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目录 contents

    摘要

    2,4,6‑三硝基甲苯(TNT)、黑索今(RDX)、季戊四醇四硝酸酯(PETN)等典型炸药可以引起肝、肾、血液及神经等多组织器官的毒性效应。本文就典型炸药的毒性效应及其作用机制进行综述,简要概述了典型炸药的细胞、微生物和动物毒性效应,以及职业人群的流行病学统计;以TNT为例,着重从氧化应激机制、代谢产物与蛋白质、DNA反应机制两个方面来阐述典型炸药毒性机制的研究进展。指出目前炸药毒性研究主要集中于炸药毒性测试方面,而对炸药毒性机制的认识比较缺乏。认为采用机器学习等方法建立炸药分子与其生物毒性之间的定量构效关系;深入研究高铁血红蛋白血症、中毒性白内障、致癌、致畸等硝基芳香类炸药典型毒性效应的分子机制等是今后的研究重点。

    Abstract

    Typical military explosives, such as trinitrotoluene(TNT), hexogen, octogen, pentaerythritol tetranitrate, can cause a variety of toxic effects on mammalian tissues and organs such as liver, kidney, blood and nerves. This paper reviewed the toxic effects and mechanisms of typical explosives, and briefly summarized their cellular, microbial and animal toxic effects, as well as the epidemiological statistics of occupational populations. Taking TNT as an example, the review also introduced the toxic mechanisms of typical explosive, emphasizing the oxidative stress and the reaction of TNT metabolites with protein and DNA. Finally, it was pointed out that the current toxicity study of explosives mainly focuses on the testing of toxicity, while the understanding on toxic mechanisms of explosives is lacking. We presented future research priorities. For example, the quantitative structure‑activity relationship between explosive molecules and biological toxicity by the machine learning technology, the investigation of toxic mechanism for nitroaromatic explosives, including hemoglobinemia, toxic cataract, carcinogenic and teratogenic, should be paid more attention.

    关键词

    炸药毒性作用机制综述

  • 1 引 言

    2,4,6‑三硝基甲苯(TNT)、黑索今(RDX)、季戊四醇四硝酸酯(PETN)等典型炸药是武器毁伤、破坏和动力能源的关键性材料。决定一种单质炸药是否可以用于武器型号,需要通过多种性能测试的考核。除了能量和感 度两个最受关注的性能以[1],炸药毒性(toxicity)也越来越受到关[2]。以TNT为例,自1919年首次报道TNT中毒病例以来,经过多国科研人员近百年的努[3,4,5,6],逐步确诊了TNT中毒性白内障、中毒性肝炎、再生障碍性贫血等毒性效应。TNT毒性认识发展的历史进程如图1所示。目前我国含能材料生产领域自动化程度不高,炸药毒性对工业化生产的限制问题没有得到根本缓解;从业人员接触后的患病率一直没有实质性下降。主要原因之一就是炸药中毒机制至今尚不明[7,8,9]。因此,开展炸药毒性机制研究具有非常重要的意义,可以为其预防、诊断和治疗提供理论支撑,进而保障从业者(包括武器使用人员)的健康安全以及生态环境安全,同时也有助于推动新型炸药的开发与应用。为此,本文就近年来几种典型炸药的毒性效应及其作用机制进行了概述,以期为新型炸药的生物安全性评价和中毒防治提供参考。

