloroform and 17
times greater than that of bromodichloromethane when estimated by similar methods on a weight basis.
The cancer potency estimates described above are based on
the assumptions that laboratory animals and humans absorb,
metabolize, and eliminate MX similarly and have similar sensitivities to this agent, that the mechanisms that caused tumors in
rats operate in humans at ambient exposures, and that a linear
extrapolation model is appropriate for estimating low-dose risk.
Currently, there is no information that would indicate that these
assumptions are inappropriate.
Exposure is also critical in characterizing risks of MX and in
comparing those of other hazardous agents. EPA’s current MCL
for trihalomethanes in drinking water is 100 ppb, whereas levels
of MX have been reported to range from 3 to 67 parts per trillion
(ppt) in the United States or Finland. Occurrence data on MX are
limited, and there is a need for better estimates of MX concentrations in U.S. drinking water supplies. Based on the highest
reported level for MX (67 ppt), human daily exposures would be
several orders of magnitude lower than those in the study by
Komulainen et al. (1), and water concentrations of trihalomethanes may be more than 1000 times larger than those of MX. The
combination of cancer potency and exposure indicates that potential risks for MX may be about one-tenth those for the trihalomethanes. If one assumes that the extrapolation described
above is appropriate, the estimated upper-bound excess cancer
risk for lifetime consumption of water containing MX at a concentration of 67 ppt is two in one million; at lower water concentrations of MX, cancer risks would be proportionally reduced.
Other classes of chemicals also contribute to the overall cancer risks associated with chlorination or other disinfection processes, and a better understanding of their risks will be essential
in the consideration of alternative water treatment strategies. The
additional risk resulting from low levels of MX, although low
relative to that of the trihalomethanes, should not be disregarded
inasmuch as nearly 200 million people in the United States
Journal of the National Cancer Institute, Vol. 89, No. 12, June 18, 1997
consume water that has been disinfected by chlorination. In response to the Safe Drinking Water Act Amendments of 1996,
the EPA is evaluating microbial risks and chemical risks for the
various disinfection processes that are used to treat drinking
water. From the standpoint of microbial risks, there is increasing
concern about the resistance of cryptosporidia cysts to the various disinfection processes, while from the chemical risk perspective, other families of chemicals in drinking water (e.g.,
haloacetic acids and bromates) have also been shown to cause
cancer in laboratory animals. The EPA is exploring methods for
reducing disinfection byproduct formation by either removing
precursors (e.g., total organic carbon) prior to chlorination or
using alternative disinfectants. Any policy decisions on water
disinfection processes in the United States must be based on
sound science with full considerations of engineering, water
chemistry, exposure assessment, toxicology, mechanism of action, and health risks. In the interest of public health, the benefits
and risks of alternative approaches must be adequately examined
so as to ensure the safest water supplies possible. The article by
Komulainen et al. is an important contribution to this evaluation.
References
(1) Komulainen H, Kosma VM, Vaittinen SL, Vartiainen T, Kaliste-Korhonen
E, Lotjonen S, et al. Carcinogenicity of the drinking water mutagen 3-chloro4-(dichloromethyl)-5-hydroxy-2(5H)-furanone in the rat. J Natl Cancer Inst
1997;89:848-56.
(2) Salazar-Lindo E, Alegre M, Rodrı́guez M, Carrión P, Razzeto N. The Peruvian cholera epidemic and the role of chlorination in its control and prevention. In: Craun GF, editor. Safety of water disinfection: balancing chemical and microbial risks. Washington (DC): ILSI Press, 1993:401-13.
(3) Dunnick JK, Melnick RL. Assessment of the carcinogenic potential of chlorinated water: experimental studies of chlorine, chloramine, and trihalomethanes. J Natl Cancer Inst 1993;85:817-22.
(4) US Environmental Protection Agency. Part III. Environmental Protection
Agency. National interim primary drinking water regulations: control of
trihalomethanes in drinking water; final rule. Federal Register November 29,
1979;44:68624-707.
(5) US Environmental Protection Agency. Part II. Environmental Protection
Agency. National primary drinking water regulations: disinfectants and disinfection by-products; proposed rule. Federal Register July 29, 1994;59:
38668-829.
Note
We thank Jennifer Jinot (U.S. Environmental Protection Agency) for providing the cancer potency estimate for MX.
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