Chromosome aberrations in Chinese hamster and human cells: a comparison using compounds with various genotoxicity profiles.
Chromosome aberrations (Cabs) can be induced in vitro by non-DNA damaging compounds, often associated with cytotoxicity and DNA synthesis inhibition, and under conditions that would not be relevant in vivo. Such misleading positive results are reported both in Chinese hamster cell lines and in human peripheral blood lymphocytes (HL). We assessed the response of HL to compounds with varied genetic toxicity profiles, all of which induced Cabs in CHO cells Seven of 10 compounds were negative or equivocal in HL. Results in purified lymphocytes for four verified that the difference was not due to the presence of blood in cultures. Two compounds that were weakly positive in the Ames test and one that induced DNA adducts were negative or equivocal in the HL assay; their overall mutagenic potential in vivo is not clear. Of four Ames-negative compounds, three of which inhibited DNA synthesis in CHO cells, three were negative and one was equivocal in the HL assay. A potent Cab inducer, which also induced micronuclei in vivo (but was negative in the Ames test) was clearly positive in the HL assay. Two compounds were clearly positive in HL only when the mitotic indices (MI) were below 50% of control. These are genotoxic in other assays but our evidence suggests that Cab induction is related more to toxicity than to primary DNA damage. For this limited set of 10 compounds, HL were more likely than CHO cells to give negative or equivocal results. It is likely that more stringent checkpoint controls in human cells prevent damaged cells reaching mitosis, and may also influence the reported greater sensitivity to induction of aneuploidy and polyploidy of normal rodent compared with human cells. In the studies reported here, two strong inducers of polyploidy in CHO cells gave weaker increases in HL. Human lymphocytes have disadvantages as a routine screening assay (finding donors, known individual variability, increased time required and the inadequacy of the MI as a toxicity measure), but may be useful in follow-up testing to assess weight of evidence about genotoxic risk to humans, for compounds that are positive in the Chinese hamster cell Cabs assays.
Hilliard
Cathy
C
Merck Research Laboratories, Department of Genetic and Cellular Toxicology, West Point, PA 19486, USA. catherine_hilliard@merck.com
Hill
Rosina
R
Armstrong
Michael
M
Fleckenstein
Clint
C
Crowley
Jessica
J
Freeland
Elizabeth
E
Duffy
Danielle
D
Galloway
Sheila M
SM
D000328:Adult; D000818:Animals; D016590:Aphidicolin / Q000494:pharmacology; D016466:CHO Cells; D002478:Cells, Cultured; D002869:Chromosome Aberrations; D002999:Clone Cells; D006224:Cricetinae; D003412:Cricetulus; D004261:DNA Replication; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects*; D009152:Mutagenicity Tests; D009153:Mutagens / Q000494:pharmacology*; D011123:Polyploidy
D009153:Mutagens; D016590:Aphidicolin