Evaluation of possible carcinogenic risk to humans based on liver tumors in rodent assays: the two-year bioassay is no longer necessary.
The two-year rodent bioassay remains the mainstay for carcinogenicity testing, although numerous difficulties have been identified. Fundamentally, a chemical can increase the risk of cancer (1) by damaging DNA directly (DNA reactive) or (2) indirectly by increasing the number of DNA replications (non-DNA reactive). Mechanistic research has identified numerous precursor lesions in the sequence of key events necessary for neoplasia development. Based on these concepts, the author has proposed a short-term (thirteen-week) assay for screening for carcinogenic potential based on a mode of action analysis and on readily available, identifiable preneoplastic changes. A screening assay that detects all potential rodent hepatocarcinogens has been previously identified (Toxicol Pathol 32 [2004], 393-401) including increased liver weight, hepatocellular necrosis, hypertrophy, and cytomegaly. Labeling index for DNA replication might supply additional support. These markers have high sensitivity but low specificity. However, most chemicals can be appropriately classified as to their mode(s) of action for hepatocarcinogenesis with follow-up mechanistic studies, and a rational evaluation of their relevance to humans can be made. A similar process can be envisioned for other tissues for evaluation for carcinogenic potential.
Cohen
Samuel M
SM
Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198-3135, USA. scohen@unmc.edu
D000818:Animals; D001681:Biological Assay / Q000379:methods*; D015197:Carcinogenicity Tests / Q000379:methods; D002273:Carcinogens / Q000633:toxicity*; D004195:Disease Models, Animal; D006801:Humans; D008113:Liver Neoplasms / Q000139:chemically induced*; D012377:Rodentia; D013995:Time
D002273:Carcinogens