title: Chromosome aberration frequency in rat peripheral lymphocytes increases with repeated dosing with hexamethylphosphoramide or cyclophosphamide.
abstract: Although there are several in vivo tests for potential genotoxicity, with the possible exception of the transgenic rodent mutation models, none is specifically intended to assess increasing damage with chronic administration. In principle, peripheral blood lymphocytes would be expected to accumulate DNA damage with repeated dosing because the majority are not in active division and appear to have limited DNA repair capability, and they are exposed to plasma levels of test materials and metabolites. However, there appear to be no published reports confirming this principle. Therefore, in the current study, after optimising culture conditions for rat lymphocytes in this laboratory, rats were given oral doses of cyclophosphamide or hexamethylphosphoramide (HMPA) for up to 28 days and peripheral lymphocytes analysed for chromosome aberrations at various time points. The results clearly show that, for both compounds, doses that gave no significant increases in aberration frequency after 2 days induced clear increases after 15 days with further damage detectable after 28 doses. With HMPA, it was shown that DNA damage persisted for at least 10 days after cessation of treatment. These data show that repeat dose studies in the rat measuring chromosome aberration frequency in lymphocytes can give a genuine indication that genotoxicity may increase with chronic administration and, therefore, maybe useful in assessing the risk of potentially genotoxic substances.
authors.affiliation: Safety Assessment and DMPK Department, AstraZeneca R&D, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK. ann.doherty@astrazeneca.com
authors.forename: Ann T
authors.initials: AT
authors.lastname: Doherty
authors.forename: Julie
authors.initials: J
authors.lastname: Hayes
authors.forename: Paul
authors.initials: P
authors.lastname: Holme
authors.forename: Mike
authors.initials: M
authors.lastname: O'Donovan
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002869:Chromosome Aberrations / Q000139:chemically induced*; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity*; D006492:Hempa / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity*; D008214:Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D009152:Mutagenicity Tests; D009153:Mutagens / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity*; D051381:Rats
chemical_list: D009153:Mutagens; D003520:Cyclophosphamide; D006492:Hempa