Timchalk C, Smith F A, Bartels M J
Dow Chemical Company, Midland, Michigan 48674.
Toxicol Appl Pharmacol. 1994 Feb;124(2):181-90. doi: 10.1006/taap.1994.1022.
This study was initiated to evaluate the pharmacokinetics/metabolism of 14C-labeled toluene 2,4-diisocyanate (2,4-[14C]-TDI) following oral and inhalation exposure in the rat. For comparison, the pharmacokinetics/metabolism of toluene 2,4-diamine (2,4-[14C]TDA) was also evaluated. Groups of 3 or 4 male rats were given either a single 60 mg/kg oral dose of 2,4-[14C]-TDI or were exposed to 2,4-[14C]TDI vapors at a target concentration of 2 ppm for a 4-hr period. Additional groups of male rats were given single 3 or 60 mg/kg oral doses or a single 3 mg/kg intravenous (iv) dose of 2,4-[14C]TDA. All rats were euthanized by 48 hr postexposure. Following oral administration of 2,4-[14C]TDI, > 93% of the administered radioactivity was recovered in the urine, feces, cage wash, and tissues. Approximately 8% of the oral dose was excreted in the urine while 81% was eliminated in the feces. It is estimated that during inhalation exposure, essentially all of the inhaled 2,4-[14C]TDI was retained by the animal. At 48 hr post-inhalation exposure approximately 15 and 47% of the recovered radioactivity was in the urine and feces, respectively. Following oral or inhalation exposure to 2,4-[14C]TDI, no radioactivity was eliminated as either expired 14C organics or 14CO2. Comparison of the 2,4-[14C]TDI inhalation group with the oral 2,4-[14C]TDI and 2,4-[14C]TDA treatment groups indicated that a larger percentage of the inhaled radioactivity was in the tissues/carcass (34% vs 2-4%) and the excretion of radioactivity into the urine was slower (t1/2 = 20 hr vs 5-8 hr) following TDI inhalation. The total amount of free+acetylated TDA metabolites detected in the urine specimens (0-12 hr) following oral and inhalation exposure to 2,4-[14C]TDI was 15 and 0.26 microgram eq 2,4-TDA, respectively. No free 2,4-TDA was detected in the urine specimen from the inhalation group. In comparison, 638 and 20 micrograms eq 2,4-TDA was detected in the urine specimen after oral administration of 60 and 3 mg/kg 2,4-[14C]TDA, respectively. Following 2,4-[14C]TDI inhalation and oral exposure approximately 90 and 65% of the quantitated urinary metabolites existed as acid-labile conjugates, respectively. In contrast, only 16-39% of the quantitated urinary metabolites existed as acid-labile conjugates following oral administration of 2,4-[14C]TDA. Inhalation exposure to 2,4-TDI primarily results in the formation of acid-labile conjugates with little or no 2,4-TDA being formed.(ABSTRACT TRUNCATED AT 400 WORDS)
本研究旨在评估大鼠经口和吸入暴露后，14C 标记的甲苯 2,4 -二异氰酸酯（2,4 - [14C] - TDI）的药代动力学/代谢情况。作为比较，还评估了甲苯 2,4 -二胺（2,4 - [14C]TDA）的药代动力学/代谢情况。将 3 或 4 只雄性大鼠分为一组，分别经口给予 60 mg/kg 的 2,4 - [14C] - TDI 单次剂量，或在目标浓度为 2 ppm 的条件下，让其暴露于 2,4 - [14C]TDI 蒸气中 4 小时。另外几组雄性大鼠分别经口给予 3 或 60 mg/kg 的 2,4 - [14C]TDA 单次剂量，或经静脉注射给予 3 mg/kg 的 2,4 - [14C]TDA 单次剂量。所有大鼠在暴露后 48 小时实施安乐死。经口给予 2,4 - [14C]TDI 后，超过 93% 的给药放射性在尿液、粪便、笼冲洗液和组织中回收。经口剂量的约 8% 通过尿液排出，而 81% 通过粪便排出。据估计，在吸入暴露期间，基本上所有吸入的 2,4 - [14C]TDI 都被动物留存。在吸入暴露后 48 小时，回收放射性的约 15% 和 47% 分别存在于尿液和粪便中。经口或吸入暴露于 2,4 - [14C]TDI 后，未发现放射性以呼出的 14C 有机物或 14CO2 的形式排出。将 2,4 - [14C]TDI 吸入组与经口给予 2,4 - [14C]TDI 和 2,4 - [14C]TDA 的治疗组进行比较，结果表明，吸入的放射性在组织/胴体中的占比更大（34% 对 2 - 4%），并且吸入 TDI 后，放射性向尿液中的排泄更慢（t1/2 = 20 小时对 5 - 8 小时）。经口和吸入暴露于 2,4 - [14C]TDI 后，在尿液标本（0 - 12 小时）中检测到的游离 + 乙酰化 TDA 代谢物总量分别为 15 和 0.26 微克当量的 2,4 - TDA。在吸入组的尿液标本中未检测到游离的 2,4 - TDA。相比之下，经口给予 60 和 3 mg/kg 的 2,4 - [14C]TDA 后，在尿液标本中分别检测到 638 和 20 微克当量的 2,4 - TDA。经 2,4 - [14C]TDI 吸入和经口暴露后，定量尿液代谢物中分别约有 90% 和 65% 以酸不稳定结合物的形式存在。相比之下，经口给予 2,4 - [14C]TDA 后，定量尿液代谢物中只有 16 - 39% 以酸不稳定结合物的形式存在。吸入暴露于 2,4 - TDI 主要导致形成酸不稳定结合物，几乎不形成 2,4 - TDA 或完全不形成 2,4 - TDA。（摘要截短于 400 字）
