Enhancing effect of butylated hydroxytoluene on the development of liver altered foci and neoplasms induced by N-2-fluorenylacetamide in rats

The enhancement of hepatocarcinogenesis by butylated hydroxytoluene (BHT) in comparison with that by phenobarbital (PB) was studied by quantifying their effects on N-2-fluorenylacetamide (FAA)-induced preneoplastic and neoplastic rat-liver lesions. Hepatocellular altered foci identified by iron exclusion and gamma-glutamyltranspeptidase (GGT) activity were induced by feeding 0.02% FAA for 8 wk. Subsequently, BHT was fed at concentrations of 300, 1000, 3000 or 6000 ppm for up to 22 wk after cessation of FAA exposure; PB was fed at concentrations of 316 or 500 ppm for comparison. The lower doses of BHT (300, 1000 and 3000 ppm) did not exert a significant effect on either foci development or the final yield of neoplasms. At 6000 ppm, BHT increased the number of foci, the area occupied by GGT-positive preneoplastic and neoplastic lesions and the neoplasm incidence, as did 316 and 500 ppm PB. Comparison of the effects of BHT and PB at equimolar concentrations revealed that BHT was a much weaker enhancer of liver carcinogenesis. Apparently, the effective dose range of BHT as an enhancer is rather restricted. On the basis of available evidence that BHT is nongenotoxic and exerts epigenetic effects, we conclude that BHT is a weak promoter of liver carcinogenesis.