Walker V E, MacNeela J P, Swenberg J A, Turner M J, Fennell T R
Chemical Industry Institute of Toxicology, Research Triangle Park 27709.
Cancer Res. 1992 Aug 15;52(16):4320-7.
The formation of N-(2-hydroxyethyl)valine (HEVal) in hemoglobin was investigated in male F344 rats (10/group) and B6C3F1 mice (20/group) exposed to 0, 3, 10, 33, 100, or 300 (rats only) ppm ethylene oxide (ETO) by inhalation for 6 h/day for 4 weeks (5 days/week) or exposed to 100 (mice) or 300 ppm (rats) ETO for 1 or 3 days, or 1, 2, or 4 weeks (5 days/week). The persistence of HEVal was studied in animals killed up to 10 days after cessation of the 4-week time-course studies. HEVal was determined by a modified Edman degradation and quantitation of the resulting pentafluorophenylthiohydantoin derivative, using gas chromatography-mass spectrometry. The resulting experimental data were compared to simulations derived with a model for the formation and removal of hemoglobin adducts (T.R. Fennell, S.C.J. Sumner, and V.E. Walker, Cancer Epidemiol., Biomarkers & Prev., 1: 213-219, 1992). Repeated exposures of rats and mice for 4 weeks to 300 and 100 ppm ETO, respectively, led to an accumulation of HEVal that was 14 (rats) and 15 (mice) times greater than that found after 1 day of exposure [28 +/- 2 (SE) and 9.4 +/- 0.4 (SE) pmol HEVal/mg globin in rats and mice, respectively]. After cessation of exposures, HEVal was lost faster than predicted by the normal erythrocyte life span alone. An initial phase of rapid decline in HEVal concentrations was consistent with the removal of older, more heavily alkylated populations of RBCs, accompanied by a burst of erythropoiesis. The dose-response curves for HEVal were linear between 3 and 33 ppm ETO, with 3.5 +/- 0.2 and 3.4 +/- 0.3 pmol adduct/mg globin formed in rats and mice, respectively, after 4 weeks of exposure to 3 ppm ETO. Above 33 ppm ETO, the slope of the dose-response curves increased. Comparison of the dose response for HEVal in rats exposed to ETO for 4 weeks to the dose-response for N tau-(2-hydroxyethyl)histidine in rats exposed to the same concentrations of ETO for 2 years (S. Osterman-Golkar et al., Teratog. Carcinog. Mutagen., 3: 395-405, 1983) suggested that exposures to ETO can reduce the life span of erythrocytes in a concentration- and time-dependent manner. Correlation of the experimental data and simulations for the formation and removal of HEVal demonstrated that perturbations in erythropoiesis and RBC life span complicate the estimation of exposures to ETO when estimates are based upon hemoglobin adduct measurements in heavily exposed individuals.(ABSTRACT TRUNCATED AT 400 WORDS)
在雄性F344大鼠（每组10只）和B6C3F1小鼠（每组20只）中，研究了吸入0、3、10、33、100或300（仅大鼠）ppm环氧乙烷（ETO），每天6小时，共4周（每周5天），或暴露于100（小鼠）或300 ppm（大鼠）ETO 1天、3天、1周、2周或4周（每周5天）后血红蛋白中N-（2-羟乙基）缬氨酸（HEVal）的形成情况。在为期4周的时间进程研究结束后，对处死时间长达10天的动物进行了HEVal持续性研究。采用改良的埃德曼降解法，通过气相色谱-质谱法对所得五氟苯基硫代乙内酰脲衍生物进行定量分析来测定HEVal。将所得实验数据与通过血红蛋白加合物形成和清除模型得出的模拟结果进行比较（T.R. 芬内尔、S.C.J. 萨姆纳和V.E. 沃克，《癌症流行病学,生物标志物与预防》，第1卷：213 - 219页，1992年）。大鼠和小鼠分别重复暴露于300和100 ppm ETO 4周后，HEVal的积累量分别比暴露1天后高14倍（大鼠）和15倍（小鼠）[大鼠和小鼠中分别为28±2（标准误）和9.4±0.4（标准误）pmol HEVal/mg球蛋白]。暴露停止后，HEVal的消失速度比仅根据正常红细胞寿命预测的速度更快。HEVal浓度快速下降的初始阶段与清除较老、烷基化程度更高的红细胞群体一致，同时伴有红细胞生成的爆发。在3至33 ppm ETO之间，HEVal的剂量反应曲线呈线性，暴露于3 ppm ETO 4周后，大鼠和小鼠中分别形成3.5±0.2和3.4±0.3 pmol加合物/mg球蛋白。在33 ppm ETO以上，剂量反应曲线的斜率增加。将暴露于ETO 4周的大鼠中HEVal的剂量反应与暴露于相同浓度ETO 2年的大鼠中Nτ-（2-羟乙基）组氨酸的剂量反应进行比较（S. 奥斯特曼-戈尔卡尔等人，《致畸、致癌、致突变》，第3卷：395 - 405页，1983年），结果表明，暴露于ETO可使红细胞寿命以浓度和时间依赖的方式缩短。HEVal形成和清除的实验数据与模拟结果的相关性表明，当基于重度暴露个体的血红蛋白加合物测量来估计暴露情况时，红细胞生成和红细胞寿命的扰动会使ETO暴露估计变得复杂。（摘要截短至400字）
