Dose response study for 1,3-butadiene-induced dominant lethal mutations and heritable translocations in germs cells of male mice

Abstract

Butadiene (BD) and its metabolites have extensively been studied in the EU sponsored research project `Multi-endpoint analysis of genetic damage induced by 1,3-butadiene and its major metabolites'. Within this project a dominant lethal test and a heritable translocation test were performed with male mice to study the dose-response relationships for the respective endpoints. BD concentrations of 130 and 500 ppm were tested in the dominant lethal assay by exposing male mice on 6 h/day for five consecutive days resulting in doses of 3900 and 15 000 ppmh, respectively. Males were mated for four consecutive weeks at a ratio of 1:2 to untreated females. A positive dominant lethal effect was observed in the first mating week in the experiment with 15 000 ppmh but no dominant lethality was found with the lower dose of 3900 ppmh. The present dominant lethal data have to be viewed together with the data already published for a BD dose of 39 000 ppmh (1300 ppm at 6 h/day on 5 consecutive days) [1]. The main difference between results with the highest and the middle dose is that mating weeks one and two (sperm and late spermatids) showed an effect at 39 000 ppmh while only mating week one (sperm) showed an effect at 15 000 ppmh. In the heritable translocation assay, males mice were exposed with a BD dose of 15 000 ppmh and mated for one week to untreated females. Among 434 F 1 offspring, we found 5 translocation carriers (1.15% vs. 0.05% in the historical control, p<0.001). In the previous heritable translocation experiment with a BD dose of 39 000 ppmh of DB exposure, 2.7% of the offspring carried a reciprocal translocation [2]. These data can be used for quantification of genetic risk. The dose response for BD-induced heritable translocations in sperm and late spermatids of mice was linear ( Y=0.05+6.9×10 −5 X) and a doubling dose of 725 ppmh could be calculated.