Safe New Technologies, Work Environment Development, Finnish Institute of Occupational Health, FI-00250 Helsinki, Finland.
Mutat Res. 2011 Jul 14;723(1):1-10. doi: 10.1016/j.mrgentox.2011.03.009. Epub 2011 Mar 29.
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.
甲苯二异氰酸酯（TDI）和 4,4'-亚甲基二苯基二异氰酸酯（MDI）用于生产聚氨酯泡沫，因其具有刺激性和致敏性而广为人知。关于它们的遗传毒性，已有相互矛盾的结果。我们通过检查骨髓和外周血中的多色红细胞微核（PCE）以及血红蛋白中 TDI 和 MDI 衍生的加合物，研究了吸入 TDI 和 MDI 在小鼠中的遗传毒性和蛋白质结合。雄性 C57Bl/6J 小鼠（每组 8 只）仅暴露于 TDI 蒸气（平均浓度分别为 1.1、1.5 和 2.4mg/m3；异构体混合物中，2,4-TDI 的平均含量为 63%，2,6-TDI 的含量为 37%）或 MDI 气溶胶（平均浓度分别为 10.7、20.9 和 23.3mg/m3），每天 1 小时，连续 5 天。最后一次暴露后 24 小时采集骨髓和外周血。TDI 的吸入会引起上呼吸道的感觉刺激（SI），并在最高暴露水平观察到累积效应。MDI 的吸入会引起 SI 和气流受限，并导致炎症细胞流入肺部。在暴露的小鼠中检测到的血红蛋白加合物是由 2,4-和 2,6-TDI 以及 MDI 直接与球蛋白结合产生的，并且观察到剂量依赖性增加，尤其是 2,4-TDI 衍生的加合物。未观察到 TDI（甲苯二胺）或 MDI（亚甲基二苯胺）的二胺衍生的加合物。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 频率的显著增加。在最高浓度的 MDI 下，PCE 和正常染色红细胞（NCE）的比例降低，并且也观察到 PCE/NCE 比例的轻微降低，这取决于累积吸入剂量，这与 TDI 有关。我们的结果表明，在诱导毒性作用和血红蛋白中形成 TDI 或 MDI 特异性加合物的水平下，吸入 TDI 或 MDI（每天 1 小时，连续 5 天），在小鼠中没有可检测的遗传毒性作用，如微核试验所示。