    图1
                            TNT中毒研究的历史进程

    图1 TNT中毒研究的历史进程

    Fig.1 Evolvement of TNT poisoning research

  • 2 典型炸药的毒性效应

  • 2.1 细胞毒性

    以苯环、苯并杂环、氮杂环等为主要母体结构的典型硝基芳香类炸药结构式见图2表1总结了上述炸药的哺乳动物细胞毒性数[9,10,11,12,13]。到目前为止,仅立陶宛生物化学研究所的Cenas小组以牛白血病病毒转化的羊肾成纤维细胞系(FLK细胞系)毒性数据较为全[10,11,12]。对比表1中的FLK细胞系实验结果可以发现,常见炸药对FLK细胞毒性顺序为:3‑硝基‑1,2,4‑三唑‑5‑酮(NTO)<5‑硝基‑1,2,4‑三唑‑3‑氨基(ANTA)<2‑氨基‑4,6‑二硝基甲苯(2A)<2,4‑二氨基‑6‑硝基甲苯(2,4‑DA)<4‑氨基‑2,6‑二硝基甲苯(4A)<TNT<2,4,6‑三硝基苯硝氨基硝酸乙酯(Pentryl)<2,4,6‑三硝基苯甲硝胺(Tetryl)(分子结构如图2所示);其中以三硝基苯为主要骨架结构的四种炸药即TNT、Tetryl、甲基匹克胺(MP)和Pentryl都具有相对较高的细胞毒性,其体外半数致死浓度(LC50)值分别约为25、2.2、40、5.0 μmol·L-1(24 h培养结果);其中FLK细胞毒性相对更高的Tetryl和Pentryl,都具有N─NO2键即硝胺炸药的典型结构特征。另外,同一炸药对不同细胞系的毒性也有较大差异,如TNT对于大鼠肝癌细胞H4IIE的毒性最高即LC50为17.6 μmol·L-1[9],而对于仓鼠肺细胞V79的毒性最低即LC50约为197 μmol·L-1[13]。另有研究显示,TNT对于人神经母细胞瘤NG108的LC50高于450 μmol·L-1(7 h培养)[14],对人肝癌HepG2的LC50为460±26 μmol·L-1(48 h培养)[15];含有68%的TNT、12%氨基代谢物和12%RDX炸药污染过的土壤提取物对人成纤维细胞GM05757的LC50接近2.1 mg·L-1[16]。在环境或生物体内,TNT通过硝基还原可以逐步转化或代谢生成羟氨基、氨基等产物,如图2中的2‑羟氨基‑4,6‑二硝基甲苯(2HA)、4‑羟氨基‑2,6‑二硝基甲苯(4HA)、2A、4A、2,4‑DA和2,4,6‑三氨基甲苯(TAT)等;这些不完全转化或代谢产物依然具有较高的毒性。如表1所示,在三氨基产物TAT之前,其它产物的细胞毒性会随着羟氨基、氨基的转化顺序逐步降低;只有羟氨基产物4HA对仓鼠卵巢K1细胞的毒性有一个例外,其LC50值为18.8 μmol·L-1,而相应TNT的LC50值仅为106 μmol·L-1。但是对于三氨基产物TAT,从仅有的仓鼠肺细胞V79和人淋巴细胞TK‑6的两个数据可以看到,其毒性相比于TNT和其它产物有显著的增加。三个苯并杂环炸药1,3,6,8‑四硝基咔唑(TNC)、4,5,6,7‑四硝基苯并咪唑‑2‑氧(TNBO)和4,6‑二氨基‑5,7‑二硝基苯并呋咱(CL‑14)的FLK细胞毒性分别约为8.0、30和250 μmol·L-1。这三种新型炸药依然具有典型硝基芳香结构特征,所以其细胞毒性与传统的硝基芳香炸药没有本质上的改变。两个氮杂环基硝基芳香炸药NTO(LC50>3500 μmol·L-1)和ANTA(LC50=3000 μmol·L-1)的细胞毒性显著低于苯环基硝基芳香炸药的细胞毒性。

    html/hncl/CJEM2019068/alternativeImage/7f94a3a5-665a-420a-b4d5-b03d6976fe4b-F003.png

    a. nitroaromatic compound

    html/hncl/CJEM2019068/alternativeImage/7f94a3a5-665a-420a-b4d5-b03d6976fe4b-F004.png

    b. nitramine compound

    html/hncl/CJEM2019068/alternativeImage/7f94a3a5-665a-420a-b4d5-b03d6976fe4b-F005.png

    c. nitrate compound

    图2 三种典型炸药分子的结构示意图

    Fig.2 Molecular structure diagrams of three types of typical explosives.

    表1 典型炸药及其代谢物对哺乳动物细胞的体外半致死浓度(LC50)

    Table 1 LC50 values of typical explosives and their metabolites on mammalian cellsμmol·L-1

    nameFLK[10]K1[9]V79[13]H4IIE[9]TK‑6[13]nameFLK
    TNT25±5.0106197±3617.622±5.0Tetryl2.2±0.3[11]
    2HA40±7.0Pentryl5.0±1.0[11]
    4HA112±1018.828.2TNC8.0±2.0[11]
    4A316±20>1270>328335248±51TNBO30±5.0[11]
    2,4‑DA350±40>1500>600>1500>600MP40±7.0[11]
    2A440±35>1270222±7691.3168±14CL‑14250±40[12]
    TAT5.2±0.80.4ANTA3000±400[12]
    NTO>3500[12]
  • 2.2 微生物毒性

