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CARCINOGENICITY OF INDIVIDUAL AND A MIXTURE OF DRINKING WATER DISINFECTION BY-PRODUCTS IN A RAT MODEL OF HEREDITARY RENAL CELL CARCINOMA
Citation:
McDorman, K, M J. Hooth, D L. Doerfler, S D. Hester, AND D C. Wolf. CARCINOGENICITY OF INDIVIDUAL AND A MIXTURE OF DRINKING WATER DISINFECTION BY-PRODUCTS IN A RAT MODEL OF HEREDITARY RENAL CELL CARCINOMA. Presented at Society of Toxicologic Pathologists 19th Annual Symposium, Litchfield Park, Arizona, June 25-29, 2000.
Description:
Carcinogenicity of Individual and a Mixture of Drinking Water Disinfection By-Products in a Rat Model of Hereditary Renal Cell Carcinoma
Eker rats develop hereditary renal cell carcinoma secondary to a germline mutation in the tuberous sclerosis 2 (Tsc2) gene and are lighly susceptible to the effects of renal carcinogens. The utility of this model in studying suspected renal carcinogens is due to an ordered progression of proliferative lesions that can be identified and counted microscopically. Renal epithelial lesions begin as atypical tubules that progress to atypical hyperplasias, adenomas, and often carcinomas. In this study, male and female Eker rats were exposed via drinking water to individual or a mixture of renal carcinogens and/or nephrotoxicants for 20 or 45 weeks. Potassium bromate (KBrO3), 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX), chloroform (CHC13), and bromodichloromethane (BDCM) were administered in drinking water at non-carcinogenic concentrations of 0.02, 0.005, 0.4, and .07 g/L, respectively and carcinogenic concentrations of 0.4, 0.07, 1.8 and 0.7 g/L, respectively. Low and high dose mixture solutions were comprised of all four chemicals at either the non-carcinogenic (low) concentrations or the carcinogenic (high) concentrations, respectively. Following necropsy, each kidney was examined microscopically for preneoplastic and neoplastic lesions. Preneoplastic lesions included atypical tubules (tubules of normal size that contain altered cell types and a visible lumen) and atypical hyperplasias (an aggregation of proliferating altered cells that is solid and does not exceed 3 times the size of the surrounding normal tubules and generally involves only one tubule). After 20 weeks of treatment, all treatment groups produced a significant preneoplastic response driven by increased numbers of preneoplastic lesions (atypical tubules and atypical rperplasias). No significant increases were observed in adenomas or carcinomas. Low and high concentrations of all chemicals and the mixtures produced significant increases in atypical tubules over control. High concentrations of CHC13 and the high dose mixture produced significant increases in atypical hyperplasias over control. The greatest effect in preneoplastic lesions was observed in animals treated with CHC13 and the mixtures. A dose response was present with all treatments at 20 weeks. Treatment with the mixtures produced no more lesions of any type than the individual compound with the greatest effect, indicating a lack of additivity. These data suggest that adding the individual risks for carcinogens exposed through drinking water may over estimate cancer risk of the mixture.
This abstract does not reflect EPA policy.