芥子气暴露的确证：家兔皮肤染毒后血红蛋白N端缬氨酸加合物的同位素稀释-NCI-GC/MS溯源性检测

素有＂毒剂之王＂之称的芥子气（HD）是目前危害最大的化学战剂之一,染毒后在体内可产生不同类型的特征性生物标志物,其对中毒诊断、溯源性分析以及毒理机制等研究有着重要的意义.本文首先采用同位素稀释-NCI-GC/MS分析方法监测和鉴定了HD体外全血染毒后产生的血红蛋白N端缬氨酸加合物（HETE-Val）;其次,研究了不同剂量HD（0.02～0.15LD50）经皮染毒家兔体内HETE-Val的时效、量效关系.结果表明,HETE-Val与家兔中毒剂量间有良好的量效关系,而时效关系表明染毒后15min内即可产生并检测到HETE-Val,一周内达到最大,随后逐渐下降,但至染毒后第103天仍可监测到该加合物.与血红蛋白N端缬氨酸加合反应的HD仅占HD染毒总量的～0.15‰,与家兔血液反应的HD约占HD染毒总量的～1%.表明HETE-Val是一种重要的生物标志物,并可应用于HD暴露的确证和化学武器核查的溯源性检测.

Determination of the N-terminal Valine Adduct in Rabbit Hemoglobin After Skin Exposure to Sulfur Mustard

Sulfur mustard (HD) is one of the most hazardous chemical warfare agents. Various biomarkers will be generated in the body under exposure to HD, which have important practical significance in diagnosis, source tracing and basic research. The N-terminal valine adduct in hemoglobin (HETE-Val) was identified and validated after human blood exposure to sulfur mustard in vitro. Based on a rabbit model of skin exposure in vivo and the sensitive isotope-dilution-NCI-GC/MS (negative chemical ionization-gas chromatography/mass spectrometry) analysis, the metabolic behavior of HETE-Val was studied after the rabbits were exposed to HD. The results show that HETE-Val levels displayed an obvious dose-response relationships and time-response relationships after HD exposure. HETE-Val was generated as early as 15 min after HD exposure and was readily detectable. The contents of HETE-Val in blood were increased in the first two days after exposure and were stable from the 3rd to 9th day. Then it gradually decreased, but HETE-Val was still detectable at the 103rd day. The present data suggest that HETE-Val may be used as a sensitive biomarker of HD exposure in diagnosis of poisoning, retrospective analysis, and toxicological mechanism research.