    炸药的微生物毒性对其在环境中的生物降解和转化至关重要。如果环境中的炸药含量超过微生物耐受浓度,就会对微生物群落活性带来影响,进而也会影响到由微生物群落介导的关键生态系统功能,如碳氮循环。炸药微生物毒性的研究主要集中在各类细菌或真菌。到目前为止,以发光细菌中的费氏弧菌作为研究对象以监测不同炸药毒性有相对较为全面的数据。表2总结了德国的Drzyzga等以费氏弧菌为对象测试了典型炸药及其代谢物的毒性数[18]。半数效应浓度即EC50,即能引起50%效应的浓度,在该研究中以费氏弧菌的发光强度下降50%表示。

    表2 典型炸药及其代谢物对费氏弧菌的半数效应浓度(EC50)[18]

    Table 2 EC50 values of typical explosives and their metabolites on Vibrio fischeri[18]μmol·L-1

    nameTNT2,6‑DNT4A2,4‑DNT2,4‑DA2ATATTNBTNBATetrylPETNHMXRDXPA
    EC5015.827.9107.4247.5287.1>380.0738.50.91.11.646.0>84.4335.7>1900

    表2可知,常见炸药对费氏弧菌的毒性顺序为2A<2,4‑DA<环四亚甲基四硝胺(HMX)<4A<TNT<PETN<Tetryl(分子结构见图2)。其中以三硝基苯为主要骨架的TNT(EC50=15.8 μmol·L-1)、Tetryl(1.6 μmol·L-1)、2,4,6‑三硝基苯(TNB,0.9 μmol·L-1)和2,4,6‑三硝基苯甲酸(TNBA,1.1 μmol·L-1)都属于具有较高毒性的一类。硝酸酯类的PETN(46.0 μmol·L-1)和硝胺类的HMX(>84.4 μmol·L-1)具有中等毒性。而RDX(335.7 μmol·L-1)炸药毒性相对较弱。就TNT及其代谢产物而言,TNT代谢产物或转化产物相较于TNT毒性都有所降低,如4A(107.4 μmol·L-1)、2,4‑DNT(247.5 μmol·L-1)、2,4‑DA(287.1 μmol·L-1)和2A(>380.0 μmol·L-1)的毒性都相对较弱,特别是三氨基产物TAT,其EC50值为738.5 μmol·L-1,是所有测试化合物中毒性最低的。然而,表1中的细胞毒性数据则显示TAT的细胞毒性几乎是最强的(见V79、TK‑6细胞毒性数据)。由此可见,炸药毒性强弱的判断比较复杂,严重依赖于测试对象。

  • 2.3 无脊椎动物毒性

    典型炸药对无脊椎动物毒性研究多集中于慢性毒性方面。炸药慢性毒性数据对于诊断在炸药生产及使用过程中长期接触炸药人员健康状况具有重要意[19]。目前的研究主要是以蚯蚓等无脊椎动物为慢性毒性实验对象,其原因有两方面:其一是含能材料的主要污染范围为土壤污染;其二是无脊椎动物具有分布广泛,与土壤紧密接触,对污染物敏感和世代周期短等优[20]表4总结了线蚓(Ench. crypticus)的EC50毒性数据,其中EC50表示50%线蚓出现亚致死效应时土壤中的炸药浓度。

    表4 典型炸药及其代谢物对线蚓(Ench. crypticus)的EC50毒性数[3]

    Table 4 EC50 values of typical explosives and their metabolites on Ench. Crypticus[3]

    EMsoil type

    toxicity benchmark

    / mg·kg-1

    endpoint
    RDXSSL51413Repr
    CL‑20SSL0.3Repr
    TNTSSL98Repr
    TNBSSL11Repr
    2,4‑DNTSSL27Repr
    2,6‑DNTSSL57Repr

    NOTE: EM=Energetic material, Repr=Juvenile production, SSL=Sassafras sandy loam soil

    仅以表4数据来看,常见炸药对线蚓的毒性顺序为RDX<TNT<2,6‑DNT<2,4‑DNT<TNB<CL‑20。其中多环硝胺类炸药CL‑20对线蚓的毒性最高,即EC50为0.1 mg·kg-1;而单环类硝铵炸药和硝基芳香类炸药对线蚓的毒性较低,其中RDX毒性最低,EC50为51413 mg·kg-1。加拿大的Robidoux[21]测定了常见含能材料的蚯蚓毒性数据,发现长期接触TNT的蚯蚓表现出幼虫出生率降低、产卵率减少等毒性效应。近年来,Berthelot[22]开始探索炸药慢性毒性的机制,通过测定蚯蚓体内超氧化物歧化酶的活性,发现长期接触TNT的蚯蚓均处于氧化应激状态,然而其氧化应激详细机制尚未见报道。目前由于慢性毒性实验周期长,影响因素众多,包括土壤有机物含量、黏粒比例、PH及蚯蚓种类等,因此对于各类含能材料的慢性毒性机制研究目前尚缺乏清晰的认识。

