ES&T
FEATURE Health effects of drinking water disinfectants and disinfectant by-products Not enough is known about the various disinfectants to assess relative health risks
Richard J. Bull Health Effects Research Laboratory U.S. Environmental Protection Agency Cincinnati, Ohio 45268 For drinking water disinfection, the alternatives to chlorine that have been considered most often are chlorine dioxide, ozone, chloramines, UV irradiation, iodination, or some combination of these. The first three have been given the greatest attention because they are effective, relatively inexpensive, and easy to use. In addition to concern over the organic by-products, it has now become clear that some of these chemicals or associated inorganic by-products possess toxic properties of their own. It is probable that no other public health issue affects a larger proportion of the U.S. population than drinking water disinfection. Proper consideration of the alternatives requires assessing the toxicological hazards of both the disinfectants and their byproducts. Final decisions involve weighing acute toxicological hazards against chronic toxicities. Both types of effects have to be considered along with the probability of carcinogenic hazards. This article attempts to review the status of these problems, to discuss some of the more recent data bearing on the issue, and finally to identify those data gaps that currently prevent a clear resolution of this problem. Toxicology of disinfectants Prior to 1976, toxicological information relevant to drinking water disinfection was virtually nonexistent. Chlorine (technically a mixture of 554A
Environ. Sci. Technol., Vol. 16, No. 10, 1982
Drinking water being double aerated to remove volatile -
HOC1 and O C 1 , depending upon pH) has received virtually no study: Common use has put it into a category generally regarded as safe. The reduction product of chlorine is C l _ , which is of no toxicological importance at the levels resulting from drinking water disinfection. Chlorine dioxide (CIO2) has been studied in recent years and has toxicological properties of concern that will be discussed. Ad-
contaminants
ditionally, when used as a disinfectant, C10 2 produces a substantial amount of chlorite (ClO^") either as a precursor or product. CIO2" presents an acute toxicological hazard. There is some evidence that combined chlorine or chloramine (C1 X NH«) is also acutely hazardous and that it has a potential for causing chronic toxic effects. Ozone will not be considered in this article because it is not stable in water.
This article not subject to U.S. Copyright. Published 1982 American Chemical Society
and after ozone treatment, no residual following administration of CIO2 is inorganic products of toxicological significant because ClOj has been concern usually remain in the water. shown to be capable of oxidizing heThe absence of systematic toxico- moglobin to a nonfunctional pigment, logical data about chlorine is a major methemoglobin, a condition known as gap in the presently available infor- methemoglobinemia (4). More recent mation. The only long-term study of studies utilizing CIO2" administered in chlorine toxicity is that of Druckrey, drinking water have revealed that hewhich indicates no harmful effects molytic anemia is produced at much from drinking water containing 100 lower levels of CIOJ than those remg/L of chlorine provided to rats over quired to produce methemoglobinemia. Although mild in character, seven generations (1 ) . It is generally believed that the relatively clear indications of hemolonger the body takes to excrete a lytic anemia are observed in rats rechemical, the greater the potential for ceiving drinking water containing 100 toxic effects; excretion times are de- mg/L of ClOj" (5). termined with metabolic studies. More However, subclinical effects (effects recent work has concentrated on the not associated with overt diseases such 36 metabolism of HOC1 using C1 as a as depleted glutathione and elevated tracer. These studies show that within 2,3-diphosphoglycerate) consistently 72 h, less than 30% of the orally ad- result from water containing ClOj at ministered dose is excreted in urine concentrations of 50 mg/L (5) and and feces (2). Similar experiments sometimes at concentrations as low as using 36C1 as a tracer in CI0 2 , ClOï, 10 mg/L (2, 6). Both C10 2 and ClOj and CIO3" indicate that 40% or more of produce depressions of red-cell glutathe material is lost in the same time thione concentrations, but these ininterval. Additionally, with 36C1 as a duced-decreases tend to disappear with tracer, HOC1 is found to have a greater continued exposure, while the ClOj tendency to concentrate in the bone induced decreases in red-cell glutamarrow than do the other three thione concentrations are stable (7). chemicals, and the half-life for elimi- These results have also been seen in nation of HOC1 from plasma is 77 h vs. monkeys, mice, and cats (8, 9). At the 35 h for C10 2 , CIO2, and ClCv relatively low levels found in drinking Clear interpretation of these results water, such effects have not been obrequires similar studies of the phar- served, except possibly in one suscepmacokinetics of 36 C1~ since the chlo- tible person with a deficiency of gludehydrogenase ride ion (CI - ) is a major by-product cose-6-phosphate and a natural constituent of the body. (10). Nevertheless, it can be concluded that The mechanism involved in the hethe body handles HOC1 quite differ- molytic activity of C10 2 and its derivently from the way it handles CIO2, atives appears to involve the in vivo ClOï, and ClOf. The longer half-life production of hydrogen peroxide (5, of HOC1 suggests that it may become / / , 12), a mechanism that is common more closely associated with cellular to most oxidants that cause hemolytic components. The toxicological signif- anemia (13-15). The creation of hyicance of this data is not yet known. drogen peroxide by C10 2 , ClOj, and When administered by stomach ClO^ raises the possibility that HOC1 tube to rats, chlorine dioxide is ap- is generated through the activation of parently absorbed primarily as Cl _ myeloperoxidase, an enzyme which and CIOj (3). Experiments designed to catalyzes the formation of HOC1 from partition C10 2 , CIO2, ClO^, and Cl" hydrogen peroxide and Cl~ (16). The indicate that 3-4% of the orally ad- long-term consequences of this process ministered dose of 36C1C>2 is recovered of producing halogenated chemicals in as CIOJ in the urine over a 72-h peri- vivo has yet to be thoroughly investiod. The major urinary metabolite of gated. either C10 2 , C10i\ or ClO^ found in Chlorine dioxide does appear to the urine over this period, however, is possess activity as an antithyroid Cl~, accounting for 20-30% of the agent, a property it does not share with orally administered dose. A critical ClOj" or ClOj (17). In African green question is: Where in the body do monkeys, this effect is seen as a deC102,C102",and ClO^ become reduced pression of serum thyroxine levels to CI - ? The oxidative damage done to following four weeks of exposure to various cells will be described. CIO2 at a concentration of 100 mg/L The presence of CIO2 systemically (about 9 mg C102/kg body weight/d). The perchlorate ion is known to produce goiter and is obviously related to This paper is reproduced from "Water Chlorination: Environmental Impact and Health Effects," Vol. 4, C10 2 (18). The extreme lability of edited by R. L. Jolley (Proceedings of the 4th Water C10 2 in the gastrointestinal tract raises Chlorination Conference al Asilomar, Calif., 1982), with permission of Ann Arbor Science Publishers. some interesting issues as to the po-
tential mechanisms involved in this effect (17). When 36CI is used as a tracer, the kinetics of C102 absorption are found to be much more rapid than those observed with the other chlorine compounds including ClOj (2). This evidence suggests the possibility that some product of CIO2, which is formed very rapidly in situ, could be responsible for the antithyroid effect. This is being investigated at our laboratory in Cincinnati. There are relatively few studies of the effects of the alternate disinfectants or their by-products on other target organs. Abdel-Rahman et al. examined the effects of C10 2 and ClOj on the turnover of cells in the gastrointestinal tract (2). At CIO2 and ClOj levels of 10 mg/L, there was evidence of increased cell turnover as measured by 3H-thymidine incorporation. Large changes in DNA synthesis are associated with cell division, and thymidine is a base used exclusively in DNA synthesis (as opposed to RNA synthesis). Therefore, increases in 3 H-thymidine incorporation indicate a higher rate of cell division. Thus, even these low doses of CIO2 and ClOj appear to cause some minimal level of cell killing and regeneration. In contrast to findings concerning the gastrointestinal tract, ^ - t h y m i dine incorporation into the testes is inhibited by ClOj at concentrations of 10 and 100 mg/L in drinking water (2). Since a large portion of the DNA synthesis that occurs in the testes is associated with the production of sperm, these data suggest the possibility that CIO2" depresses spermatogenesis. Obviously, this effect requires further study. The use of chloramine in drinking water disinfection has been associated with the production of methemoglobin in dialysis patients (19). However, methemoglobinemia and other hematologic effects have not been observed in experimental animals exposed to chloramine by the oral route (17,20). A final cause for concern with chloramines is evidence that monochloramine is mutagenic in B. subtilis, a bacterium used for mutagenesis testing (/). For this reason, the National Toxicology Program (NTP) is investigating the possibility that monochloramine is a carcinogen in mice and rats. Toxicology of by-products The problem of disinfection byproducts must be discussed in two parts. First, there are the established by-products of disinfection, such as the trihalomethanes, which are created Environ. Sci. Technol., Vol. 16, No. 10, 1982
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from reactions between background organic chemicals and chlorine. Sec ond, a vast group of oxidation and chlorination products can result from the production of new functional groups in the background organic material present in the source water. This results in biological activity in fractions of organic material isolated from water that is distinct from the activity associated with the identified products of disinfection (21-23, 24). Identified by-products. Of the known products of disinfection, those formed by chlorination have been studied most extensively. The trihalo methanes (THMs) began to receive a great deal of attention after it was learned that chloroform is carcino genic in both mice and rats (25). The other trihalomethanes that occur with a high degree of regularity—bromoform, dibromochloromethane, and dichlorobromomethane—are being examined in the NTP carcinogenesis bioassay program. In the meantime, a variety of mechanistic questions have been raised concerning the way in which chloro form causes cancer. The basic argu ment is whether chloroform-induced tumors are produced when chloroform interacts with genetic material of the target cell or whether chloroform acts through an epigenetic mechanism. In other words, is chloroform an initiator or a promoter? Tumor initiators are chemicals that produce an irreversible change in a cell characteristic that is generally believed to involve alteration of cellular DNA. Because the effects of tumor initiators are irreversible, they are commonly believed to act by nonthreshold mechanisms. (That is, any dose of such a chemical possesses a fi nite probability of causing cancer, al though this probability always de creases with decreased exposure.) Tumor promoters are chemicals that can increase the likelihood that an in itiated cell will develop into a tumor. To promote permanent damage, however, continuous exposure to such chemicals is often necessary. There fore, the effects of such chemicals are felt to be reversible and to result from mechanisms that have definite thresholds. One type of mechanism by which such chemicals act is to produce obvious damage to an organ such as the liver. The resulting hyperplastic response to such damage—that is, the stimulation of cell division—can pro mote the development of tumors in the organ. Clarifying the argument about whether chloroform is an initiator or a promoter could significantly affect the level at which it is regulated in drink ing water (26). 556A
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TABLE 1
Liver fat content and pathology in B6C3Fi mice treated with chloroform in drinking water Percent liver f a t a 90 d 6 180 d
Chloroform (mg/L)
b
Number of animals with centrilobular fatty change 30 d 60 d 80 d
a
Total
0
0
0
0
0
0
0
0
6.77
3
0
0
3
—
0
0
0
0
4.51"
7.11c
2
0
0
2
1800
6.36d
10.40"
5
0
4
9
2700
—-
—
6
5
2
13
0
3.33
5.82
200
3.45
7.93
3.89 "
—
900
400 600
:
c
" Average value for 10 animals at each dose and time. 6 Duration of exposure to chloroform at the indicated concentrations. c Statistically significant from control at Ρ
