title: Analysis of preneoplastic and neoplastic renal lesions in Tsc2 mutant Long-Evans (Eker) rats following exposure to a mixture of drinking water disinfection by-products.
abstract: Disinfection of surface water for human consumption results in the generation of a complex mixture of chemicals in potable water. Cancer risk assessment methodology assumes additivity of carcinogenic effects in the regulation of mixtures. A rodent model of hereditary renal cancer was used to investigate the carcinogenic response to a mixture of drinking water disinfection by-products (DBPs). Rats carrying a mutation in the Tsc2 tumor suppressor gene (Eker rats) readily develop renal preneoplastic and neoplastic lesions, and are highly susceptible to the effects of renal carcinogens. Male and female Eker rats were exposed via drinking water to individual or a mixture of DBPs for 4 or 10 months. Potassium bromate, 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX), chloroform, and bromodichloromethane were administered at low concentrations of 0.02, 0.005, 0.4 and 0.07 g/l, respectively, and high 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 low concentrations or high concentrations, respectively, Following necropsy, each kidney was examined microscopically for preneoplastic lesions (atypical tubules and hyperplasias) and tumors. While some of the mixture responses observed in male rats did fall within the range expected for an additive response, especially at the high dose, predominantly antagonistic effects on renal lesions were observed in response to the low dose mixture in male rats and the high dose mixture in female rats. These data suggest that current default risk assessments assuming additivity may overstate the cancer risk associated with exposure to mixtures of DBPs at low concentrations.
authors.affiliation: Curriculum in Toxicology, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Kevin S
authors.initials: KS
authors.lastname: McDorman
authors.forename: Michelle J
authors.initials: MJ
authors.lastname: Hooth
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Starr
authors.forename: Douglas C
authors.initials: DC
authors.lastname: Wolf
mesh_terms: D000818:Animals; D001959:Bromates / Q000633:toxicity; D015197:Carcinogenicity Tests; D002274:Carcinogens, Environmental / Q000633:toxicity*; D002725:Chloroform / Q000633:toxicity; D004202:Disinfectants / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004326:Drinking; D004357:Drug Synergism; D005260:Female; D005663:Furans / Q000633:toxicity; D016147:Genes, Tumor Suppressor; D007680:Kidney Neoplasms / Q000139:chemically induced* / Q000235:genetics / Q000473:pathology; D008297:Male; D011230:Precancerous Conditions / Q000139:chemically induced* / Q000235:genetics / Q000473:pathology; D051381:Rats; D020318:Rats, Long-Evans; D011922:Rats, Mutant Strains; D012097:Repressor Proteins / Q000235:genetics; D012737:Sex Factors; D013997:Time Factors; D022882:Trihalomethanes / Q000633:toxicity; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D018508:Water Purification / Q000592:standards
chemical_list: D001959:Bromates; D002274:Carcinogens, Environmental; D004202:Disinfectants; D005663:Furans; D012097:Repressor Proteins; C000624653:TSC2 protein, human; D022882:Trihalomethanes; C000624655:Tsc2 protein, rat; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; C019536:potassium bromate; C054121:3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone; C025191:bromodichloromethane; D002725:Chloroform