Assessing the risk of heritable gene mutation in mammals: drosophila sex-linked recessive lethal test and tests measuring DNA damage and repair in mammalian germ cells.
The former U.S. EPA OPPT tiered test scheme for heritable gene mutations included the Drosophila sex-linked recessive lethal (SLRL) test in which positive results triggered the mouse specific locus (MSL) test. However, review of available literature indicated that the evaluation of mutations in the germ cells of this insect is not a good predictor of the risk of heritable gene mutations in mammals. The database contained 29 compounds for which there were conclusive MSL test results in either spermatogonial and/or postspermatogonial cells. Results in the SLRL test were available for 27 of those compounds. Of the 24 SLRL-positive chemicals, only 13 (54%) induced heritable mutations in mice; the three SLRL-negative compounds were nonmutagenic in mouse germ cells. The overall concordance between the two tests was 59%. In contrast, results of unscheduled DNA synthesis (UDS: 18 chemicals) and alkaline elution (AE: 14 chemicals) assays in rodent testicular cells following in vivo exposure correlated well with results in the MSL test (83% and 86%, respectively). MSL test results in spermatogonia and postspermatogonia were also compared separately to the SLRL, UDS, and AE assays. The concordances for the two cell types in the SLRL relative to the MSL test were 36% and 79%, respectively, indicating that the SLRL test is extremely poor in predicting heritable gene mutations in mammalian spermatogonia. Concordances for UDS and AE assays relative to MSL test results in spermatogonia (53% and 54%, respectively) and postspermatogonia (91% and 100%, respectively) were greater. Based on these analyses, the U.S. EPA OPPT has revised its tiered test scheme using assays for interaction with gonadal DNA (e.g., UDS and AE) in place of the SLRL test.
Bentley
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KS
Haskell Laboratory for Toxicology and Industrial Medicine, E.I. du Pont de Nemours and Company, Newark, DE 19714.
Sarrif
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AM
Cimino
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MC
Auletta
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AE
D000818:Animals; D003432:Cross-Linking Reagents; D004247:DNA / Q000096:biosynthesis / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair; D016208:Databases, Factual; D004330:Drosophila / Q000235:genetics; D018095:Germ-Line Mutation; D008297:Male; D051379:Mice; D016297:Mutagenesis, Site-Directed; D009152:Mutagenicity Tests / Q000379:methods*; D009153:Mutagens / Q000633:toxicity*; D011237:Predictive Value of Tests; D051381:Rats; D012307:Risk Factors; D013093:Spermatogonia / Q000187:drug effects*; D013737:Testis / Q000166:cytology / Q000187:drug effects; D014481:United States; D014484:United States Environmental Protection Agency
D003432:Cross-Linking Reagents; D009153:Mutagens; D004247:DNA