Synergism of Environmental Carcinogens and Promoters on Bladder Cancer Development Initiated by N‐Butyl‐N‐(4‐hydroxybutyl)nitrosamine in F344 Rats

Synergistic or additive effects of combined treatments with carcinogens or promoters on N‐butyl‐N‐(4‐hydroxybutyl)nitrosamine (BBN)‐initiated rat bladder carcinogenesis were examined. Male F344 rats were given BBN as an initiator followed by low doses of 3 sodium salts (sodium bicarbonate, sodium L‐ascorbate and sodium citrate) and/or 3 antioxidants (butylated hydroxyanisole, butylated hydroxytoluene and tertiary butylhydroxyquinone). Combined treatments with 3 sodium salts or 3 antioxidants, and especially all 6 chemicals together promoted bladder carcinogenesis. In addition, these combined treatments were associated with increased DNA synthesis of the bladder epithelium. Combined administration of the carcinogens, o‐anisidine, p‐cresidine, and 4‐chloro‐o‐phenylenedi‐amine at low doses also enhanced BBN‐initiated bladder carcinogenesis. These results indicate that environmental carcinogens or promoters can exert synergistic or additive actions on bladder cancer induction.