Toluene diisocyanate (TDI) and 4,4'-methylenediphenyl diisocyanate (MDI), used in the production of polyurethane foam, are well known for their irritating and sensitizing properties. Contradictory results have been obtained on their genotoxicity. We investigated the genotoxicity and protein binding of inhaled TDI and MDI in mice by examining micronucleated polychromatic erythrocytes (PCEs) in bone marrow and peripheral blood and TDI- and MDI-derived adducts in hemoglobin. Male C57Bl/6J mice (8 per group) were exposed head-only to TDI vapour (mean concentrations 1.1, 1.5, and 2.4mg/m(3); the mixture of isomers contained, on the average, 63% 2,4-TDI and 37% 2,6-TDI) or MDI aerosol (mean concentrations 10.7, 20.9 and 23.3mg/m(3)), during 1h/day for 5 consecutive days. Bone marrow and peripheral blood were collected 24h after the last exposure. Inhalation of TDI caused sensory irritation (SI) in the upper respiratory tract, and cumulative effects were observed at the highest exposure level. Inhalation of MDI produced SI and airflow limitation, and influx of inflammatory cells into the lungs. Hemoglobin adducts detected in the exposed mice resulted from direct binding to globin of 2,4- and 2,6-TDI and MDI, and dose-dependent increases were observed especially for 2,4-TDI-derived adducts. Adducts originating from the diamines of TDI (toluene diamine) or MDI (methylene dianiline) were not observed. No significant increase in the frequency of micronucleated PCEs was detected in the bone marrow or peripheral blood of the mice exposed to TDI or MDI. The ratio of PCEs and normochromatic erythrocytes (NCEs) was reduced at the highest concentration of MDI, and a slight reduction of the PCE/NCE ratio, dependent on cumulative inhaled dose, was also seen with TDI. Our results indicate that inhalation of TDI or MDI (1h/day for 5 days), at levels that induce toxic effects and formation of TDI- or MDI-specific adducts in hemoglobin, does not have detectable genotoxic effects in mice, as studied with the micronucleus assay.

译文

用于生产聚氨酯泡沫的甲苯二异氰酸酯 (TDI) 和4,4 '-亚甲基二苯基二异氰酸酯 (MDI) 因其刺激性和敏化性能而众所周知。在其遗传毒性方面获得了矛盾的结果。我们通过检查骨髓和外周血中的微核多色红细胞 (PCEs) 以及血红蛋白中TDI和MDI衍生的加合物,研究了小鼠吸入TDI和MDI的遗传毒性和蛋白质结合。雄性C57Bl/6J小鼠 (每组8只) 仅头部暴露于TDI蒸气 (平均浓度1.1、1.5和2.4 mg/m(3); 异构体混合物平均含有63% 2,4-TDI和37% 2,6-TDI) 或MDI气溶胶 (平均浓度10.7,20.9和23.3 mg/m(3)),在1h/天内连续5天。在最后一次暴露后24小时收集骨髓和外周血。吸入TDI会引起上呼吸道的感觉刺激 (SI),并且在最高暴露水平下观察到累积效应。吸入MDI会导致SI和气流受限,并使炎症细胞流入肺部。在暴露的小鼠中检测到的血红蛋白加合物是由与2,4-和2,6-tdi和MDI的珠蛋白直接结合引起的,并且观察到剂量依赖性增加,特别是对于2,4-tdi衍生的加合物。未观察到源自TDI (甲苯二胺) 或MDI (亚甲基二胺) 的二胺的加合物。在暴露于TDI或MDI的小鼠的骨髓或外周血中未检测到微核pce的频率显着增加。在最高浓度的MDI下,PCE和常染红细胞 (NCEs) 的比率降低,并且TDI还观察到PCE/NCE的比率略有降低,这取决于累积吸入剂量。我们的结果表明,吸入TDI或MDI (1小时/天,持续5天),其水平可诱导毒性作用并在血红蛋白中形成TDI或MDI特异性加合物,在小鼠中没有可检测到的遗传毒性作用,用微核测定法进行研究。

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