Effects of extended chronic exposures on endogenous and transgenic loci: Implications for low-dose extrapolations
✍ Scribed by Lidia Cosentino; John A. Heddle
- Book ID
- 101265451
- Publisher
- John Wiley and Sons
- Year
- 1999
- Tongue
- English
- Weight
- 152 KB
- Volume
- 34
- Category
- Article
- ISSN
- 0893-6692
No coin nor oath required. For personal study only.
✦ Synopsis
Although transgenic and endogenous loci generally respond alike to acute mutagenic exposures, those loci that have been tested respond differently to daily or continuous exposures. During chronic exposures, the transgenes accumulate mutations linearly, whereas the endogenous loci are less mutable initially but later accumulate mutations at an accelerating rate. The result is a reverse dose rate effect in which the same total dose is more mutagenic for the endogenous locus when spread over a longer time. This makes extrapolations to still lower chronic exposures uncertain. Here we report extension of a chronic exposure to N-ethyl-N-nitrosourea (ENU) in drinking water to longer times and to lower doses. The F 1 of Muta ™ Mouse males ϫ SWR that were used permit detection of mutations at both lacZ and Dlb-1. Both of these mutations were found to be genetically neutral over this pe-riod. Extension of the exposure from 30 to 90 days at 94 g/ml/d showed a continuation of the curves found previously for 10 to 30 days, namely, linear for mutations of the lacZ transgene and concave upward for the Dlb-1 endogenous gene. A simple model for these data is presented. Of the extended exposures, only the highest dose produced a significant increase in Dlb-1 mutant frequency, an increase consistent with the model. The time (at 2.8 g/ml/d), concentration (after 480 days exposure), and dose (concentration ϫ duration of exposure) response curves were not significantly different from linearity. The data for the transgene are not as convincing, due to the high spontaneous mutant frequency, obscuring the induced response.