The mechanisms of action of nongenotoxic carcinogens or tumor promoters have been studied using in vivo models of mouse and rat liver, rat kidney and bladder carcinogenesis and tumor promotion. A mouse liver system with initiation by N- nitrosodiethylamine at 4 weeks of age and exposure to the test agent 1-2 weeks later revealed that tumor promoters could be detected in as short a period as 12 weeks. Butylated hydroxyanisole was shown for the first time to be a potent mouse liver tumor promoter. Acetaminophen, a known human and rodent hepatotoxin, was found not to be carcinogenic for mouse liver but was a weak tumor promoter. In order to understand the role of chronic toxicity and hyperplasia, models were developed to study the role of hyperplasia in carcinogenesis and tumor promotion by nongenotoxic agents. Tritiated thymidine autoradiography and bromodeoxyuridine (BrDU) immunohistochemistry were used to evaluate levels of DNA synthesis in mice exposed to chronic hepatic and renal toxins. The new BrDU method was applied to our studies and was highly successful. Although several nongenotoxic carcinogens or promoters produced a chronic increase in levels of DNA synthesis in target organs, some of these chemicals produced chronic hyperplasia without tumor promotion or carcinogenesis. In vitro models for rat bladder urothelium and renal epithelium are being developed. Rat urothelium responded to urothelial tumor promoters but cyclamate, a noncarcinogen and not a tumor promoter for bladder in vivo, was the most effective hyperplastic agent in vitro. Continuing studies will attempt to define the role of chronic hyperplasia in carcinogenesis and tumor promotion by nongenotoxic agents.
