A MEDIUM-TERM RAT-LIVER BIOASSAY AS A RAPID IN-VIVO TEST FOR CARCINOGENIC POTENTIAL - A HISTORICAL REVIEW OF MODEL DEVELOPMENT AND SUMMARY OF RESULTS FROM 291 TESTS

A bioassay system for rapid detection of carcinogenic agents has been developed using male Fischer 344 rats to bridge the gap between long-t erm carcinogenicity tests and short-term screening assays. The system, called the medium-ten liver bioassay, is fundamentally based on the 2 -stage hypothesis of tumor production, employing initiation by diethyl nitrosamine (200 mg/kg, ip) in the first stage and test chemical admin istration during the second, in combination with two-thirds partial he patectomy. It requires only 8 wk for animal experimentation and a furt her few weeks for quantitative analysis of immunohistochemically demon strated glutathione S-transferase placental form positive hepatic foci . A total of 291 chemicals/substances have already been analyzed in ou r laboratory. Among 63 chemicals that were proved to be carcinogenic i n the liver of rat and/or mouse, 57 (90%) gave Positive results irresp ective of their mutagenicity. Negative compounds include peroxisome pr oliferators and tamoxifen. Even nonhepatocarcinogens were positive at a rate of 24%. Eighty-six percent (12/14) of mouse liver carcinogens w ere also positive. On the other hand, only 2 out of 45 noncarcinogens showed very weak positivity. Thus, the efficacy of the system for hepa tocarcinogens has been well established. This bioassay is increasingly regarded as an appropriate alternative test-for carcinogenicity risk assessment and is practically used for a rapid evaluation of hepatocar cinogenicity of chemicals.