title: Lack of promotional effects of groundwater contaminant mixtures on the induction of preneoplastic foci in rat liver.
abstract: F344 rats were exposed to drinking water mixtures of seven of the most common groundwater contaminants associated with hazardous waste sites [arsenic, benzene, chloroform, chromium, lead, phenol, and trichloroethylene (TCE)] as the full mixture or submixtures of the organic and/or inorganic chemicals. The lowest concentrations (1x) of the individual chemicals were environmentally realistic and below what would be expected to induce significant short-term toxicity. This study was intended to determine if previously reported increases in localized hepatocellular proliferation in response to these chemicals might be correlated with increased risk for hepatocarcinogenesis. Rats were exposed via a drinking water solution to the full seven- chemical mixture (at 1x and 10x concentrations), submixtures of the organic or inorganic chemicals (at 10x concentrations), a mixture of TCE, lead, and chloroform (TLC submixture at 10x and 100x concentrations), or deionized water as a control. The rats were evaluated for promotion of placental glutathione-S-transferase (GST-P) positive preneoplastic liver cell foci after diethylnitrosamine (DEN) initiation and partial hepatectomy. Focus formation, cell proliferation, and apoptosis were evaluated after exposure to DEN or saline controls, the chemical mixtures or deionized water controls, or combinations of these treatments. The total number and area of GST-P positive foci in DEN-treated rats exposed to the full seven-chemical mixture was increased as compared with the DEN-water controls, but this was statistically significant only for total focus area in the 1x dose group. In DEN-treated rats, the inorganic or TLC submixtures resulted in a significant reduction in number and area of GST-P positive foci. Focus area also was decreased in the organic submixture-treated group, but not significantly. Hepatocellular proliferation was not significantly changed in the chemical mixture saline groups as compared with the mixture water controls. After DEN treatment, however, cell proliferation was significantly decreased after the 10x seven-chemical and organic mixture treatments and the 100x TLC mixture treatment. Different groups showed either increased or decreased apoptotic rates which did not correlate well with proliferation rates or focus formation. Mixtures of these seven chemicals, therefore, did not appear to act as promoters of hepatic foci at environmentally relevant concentrations, and some mixture combinations appeared to decrease promotional activity.
authors.affiliation: Center for Environmental Toxicology and Technology, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins 80523, USA. benjamin@cvmbs.colostate.edu
authors.forename: S A
authors.initials: SA
authors.lastname: Benjamin
authors.forename: R S
authors.initials: RS
authors.lastname: Yang
authors.forename: J D
authors.initials: JD
authors.lastname: Tessari
authors.forename: L W
authors.initials: LW
authors.lastname: Chubb
authors.forename: M D
authors.initials: MD
authors.lastname: Brown
authors.forename: C E
authors.initials: CE
authors.lastname: Dean
authors.forename: T J
authors.initials: TJ
authors.lastname: Keefe
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic; D017209:Apoptosis / Q000187:drug effects; D001681:Biological Assay; D001835:Body Weight / Q000187:drug effects; D001973:Bromodeoxyuridine; D002455:Cell Division / Q000187:drug effects; D008099:Liver / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced* / Q000473:pathology; D008297:Male; D009929:Organ Size / Q000187:drug effects; D011230:Precancerous Conditions / Q000139:chemically induced* / Q000473:pathology; D051381:Rats; D011916:Rats, Inbred F344; D014873:Water Pollutants / Q000633:toxicity*; D014881:Water Supply / Q000032:analysis*
chemical_list: D000964:Antimetabolites, Antineoplastic; D014873:Water Pollutants; D001973:Bromodeoxyuridine