Walker Dale M, McDonald Jacob D, Meng Quanxin, Kracko Dean A, Bauer Michael J, Seilkop Steven K, Walker Elizabeth L, Henderson Rogene F, Walker Vernon E
Lovelace Respiratory Research Institute, Albuquerque, NM 87108, USA.
Chem Biol Interact. 2007 Mar 20;166(1-3):191-206. doi: 10.1016/j.cbi.2007.01.017. Epub 2007 Feb 12.
Studies were performed to determine if the detoxification pathway of 1,3-butadiene (BD) through 3-butene-1,2-diol (BD-diol) is a major contributor to mutagenicity in BD-exposed mice and rats. First, female and male mice and rats (4-5 weeks old) were exposed by nose-only for 6h to 0, 62.5, 200, 625, or 1250 ppm BD or to 0, 6, 18, 24, or 36 ppm BD-diol primarily to establish BD and BD-diol exposure concentrations that yielded similar plasma levels of BD-diol, and then animals were exposed in inhalation chambers for 4 weeks to BD-diol to determine the mutagenic potency estimates for the same exposure levels and to compare these estimates to those reported for BD-exposed female mice and rats where comparable blood levels of BD-diol were achieved. Measurements of plasma levels of BD-diol (via GC/MS methodology) showed that (i) BD-diol accumulated in a sub-linear fashion during single 6-h exposures to >200 ppm BD; (ii) BD-diol accumulated in a linear fashion during single or repeated exposures to 6-18 ppm BD and then in a sub-linear fashion with increasing levels of BD-diol exposure; and (iii) exposures of mice and rats to 18 ppm BD-diol were equivalent to those produced by 200 ppm BD exposures (with exposures to 36 ppm BD-diol yielding plasma levels approximately 25% of those produced by 625 ppm BD exposures). Measurements of Hprt mutant frequencies (via the T cell cloning assay) showed that repeated exposures to 18 and 36 ppm BD-diol were significantly mutagenic in mice and rats. The resulting data indicated that BD-diol derived metabolites (especially, 1,2-dihydroxy-3,4-epoxybutane) have a narrow range of mutagenic effects confined to high-level BD (>or=200 ppm) exposures, and are responsible for nearly all of the mutagenic response in the rat and for a substantial portion of the mutagenic response in the mouse following high-level BD exposures.
开展了多项研究，以确定1,3 - 丁二烯（BD）通过3 - 丁烯 - 1,2 - 二醇（BD - 二醇）的解毒途径是否是导致BD暴露的小鼠和大鼠发生致突变性的主要因素。首先，对4 - 5周龄的雌性和雄性小鼠及大鼠采用仅经鼻暴露6小时的方式，使其暴露于0、62.5、200、625或1250 ppm的BD中，或暴露于0、6、18、24或36 ppm的BD - 二醇中，主要目的是确定能产生相似血浆BD - 二醇水平的BD和BD - 二醇暴露浓度。然后，将动物置于吸入舱中暴露于BD - 二醇4周，以确定相同暴露水平下的致突变性效力估计值，并将这些估计值与已报道的在达到可比BD - 二醇血药浓度的BD暴露的雌性小鼠和大鼠中的估计值进行比较。通过气相色谱/质谱法对血浆BD - 二醇水平的测量结果表明：（i）在单次6小时暴露于>200 ppm BD期间，BD - 二醇以亚线性方式蓄积；（ii）在单次或重复暴露于6 - 18 ppm BD期间，BD - 二醇呈线性蓄积，然后随着BD - 二醇暴露水平的增加以亚线性方式蓄积；（iii）小鼠和大鼠暴露于18 ppm BD - 二醇相当于暴露于200 ppm BD所产生的情况（暴露于36 ppm BD - 二醇所产生的血浆水平约为625 ppm BD暴露所产生血浆水平的25%）。通过T细胞克隆试验对次黄嘌呤 - 鸟嘌呤磷酸核糖转移酶（Hprt）突变频率的测量结果表明，在小鼠和大鼠中，重复暴露于18和36 ppm BD - 二醇具有显著的致突变性。所得数据表明，BD - 二醇衍生的代谢产物（尤其是1,2 - 二羟基 - 3,4 - 环氧丁烷）的致突变作用范围较窄，仅限于高水平BD（≥200 ppm）暴露，并且在高水平BD暴露后，几乎导致了大鼠的所有致突变反应以及小鼠致突变反应的很大一部分。
