A Medium-Term, Rapid Rat Bioassay Model for the Detection of Carcinogenic Potential of Chemicals

Abstract

The Ito Liver Model and the Ito Multi-organ Model are used in conjunction and constitute an efficient and rapid bioassay for the identification of both genotoxic and nongenotoxic carcinogenic chemicals. The Ito Liver Model is an 8-week bioassay system that uses the number and size of foci of hepatocytes positive for glutathione S-transferase placental form (GST-P) as the end-point marker. One hundred fifty-nine compounds were tested using the Ito Liver Model: 61 of 66 hepatocarcinogens tested positive, and 10 of 43 nonliver carcinogens were also positive. The false-positive detection of noncarcinogens was low; a single false-positive result was obtained from the 50 noncarcinogens tested. Since more than half of all known carcinogens are hepatocarcinogens in rodents, the initial 8-week bioassay is able to detect most carcinogens. The Ito Multi-organ Model is a 28-week bioassay system for the detection of carcinogens that were not identified by the Ito Liver Model. Results are evaluated by preneoplastic and neoplastic lesions in major organs. Forty-four compounds were tested using the Ito Multi-organ Model: 17 out of 17 liver carcinogens were positive, and 19 out of 22 (86%) nonliver carcinogens were positive. None of the five noncarcinogens tested positive.

Cleistocalyx nervosum Extract Ameliorates Chemical-Induced Oxidative Stress in Early Stages of Rat Hepatocarcinogenesis

“…The hepatic GST-P positive foci, a preneoplastic lesion of rat hepatocarcinogenesis in diethylnitrosamine initiated rats, are commonly detected approximately 4 weeks after a single injection (Tsuda et al, 2010). Repeated exposures to overdoses of phenobarbital, a classical non-genotoxic carcinogen in rodents, could accelerate tumor promotion by CYP2B1 mediating reactive oxygen species (Kinoshita et al, 2002;Imaoka et al, 2004;Puatanachokchai, Kakuni et al, 2006).…”

Comparative Histomorphological Review of Rat and Human Hepatocellular Proliferative Lesions

“…The significance of hepatic neoplastic findings in animal models has been questioned with regard to their predictive value, as humans appear resistant to many agents that readily produce liver tumors in rodents 46 . As toxicity to the liver is reported to be the second most frequent cause of drug failure due to adverse effects in clinical trials of potential drugs 15 , 47 , 48 , the early detection and interpretation of proliferative lesions as well as nonproliferative hepatic lesions is of vital importance. One of the safety issues after long-term administration of a xenobiotic is carcinogenicity assessment, and both early and late proliferative liver lesions might be indicative of potential hepatocarcinogenesis or carcinogenesis at other sites in humans 1 , 16 , 37 , 49 , 50 , 51 , 52 , 53 , 54 .…”

“…The rodent experimental model is used to identify potential human carcinogenic risk from exposure to drugs, environmental agents, and other xenobiotics. Rat hepatocellular adenomas (HCAs) and carcinomas are commonly used in tumor response and carcinogenicity bioassays and share some common features with human adenomas and carcinomas 15 .…”

Cancer Chemopreventive Effect of Spirogyra Neglecta (Hassall) Kützing on Diethylnitrosamine-Induced Hepatocarcinogenesis in Rats

“…These foci have been recognized as reliable and sensitive markers for identifying preneoplastic lesions in the liver. Thus, the number and size of the GST-P positive foci have been widely used as the end-point marker of carcinogenicity screening and chemoprevention studies for hepatocarcinogenesis (Tsuda et al, 2010;Punvittayagul et al, 2012).…”