  • 2.4 哺乳动物毒性

    关于典型炸药的哺乳动物急性毒性,国内外则有较多的报[23]图3总结列出了8种典型炸药以及推进剂偏二甲肼(UDMH)对大鼠的急性经口毒性数[24]。由图3可知,常见炸药对大鼠的毒性顺序为HMX<NTO<PETN<TNT<2,4‑DNT<2,4,6‑三硝基苯酚(PA)<UDMH<硝化甘油(NG)<RDX。如仅以大鼠经口急性毒性数据来看,按全球化学品统一分类标准(Globally Harmonized System of Classification and Labeling of Chemicals, GHS)[25],RDX(100 mg·kg-1)、NG(105 mg·kg-1)、UDMH(122 mg·kg-1)、PA(200 mg·kg-1)和2,4‑DNT(268 mg·kg-1)属于三类毒性物质(LD50为50~300 mg·kg-1)。另外,结构相似的炸药,其大鼠毒性数据却有非常大的差异,如硝胺类的RDX半致死剂量LD50为100 mg·kg-1,亦属于三类毒性物质;而HMX的LD50为6490 mg·kg-1,毒性未达到分类标准,属于微毒物质。又如硝酸酯类NG的LD50为105 mg·kg-1,属于三类毒性物质;而同属硝酸酯类的PETN的LD50仅为1660 mg·kg-1,属于五类毒性物质(LD50为300~2000 mg·kg-1)。可见,在生物个体层次影响毒性物质代谢的因素较多,简单以化合物种类、结构等因素来推断其毒性的强弱,难以得出规律性结论。

    图3
                            常见含能材料对哺乳动物(大鼠)急性毒性数据[24]

    图3 常见含能材料对哺乳动物(大鼠)急性毒性数[24]

    Fig.3 LD50 values of typical explosives and their metabolites on mammal (rat)[24]

  • 2.5 职业人群流行病学调查

    炸药毒性已经严重威胁到从业人员的健康。TNT是目前临床数据统计较为全面的典型炸药。最早的TNT中毒发现于20世纪20年[26]。国内最早是在1959年发现了TNT中毒性黄疸病[27]。经过长期流行病学监测发现,TNT可以导致中毒性白内障、肝炎、黄疸、再生障碍性贫血、神经损伤等病[28]。据早期国内普查资料显示,TNT中毒患病率为4%,检出率25%,居全国五种职业中毒之[29]。另外,第一次世界大战期间出现大量TNT中毒性黄疸病例,其中英国的死亡率高达25.9%[30]表3总结了1973~2012年国内不同地区的TNT生产从业人员的流行病学调查结果,主要是针对眼晶状体损伤及白内[31]表3显示,TNT导致眼晶状体损伤以及白内障的患病率非常高。周承来[32]对浙江省某化工厂的81名工人流行病学调查发现,TNT导致的晶状体受损率竟高达87.7%。近年来随着职业病防护措施的加强,相关从业人员的晶状体受损率和白内障发病率呈有限的下降趋势。此外,TNT代谢物与蛋白质的加合物常作为生物标记物,可用于监测TNT暴露环境下作业人员的健康。

    表3 国内TNT中毒流行病学调查结果统[31]

    Table 3 Statistics on the domestic epidemiological survey result of TNT poisoning [31]

    yeararealens damnify / %cataract / %
    1973China-33.0
    1986Baotou-40.8
    1988Qinghai57.3---
    199346.2---
    199840.3---
    200335.1---
    200837.2---
    1998Zhejiang83.938.725.819.4
    2000Xiangxi35.012.212.21.6
    200419.46.51.6
    2002Shangluo39.211.84.51.6
    2003Fujian39.214.9
    2004Guangxi37.3---
    2005Lianyuan24.912.94.4-
    2007Chongqing45.732.011.32.3
    2008Chenzhou24.85.24.6-
    2010Nanjing42.98.95.91.7
    2012Linyi13.0---

    另外,硝胺类炸药的代表RDX,可以导致眩晕、呕吐、痉挛、昏迷等;过量摄入可以致[33]。硝酸酯类炸药的代表NG,可以导致血管收缩、动脉血压过低、心动过速等症状,停止接触后有间歇性胸痛及心肌梗塞的危[34]

