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THE COMBINED CARCINOGENIC RISK FOR EXPOSURE TO MIXTURES OF DRINKING WATER DISINFECTION BY-PRODUCTS MAY BE LESS THAN ADDITIVE
Citation:
Hooth, M J., S D. Hester, K McDorman, M H. George, D L. Doerfler, L R. Brooks, A E. Swank, AND D C. Wolf. THE COMBINED CARCINOGENIC RISK FOR EXPOSURE TO MIXTURES OF DRINKING WATER DISINFECTION BY-PRODUCTS MAY BE LESS THAN ADDITIVE. Presented at Society of Toxicologic Pathologists 19th Annual Symposium, Litchfield, AZ, June 25-29, 2000.
Description:
The Combined Carcinogenic Risk for Exposure to Mixtures of Drinking Water Disinfection By-Products May be Less Than Additive
Risk assessment methods for chemical mixtures in drinking water are not well defined. Current default risk assessments for chemical mixtures assume additivity of carcinogenic effects but there is little empirical evidence that this method accurately reflects biological response. We utilized a rodent model of hereditary renal cancer to evaluate the carcinogenicity of mixtues of later disinfection by-products (DBPs). The Eker rat model is characterized by a germline mutation in the Tuberous Sclerosis 2 gene, which predisposes the animals to develop multiple spontaneous renal, splenic, and uterine tumors as early as 4 months of ge. This model provides a powerful quantitative tool to detemline the interaction of chemical mixtures and to determine
if genetically susceptible population is more sensitive to the carcinogenic effects of DBPs. Male and female Eker rats were treated with drinking water renal carcinogens and/or nephrotoxicants individually or in a mixture for an average of 20 land 45 weeks. Potassium bromate (KBrO3), 3-chloro-4-(dichloromet1lyl)-5-hydroxy-2(5H)-furanone (MX), chloroform (CHCI3), and .omodichloromet1lane were adminstered in drinkng water at previously determined noncarcinogenic concentrations of 0.02, 005,0.4, mld 0.07 g/L, respectively and carcinogenic concentrations of 0.4, 0.07,1.8 and 0.7 g/L, respectively. Low and lligh concentration mixture solutions were comprised of all four chemicals at either the non- carcinogenic (low) concentration or the carcinogenic (high) concentration. Body weights, water consumption, and water chemical concentrations were measured monthly. Liver weights were recorded at necropsy and tissues were examined macroscopically for gross lesions. Compared to control animals, uterine masses were increased 2-fold in females treated with either mixture solution for 45 weeks. Splenic masses were inreased 4-fold in male rats treated with 0.02 mld 0.4 g/L I(BrO3 for 45 weeks. Seven adrenal tumors were present in female rats treated with KBrO3 (6/7) and CHCl3 (1/7). Urinary bladder masses were present in 2/14 (14%) of male rats treated with the low concentration mixture solution for 45 weeks. Total renal lesions have been quantitated microscopically in male rats treated for 20 weeks. Treatment of Eker rats with each of the chemicals at its high concentration resulted in a statistically significant increase in preneoplastic lesions compared to controls. Treatment with high concentration CHCl3 or the high concentration lnixttUe resulted a 3-fold increase in total renal lesions. Although MX is not classified as a renal carcinogen in other rat species, a significant response was present in the genetically susceptible Eker rats. The carcinogenic effects of D BPs were not additive, but instead, were similar to the effects of the individual chemical producing the greatest number of lesions. This study provides empirical evidence that the default assumption of additivity may overestimate carcinogenic effects of chemical mixtures in drinking water.
This abstract does not reflect EPA policy.