Evaluation of Possible Carcinogenic Risk to Humans Based on Liver Tumors in Rodent Assays:The Two-Year Bioassay Is No Longer Necessary

Research output: Contribution to journalReview article

76 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)487-501
Number of pages15
JournalToxicologic Pathology
Volume38
Issue number3
DOIs
StatePublished - Apr 2010

Keywords

  • PPARα agonists
  • cytotoxicity
  • estrogen
  • genotoxicity
  • mitogenesis
  • phenobarbital
  • regeneration

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Molecular Biology
  • Toxicology
  • Cell Biology

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