  • 2.6 职业人群TNT典型毒性效应分析

  • 2.6.1 中毒性白内障

    白内障是TNT特有的毒性效应,未见于其它炸药报道;其晶状体受损的特征一般为周边点状浑浊聚集成楔形、进而成环状甚至盘状浑浊。由前面的流行病学统计数据可以知道,TNT中毒白内障发病率非常之高,是TNT中毒最显著症状之一,已严重影响到从业人员的工作与生活。黄莉莉[35]通过给大鼠皮下注射TNT建立了动物白内障模型,并发现TNT染毒大鼠晶状体脂质过氧化物含量升高,谷胱甘肽过氧化物酶和谷胱甘肽S‑转移酶活性降低。随后,王克维[36]借助大鼠白内障模型进一步确认了晶状体中脂类过氧化是TNT诱发白内障的原因。Kumagai[37]发现牛晶状体中的ζ‑晶状体蛋白可以单电子还原TNT,导致氧化应激增强,是诱导白内障发病的潜在原因。

  • 2.6.2 血液疾病

    TNT经皮肤、消化道或呼吸道粘膜进入人体后,主要分布于血液、肝、肾组织中,其中以血液中含量最高。接触TNT可导致血液中的多项指标发生显著变化,如血清白蛋白和粘蛋白含量下降、血清超氧化物歧化酶活性升高等。当空气中的TNT浓度为0.85 mg·cm-3时,即可导致血液中平均红细胞容积增高,平均红细胞血红蛋白含量和平均红细胞血红蛋白浓度显著降[38]。重症时可导致全血细胞减少,并引起致命的再生障碍性贫血。在血液中,TNT主要是与血红蛋白、血浆蛋白等以共价结合加合物的形式存在;而对于加合物的形成机理则有不同的观点:一是单电子还原酶作用于TNT,生成硝基自由基,然后启动氧化应激机制。刘玉瑛[39]通过给予抑制剂的体内试验,发现P450酶系对TNT与蛋白加合物的生成仅是起到一定的作用。二是双电子还原酶催化代谢TNT或羟氨产物氧化,生成亚硝基产物,然后与蛋白中的巯基反应生成加合物。当血红蛋白的浓度低到一定水平时,中毒者可出现发绀,并伴有缺氧,心动过速、呼吸困难、头晕等症状,同时出现轻度溶血;严重时可发生急性循环衰竭、昏迷及休克,有生命危险。

  • 3 TNT毒性机制

    基于以上全部统计分析可以发现,典型炸药对多层次不同生物体系的毒性效应非常复杂,很难从简单的结构‑效应关系进行相对准确的判断,这也为无毒或低毒新型含能化合物的设计及应用提出了挑战。因此,深入认识炸药毒性机制,成为了一项关键且有实际意义的工作。到目前为止,针对TNT提出了两种胞内毒性机制:(1)氧化应激反应机制;(2)TNT代谢产物与DNA、蛋白质的共价结合。下面将从分子反应角度详细分析TNT的两种毒性机制。

  • 3.1 氧化应激

    氧化应激是被广泛承认的TNT中毒机制之一。一般认为,TNT进入细胞后会经过某些酶的催化,如单电子还原生成阴离子自由基(ArNO2-•);该自由基再与体内的O2反应生成超氧阴离子自由基(O2-•),见方程(1)和(2)所[10]。然后在体内超氧化物歧化酶(SOD)的催化下,O2-•会歧化反应生成过氧化氢(方程3);再继续经过氧化氢酶等催化生成H2O,最后实现活性氧(ROS)的清[40,41,42]。如果ROS大量生成,超出体内清除系统的能力,将会促使体内氧化与抗氧化作用失衡而发生氧化应激。

    ArNO2+e-ArNO2-
    (1)
    ArNO2-+O2ArNO2+O2-
    (2)
    2O2-+2H+H2O2+O2
    (3)

    基于电子自旋共振(ESR)方法,杨正[43]等在肝微粒体中以及王克维[44]在晶状体微粒体中都检测到了TNT阴离子自由基的信号,并通过脂质过氧化(LPO)、超氧化物歧化酶、过氧化物酶和过氧化氢酶等指标的变化,以证明发生了氧化应激。在此基础上,Cenas[10,12]进一步指出硝基芳香烃还原电位值越高,硝基芳香烃接受电子的能力及和单电子转移的反应能力就越强;并通过实验发现硝基芳香烃在FLK细胞系中的细胞毒性随着其单电子还原电位增加而增加,这表明与单电子转移相关的氧化应激是影响其细胞毒性的重要因素。能通过单电子转移还原TNT的酶,可以称之为单电子转移酶,主要包括肝脏中较多的NADPH:细胞色素P‑450还原酶(EC 1.6.2.4)、NADH:细胞色素b5还原酶(EC 1.6.22)、NADH:泛醌氧化还原酶(EC 1.6.5.3)、NADPH:肾上腺皮质激素还原酶(FNR,EC 1.18.1.2)、硫氧还蛋白还原酶(EC 1.6.4.5),以及晶状体中的ζ‑晶状体蛋白(EC 1.6.5.5)等(部分酶的活性中心结构如图4[45,46,47,48])。对于不同的外源化合物,其氧化应激机制都有其各自的特点,然而针对TNT导致氧化应激的关键过程的认识还是十分缺乏的。例如,TNT与单电子转移酶还原反应的物理化学本质以及热动力学信息;TNT在单电子还原的过程中再氧化和硝基化合物歧化反应之间的竞争等。

