title: Improvements in the reliability of in vitro genotoxicity testing.
abstract: BACKGROUND
  In vitro genotoxicity assays have a high sensitivity to detect rodent carcinogens, but mammalian cell tests have a propensity for misleading positive results (poor specificity). Recent data show a greater risk of misleading positive results in p53-deficient rodent cell lines than in p53-competent human cells. Measures of cytotoxicity, source and stability of cells used are also important.
  
  
  METHODS
  In this review, potential reduction in the top concentration for testing (10 mM) is discussed. Indirect effects on non-DNA targets, which may not be relevant for humans or may exhibit a threshold, have been identified.
  
  
  CONCLUSIONS
  The reliability of in vitro genotoxicity tests could be improved by selecting p53-proficient, human cells. The provenance and stability of the cells used should be demonstrated. Measures of cytotoxicity based on cell proliferation should be used. Lowering the top concentration for testing from 10 mM to 4 mM or 2000 μg/ml, whichever is the lower, as proposed by some experts, would seem to be justified. Artefacts that may be caused by reaction of test substance with culture medium should be avoided. Better understanding and investigation of the potential for threshold and irrelevant modes of action are encouraged.
authors.affiliation: Kirkland Consulting, PO Box 79, Tadcaster, LS24 0AS, UK. dkirkland@genetoxconsulting.co.uk
authors.forename: David
authors.initials: D
authors.lastname: Kirkland
mesh_terms: D000818:Animals; D002273:Carcinogens / Q000633:toxicity; D018929:Cell Culture Techniques; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D009152:Mutagenicity Tests / Q000379:methods*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015203:Reproducibility of Results
chemical_list: D002273:Carcinogens; D017382:Reactive Oxygen Species