title: NTP Toxicology and Carcinogenesis Studies of Chlorinated Water (CAS Nos. 7782-50-5 and 7681-52-9) and Chloraminated Water (CAS No. 10599-90-3) (Deionized and Charcoal-Filtered) in F344/N Rats and B6C3F1 Mice (Drinking Water Studies).
abstract: Chlorine and chloramine are used as disinfectants in water supplies to prevent the spread of waterborne diseases. The U.S. Environmental Protection Agency and the U.S. Congress, through the Safe Drinking Water Acts and Amendments, initiated studies to determine the most effective way to disinfect water supplies and, at the same time, minimize any potential long-term health effects associated with direct chemical exposure or indirect chemical exposure through the formation of byproducts. As part of this evaluation, 2-year studies of chlorinated or chloraminated deionized charcoal-filtered drinking water were conducted in F344/N rats and B6C3F1 mice to determine the potential toxicity and carcinogenicity associated with prolonged exposure and eliminate possible confounding effects of byproducts of chlorination. Chlorinated Water Studies: Water containing 0, 70, 140, or 275 ppm chlorine (based on available atomic chlorine) was provided to groups of 70 F344/N rats or B6C3F1 mice of each sex for up to 2 years. Groups of 10 rats or mice of each sex were predesignated for evaluation at 14 or 15 weeks and 66 weeks. Survival at 2 years of rats and mice receiving chlorinated water was similar to that of the controls. Mean body weights of dosed male rats, high-dose female rats, and dosed mice were slightly lower than those of their respective control groups. There was a dose-related decrease in water consumption by rats and mice. Water consumption by high-dose rats during the second year of the studies was 21% lower than controls for males and 23% lower than controls for females; water consumption by high-dose mice was 31% lower than controls for males and 26% lower than controls for females. The incidence of mononuclear cell leukemia in mid-dose, but not high-dose, female rats was significantly higher than that in controls (control, 8/50; low-dose, 7/50; mid-dose, 19/51; high-dose, 16/50). The proportion of female rats that died of leukemia before the end of the study and the mean time for observation of animals dying with leukemia were similar among all dose groups and controls. Although the marginal increase in leukemia incidence in the mid- and high-dose female rats suggested a possible association with the administration of chlorinated water, the incidence of leukemia was not clearly dose related. There was no indication of reduced latency of leukemia, and the incidence of leukemia in concurrent controls was less than the mean for historical controls; furthermore, there was no supporting evidence of an effect in male rats. Thus, the marginal increase in leukemia incidence in female rats was considered equivocal evidence of carcinogenic activity. There were no neoplasms or nonneoplastic lesions in male rats or in male or female mice that were clearly associated with the consumption of chlorinated water. Chloraminated Water Studies: Water containing 50, 100, or 200 ppm chloramine was provided to groups of 70 F344/N rats or B6C3F1 mice of each sex for up to 2 years. The same control groups were used for the chlorinated water and chloraminated water studies. Groups of 9 or 10 rats or mice of each sex were evaluated at 14 or 15 weeks and 66 weeks. Survival at 2 years of rats and mice receiving chloraminated water was similar to that of the controls. Mean body weights of high-dose rats and dosed mice were lower than those of their respective control groups. There was a dose-related decrease in water consumption by rats and mice. Water consumption during the second year of the studies by high-dose rats was 34% lower than controls for males and 31% lower than controls for females; water consumption by high-dose mice was 42% lower than controls for males and 40% lower than controls for females. Mononuclear cell leukemia occurred with a marginally increased incidence in the mid- and high-dose female rats receiving chloraminated water (control, 8/50; low dose, 11/50; mid dose, 15/50; and high dose, 16/50). As in female rats receiving chlorinated water, the proportion of female rats that died of leukemia before the end of the study and t that died of leukemia before the end of the study and the mean time for observation of animals dying with leukemia were similar among all dose groups and controls. The marginal increase in leukemia incidence in females receiving chloraminated water was considered equivocal evidence of carcinogenic activity for the same reasons given for female rats receiving chlorinated water. There were no neoplasms or nonneoplastic lesions in male rats or in male or female mice that were clearly associated with the consumption of chloraminated water. Conclusions: Under the conditions of these 2-year drinking water studies, there was no evidence of carcinogenic activity of chlorinated water in male F344/N rats receiving 70, 140, or 275 ppm. There was equivocal evidence of carcinogenic activity of chlorinated water in female F344/N rats based on an increase in the incidence of mononuclear cell leukemia. There was no evidence of carcinogenic activity of chlorinated water in male or female B6C3F1 mice receiving 70, 140, or 275 ppm. Under the conditions of these 2-year drinking water studies, there was no evidence of carcinogenic activity of chloraminated water in male F344/N rats receiving 50, 100, or 200 ppm. There was equivocal evidence of carcinogenic activity of chloraminated water in female F344/N rats based on an increase in the incidence of mononuclear cell leukemia. There was no evidence of carcinogenic activity of chloraminated water in male or female B6C3F1 mice receiving 50, 100, or 200 ppm.