    图4
                            部分单电子酶活性中心结构

    图4 部分单电子酶活性中心结构

    Fig.4 Structure diagrams of the active centers of four single electron enzymes

  • 3.2 TNT代谢产物与蛋白质、DNA的共价结合

  • 3.2.1 TNT代谢产物与血红蛋白反应

    实验已证实TNT进入人体内可与大分子的蛋白共价结合形成加合物,其中包括血红蛋白、血浆蛋白及肝、肾组织蛋白。刘玉瑛[49]对所形成的血红蛋白和肝组织蛋白加合物结构进行了鉴定,证实了其主要成分为TNT的还原代谢产物2A和4A,残存TNT原型很少。Leung[50]进一步通过小分子GSH等的抑制反应证明,大鼠肝脏中的蛋白加合物是由TNT的亚硝基代谢物与蛋白巯基反应生成。亚硝基代谢物主要来自于酶催化TNT的双电子还原中间产物或TNT羟氨代谢产物的氧化;除了TNT经两步双电子还原生成外,还可以来自于TNT单电子还原的副产物。直到近年,Pathak[51]首次在生物体内表征出完整的芳香胺与血红蛋白的加合物。基于上述实验结果,可以推测出TNT与血红蛋白较为详细的反应机制,如图5所示。

    图5
                            TNT代谢物与血红蛋白形成加合物反应路径

    图5 TNT代谢物与血红蛋白形成加合物反应路径

    Fig.5 The mechanism of the reaction of TNT metabolites and hemoglobin forming adduct

    血红蛋白是一种α2β2四聚体蛋白质,含有6个还原性的半胱氨酸(Cys)残基,其中两个β‑Cys93残基位于蛋白质表面并且易于亲电试剂发生加合反应。由图5可见,TNT进入体内循环系统后,在P‑450R[52]等双电子还原酶的参与下被还原为亚硝基代谢物;亚硝基代谢物再经过一次双电子还原后生成羟胺代谢产物(ArNHOH)。亚硝基和羟胺代谢代谢物是引起TNT血液毒性效应的两种主要代谢物。亚硝基产物会对裸露在外的血红蛋白β‑Cys93残基末端的巯基进行氧化修饰,形成亚磺酰胺加合物,从而导致蛋白质分子天然构象遭到破坏;即加合物的形成会导致血红蛋白二级结构改变,使其失去携氧能[53]。该过程的分子反应机制如Scheme 1所示,半胖氨酸末端巯基电离形成巯基阴离子与苯环上的硝基发生反应得到中间产物碱式半硫醛,该中间产物失去一个氢氧根负离子后,以另外一种共振形式ArN=S+R和水反应形成亚磺酰胺化合[54]。此外,kiese[55]发现羟胺代谢物也可以与还原血红蛋白(HbO2)直接发生反应,生成高铁血红蛋白(MetHb)与亚硝基代谢物;但这一过程的分子反应机理尚不明确。

    Scheme 1 The mechanism of the reaction of TNT metabolites and the thiol group[54]

    另外,TNT的单电子还原过程中会产生活性氧中间体(O2-•),O2-•可以启动与血红蛋白(HbFe2+)的氧化还原循环反应(如反应(4)~反应(6)所示)[56],造成血红蛋白氧化损伤,失去携氧能力。

    HbFe2+O2+O2-+2H+HbFe3++H2O2+O2
    (4)
    HbFe2+O2+H2O2HbFe3++OH+OH-+O2
    (5)
    HbFe2+O2+OHHbFe3++OH-+O2
    (6)

    总之,TNT导致的血液毒性效应至少有两种途径,即蛋白加合物与高铁血红蛋白。蛋白加合物主要是来自于亚硝基代谢物与巯基的反应。这一过程的分子机制从已有的工作中可以有清晰的认识。至于高铁血红蛋白,主要是羟氨产物与还原血红蛋白(HbO2)的反应结果以及自由基的氧化损伤。这一过程的分子机制还缺少足够的研究,以至于还无法排除羟氨与HbO2反应也是自由基损伤机制的可能。

