The Reproductive Effects Assessment Group's report on the mutagenicity of 1,3-butadiene and its reactive metabolites

Abstract

A major data gap for assessing heritable risk from exposure to 1,3-butadiene is the lack of mammalian mutagenicity data. The data base on the mutagenic potential of 1,3-butadiene is limited to three bacterial studies from the same laboratory. Two of these studies were positive only in the presence of liver S9 mix from chemically pretreated animals. In vitro data suggest that 1,3-butadiene is metabolized to two epoxide intermediates. 3,4-Epoxybutene, one potential reactive metabolite of 1,3-butadiene, is a monofunctional alkylating agent and is a direct-acting mutagen in bacteria. In addition, unpublished data suggest that 3,4-epoxy-butene induces DNA damage and chromosomal aberrations in mice. Another potential reactive metabolite, 1,2:3,4-diepoxybutane, is a bifunctional alkylating agent and is mutagenic in a wide variety of organisms (bacteria, fungi, and the germ cells of Drosophila). This metabolite also induces DNA damage in mice and in cultured hamster cells, is clastogenic in fungi and cultured rat cells, and produces chromosome damage/breakage in Drosophila germ cells. These data, when combined with evidence that 1,3-butadiene is carcinogenic in rodent gonadal tissues and is associated with gonadal atrophy in mice, constitute suggestive evidence that 1,3-butadiene may be a human germ cell mutagen. However, because the mutagenicity of 1,3-butadiene has been studied only in bacteria, studies in mammalian test systems are needed to further characterize the mutagenic potential of 1,3-butadiene.