ASSESSING THE RISK OF HERITABLE GENE MUTATION IN MAMMALS - DROSOPHILASEX-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 mutatio ns 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 conta ined 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-pos itive chemicals, only 13 (54%) induced heritable mutations in mice; th e three SLRL-negative compounds were nonmutagenic in mouse germ cells. The overall concordance between the two tests was 59%. In contrast, r esults of unscheduled DNA synthesis (UDS: 18 chemicals) and alkaline e lution (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 postspermat ogonia were also compared separately to the SLRL, UDS, and AE assays. The concordances for the two cell types in the SLRL relative to the MS L test were 36% and 79%, respectively, indicating that the SLRL test i s extremely poor in predicting heritable gene mutations in mammalian s permatogonia. Concordances for UDS and AE assays relative to MSL test results in spermatogonia (53% and 54%, respectively) and postspermatog onia (91% and 100%, respectively) were greater. Based on these analyse s, the U.S. EPA OPPT has revised its tiered test scheme using assays f or interaction with gonadal DNA (e.g., UDS and AE) in place of the SLR L test. (C) 1994 Wiley-Liss, Inc.