  • 3.2.2 TNT代谢产物与DNA反应

    炸药的基因毒性会带来更隐蔽的长期健康危害。因此研究人员以细菌、哺乳动物细[57]、无脊椎动[58]等为对象探索了典型炸药对DNA的损伤。就目前研究进展来看,TNT及其代谢物对DNA的损伤研究主要有两种认识:一是TNT在代谢过程中产生的自由基与DNA双链上鸟嘌呤发生反应,二是TNT的氨基代谢物与DNA形成加合物对DNA造成损伤。

    Homma[59]利用DNA修复酶含量较低的精子细胞研究TNT的遗传毒性机制,发现TNT的羟胺代谢物4HA,可以在Cu(Ⅱ)的存在下生成羟基自由基,进而诱导DNA损伤;TNT及其氨基代谢物并没有此类毒性机制。Talaska[60]在吸烟者的尿路上皮细胞中发现N‑(脱氧鸟苷‑8‑基)‑4‑氨基联苯,表明芳香硝基类化合物的代谢物可以与DNA形成加合物,而对DNA造成损伤;这一过程可能与芳香羟胺乙酰化和N‑羟基化过程有关。另有报[61] 称芳香羟胺可以通过形成O‑乙酰化中间体来修饰DNA,乙酰化中间体可以被转化为具有强亲电子性的ArNH+,其能够通过修饰鸟嘌呤碱基来形成加合物。TNT代谢过程中诱导DNA损伤的可能分子机制,如Scheme 2所示。

    Scheme 2 The mechanism of DNA damage induced by free radical

    羟基自由基产生的具体过程如Scheme 3所示,TNT代谢物由羟胺自由基在NADPH的作用下被还原为羟胺的过程中,在过渡金属Cu(Ⅱ)的介导下产生O2-O2-再与质子反应生成H2O2(方程3),H2O2和Cu(Ⅰ)反应生成碱式氧化亚铜,碱式氧化亚铜不稳定,分解产生羟基自由基(OH)。OH对双链DNA上的连续鸟嘌呤碱基具有高反应活性,其通过与鸟嘌呤上的双键反应在C4、C5和C8位置形成羟基加合物,从而对DNA造成损伤;与特定位置的鸟嘌呤反应甚至可以导致DNA链的断[62]

    Scheme 3 The mechanism of free radical generation induced by TNT[62]

    鸟嘌呤自由基加合物对DNA造成损伤目前发现主要有两种途径:一是游离的鸟嘌呤的C4‑OH自由基加合物通过消除OH-形成鸟嘌呤阳离子自由基。鸟嘌呤阳离子自由基会与DNA中2′‑脱氧核糖的H反应,导致DNA链断裂。二是DNA上的鸟嘌呤阳离子自由基发生水合反应生成C8‑OH自由基加合物,在氧化作用下产生8‑羟基‑鸟嘌呤,造成氧化损伤。如果细胞不能及时修复这种DNA损伤,那么这种氧化修饰的碱基比例将迅速升[63]

  • 4 结 论

    本文总结了TNT及其代谢物、RDX、HMX等几种典型炸药对细胞、微生物以及哺乳动物的毒性数据。可以看出,即使同一种炸药对于不同的试验对象也有不同的毒性表现,很难简单的总结出以分子结构来推断炸药毒性的普适性规律,实际上这也为无毒低毒的新型炸药开发带来了挑战。因此,毒性机制的研究就显得尤为重要;遗憾的是,目前仅有TNT一种炸药的毒性机制有相对较为深入的认识,其毒性机制主要有两种:一是自由基导致的氧化损伤;二是代谢物与蛋白质、DNA的加合反应。氧化损伤机制中的自由基来源已较为清楚,主要是硝基芳香化合物易受单电子转移酶催化而还原成高活性的硝基阴离子自由基而引发的系列反应;参与这一过程的单电子转移酶(图4)主要存在于肝肾脑、血液及眼晶体等组织器官的细胞中。由此可见,自由基机制几乎参与了TNT所有中毒过程;但是该机制的确定还是基于自由基防卫系统中酶活性变化的间接证据。加合反应机制中的代谢物主要来自于双电子转移酶催化还原TNT所形成的亚硝基、羟氨基以及氨基产物。

    未来含能材料毒性研究的几个重要方向:(1)除TNT外,其它典型炸药的基础毒性数据;(2)基于大量基础毒性数据,运用机器学习等方法建立炸药分子描述符与其生物毒性之间的定量构效关系,以推动新型炸药毒性的快速判断;(3)高铁血红蛋白血症、中毒性白内障、致癌致畸效应等硝基芳香类炸药典型毒性效应的分子机制;(4)新一代炸药的细胞和遗传毒性研究;(5)炸药分子的跨膜输运机制及其对细胞膜结构与性能的影响等。

    (责编:张 琪)

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      WANG Ke‑wei, ZHANG Lian‑feng, CAI You‑yu. Study on experimental animals of trinitrotoluene toxic cataract [J]. Chinese Journal of Laboratory Animal Science, 1994(4):201-204.

