Carcinogenicity of the Drinking Water Mutagen 3-Chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone in the Rat

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Abstract
Background: Several epidemiologic studies have suggested that the consumption of chlorinated drinking water may be associated with the development of certain cancers in humans. 3-Chloro-4-(dichloromethyl)-5-hydroxy-2( 5H )- furanone (MX), a byproduct of the chemical reactions that occur in chlorinated drinking water, has been found to be mutagenic in bacteria and mammalian cells; however, its potential to cause tumors in animals has not been tested previously. Purpose: The objective of this study was to evaluate the carcinogenicity of MX in rats given MX in their drinking water. Methods: MX was administered to male and female Wistar rats (50 rats per dose group) in drinking water for 104 weeks at concentrations yielding the average daily doses of MX of 0.4 mg/kg of animal weight (low dose), 1.3 mg/kg (mid dose), and 5.0 mg/kg (high dose) for males and 0.6 mg/kg, 1.9 mg/kg, and 6.6 mg/kg for females, respectively. Control rats received water from the same source used for preparation of the MX dose formulations (after its adjustment to the same pH range). Body weight, clinical signs, and food and water consumption were recorded regularly. At the end of the treatment period, the animals were killed and full histopathologic analysis was performed on 47 tissues and all lesions. Results: Dose-dependent increases in tumor incidence were observed in rats given MX-containing drinking water; the same MX doses had no obvious toxic effects on animals. MX consumption increased most drastically the prevalence of follicular adenoma (up to 43% and 72% in high-dose males and females, a test [one-sided] for positive trend in all dose groups P = .0045 and P = .0000, respectively) and carcinoma (55% [P = .0000] and 44% [P = .0000], respectively) in thyroid glands and cholangioma in the liver (8% [ P = .0009] and 66% [ P = .0000] in the high-dose males and females, respectively). Among rats given the higher doses of MX in their drinking water, cortical adenomas of the adrenal glands were increased in both sexes, alveolar and bronchiolar adenomas of the lungs and Langerhans' cell adenomas of the pancreas were increased in males, and lymphomas, leukemias, and adenocarcinomas and fibroadenomas of the mammary glands were increased in females. Even the lowest MX dose studied was carcinogenic. Conclusion: MX is a potent carcinogen in both male and female rats, and it causes tumors at doses that are not overtly toxic to rats. Implications: Although these findings cannot be extrapolated to humans, MX should be studied as a candidate risk factor in the possible association between consumption of chlorinated drinking water and cancer in humans.

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