Lack of promotional effects of groundwater contaminant mixtures on the induction of preneoplastic foci in rat liver

F344 rats were exposed to drinking water mixtures of seven of the most comm on 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 chemical s. The lowest concentrations (1 x) of the individual chemicals were environ mentally realistic and below what would be expected to induce significant s hort-term toxicity. This study was intended to determine if previously repo rted increases in localized hepatocellular proliferation in response to the se chemicals might be correlated with increased risk for hepatocarcinogenes is. Rats were exposed via a drinking water solution to the full seven- chem ical mixture (at 1 x and 10 x concentrations), submixtures of the organic o r inorganic chemicals (at 10 x concentrations), a mixture of TCE, lead, and chloroform (TLC submixture at 10 x and 100 x concentrations), or deionized water as a control. The rats were evaluated for promotion of placental glu tathione-S-transferase (GST-P) positive preneoplastic liver cell foci after diethylnitrosamine (DEN) initiation and partial hepatectomy. Focus formati on, cell proliferation, and apoptosis were evaluated after exposure to DEN or saline controls, the chemical mixtures or deionized water controls, or c ombinations of these treatments. The total number and area of GST-P positiv e foci in DEN-treated rats exposed to the full seven-chemical mixture was i ncreased as compared with the DEN-water controls, but this was statisticall y significant only for total focus area in the 1 x dose group. In DEN-treat ed rats, the inorganic or TLC submixtures resulted in a significant reducti on in number and area of GST-P positive foci. Focus area also was decreased in the organic submixture-treated group, but not significantly. Hepatocell ular proliferation was not significantly changed in the chemical mixture-sa line groups as compared with the mixture-water controls. After DEN treatmen t, however, cell proliferation was significantly decreased after the 10 x s even-chemical and organic mixture treatments and the 100 x TLC mixture trea tment. Different groups showed either increased or decreased apoptotic rate s which did not correlate well with proliferation rates or focus formation. Mixtures of these seven chemicals, therefore, did not appear to act as pro moters of hepatic foci at environmentally relevant concentrations, and some mixture combinations appeared to decrease promotional activity. (C) 1999 E lsevier Science Ireland Ltd. All rights reserved.