THE EFFECT OF THE INTERVAL BETWEEN DOSE APPLICATIONS ON THE OBSERVED SPECIFIC-LOCUS MUTATION-RATE IN THE MOUSE FOLLOWING FRACTIONATED TREATMENTS OF SPERMATOGONIA WITH ETHYLNITROSOUREA

Our earlier analyses have suggested an apparent threshold dose-respons e for ethylnitrosourea-induced specific-locus mutations in treated spe rmatogonia of the mouse to be due to a saturable repair process. In th e current study a series of fractionated-treatment experiments was car ried out in which male (102 X C3H)F-1 mice were exposed to 4 X 10, 2 X 40, 4 X 20 or 4 X 40 mg ethylnitrosourea per kg body weight with 24 h between applications; 4 X 40 mg ethylnitrosourea per kg body weight w ith 72 h between dose applications; and 2 X 40, 4 X 20 and 4 X 40 mg e thylnitrosourea per kg body weight with 168 h between dose application s. For all experiments with 24-h intervals between dose applications, there was no effect due to dose fractionation on the observed mutation rates, indicating the time interval between dose applications to be s horter than the recovery time of the repair processes acting on ethyln itrosourea-induced DNA adducts. In contrast, a fractionation interval of 168 h was associated with a significant reduction in the observed m utation rate due to recovery of the repair process. However, although reduced, the observed mutation rates for fractionation intervals of 16 8 h were higher than the spontaneous specific-locus mutation rate. The se observations contradict the expectation for a true threshold dose r esponse. We interpret this discrepancy to be due to the differences in the predictions of a mathematical abstraction of experimental data an d the complexities of the biological system being studied. Biologicall y plausible explanations of the discrepancy are presented.