Superfund Research Program
Activation of PCBs to Genotoxins in vivo
Project Leader: Larry W. Robertson (University of Iowa)
Grant Number: P42ES007380
Funding Period: 1997 - 2005
Final Progress Reports
Year: 2004 1999
Metabolic activation of a PCB (4-chlorobiphenyl) to an initiating carcinogen was studied in rats. In animal models PCB commercial mixtures are complete carcinogens, while in two-stage hepatocarcinogenesis both commercial PCB mixtures as well as individual congeners have activity as promoters. Dr. Robertson’s team has recently reported that several mono- to tetra-chlorinated biphenyls have initiating activity in the livers of Fischer 344 rats. Subsequently, they investigated the metabolic activation of one of those compounds, 4-chlorobiphenyl. Using decreasing doses, mono-hydroxy, di-hydroxy and quinone metabolites of 4-chlorobiphenyl were evaluated for their initiating activity in Fischer 344 male rats. Livers were evaluated for changes in morphology, and the number and volume of enzyme-altered foci (preneoplastic lesions). Of the metabolites tested, one mono-hydroxy and one quinoid metabolite showed initiating activity. The metabolic activation of 4-chlorobiphenyl therefore proceeds via para hydroxylation and oxidation to the ortho-(3,4)-quinone, the ultimate carcinogen. This is the first report of the metabolic activation of a PCB to a proximate and an ultimate carcinogen.