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魏桐

机 构:

1. 中国工程物理研究院化工材料研究所, 四川 绵阳 621999

2. 中国工程物理研究院研究生院, 四川 绵阳 621999

Affiliation:

1. Institute of Chemical Materials, CAEP, Mianyang 621999, China

2. Graduate school, CAEP, Mianyang 621999, China

邮 箱:317817244@qq.com

作者简介:魏桐(1994-),男,硕士生,主要从事含能材料酶催化代谢分子机制研究。e‑mail:317817244@qq.com

周阳

机 构:中国工程物理研究院化工材料研究所, 四川 绵阳 621999

Affiliation:Institute of Chemical Materials, CAEP, Mianyang 621999, China

角 色:通讯作者

Role:Corresponding author

邮 箱:zhouy@caep.cn

作者简介:周阳(1980-),男,副研究员,主要从事含能材料与生物学交叉方向研究。e‑mail: zhouy@caep.cn

杨治林

机 构:

1. 中国工程物理研究院化工材料研究所, 四川 绵阳 621999

2. 中国工程物理研究院研究生院, 四川 绵阳 621999

Affiliation:

1. Institute of Chemical Materials, CAEP, Mianyang 621999, China

2. Graduate school, CAEP, Mianyang 621999, China

杨宏

机 构:

1. 中国工程物理研究院化工材料研究所, 四川 绵阳 621999

3. 清华大学材料学院, 北京 100084

Affiliation:

1. Institute of Chemical Materials, CAEP, Mianyang 621999, China

3. School of Material Science and Engineering, Tsinghua University, Beijing 100084, China

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html/hncl/CJEM2019068/alternativeImage/7f94a3a5-665a-420a-b4d5-b03d6976fe4b-F005.png
nameFLK[10]K1[9]V79[13]H4IIE[9]TK‑6[13]nameFLK
TNT25±5.0106197±3617.622±5.0Tetryl2.2±0.3[11]
2HA40±7.0Pentryl5.0±1.0[11]
4HA112±1018.828.2TNC8.0±2.0[11]
4A316±20>1270>328335248±51TNBO30±5.0[11]
2,4‑DA350±40>1500>600>1500>600MP40±7.0[11]
2A440±35>1270222±7691.3168±14CL‑14250±40[12]
TAT5.2±0.80.4ANTA3000±400[12]
NTO>3500[12]
nameTNT2,6‑DNT4A2,4‑DNT2,4‑DA2ATATTNBTNBATetrylPETNHMXRDXPA
EC5015.827.9107.4247.5287.1>380.0738.50.91.11.646.0>84.4335.7>1900
EMsoil type

toxicity benchmark

/ mg·kg-1

endpoint
RDXSSL51413Repr
CL‑20SSL0.3Repr
TNTSSL98Repr
TNBSSL11Repr
2,4‑DNTSSL27Repr
2,6‑DNTSSL57Repr
html/hncl/CJEM2019068/alternativeImage/7f94a3a5-665a-420a-b4d5-b03d6976fe4b-F006.png
yeararealens damnify / %cataract / %
1973China-33.0
1986Baotou-40.8
1988Qinghai57.3---
199346.2---
199840.3---
200335.1---
200837.2---
1998Zhejiang83.938.725.819.4
2000Xiangxi35.012.212.21.6
200419.46.51.6
2002Shangluo39.211.84.51.6
2003Fujian39.214.9
2004Guangxi37.3---
2005Lianyuan24.912.94.4-
2007Chongqing45.732.011.32.3
2008Chenzhou24.85.24.6-
2010Nanjing42.98.95.91.7
2012Linyi13.0---
html/hncl/CJEM2019068/alternativeImage/7f94a3a5-665a-420a-b4d5-b03d6976fe4b-F007.png
html/hncl/CJEM2019068/alternativeImage/7f94a3a5-665a-420a-b4d5-b03d6976fe4b-F008.png
html/hncl/CJEM2019068/alternativeImage/7f94a3a5-665a-420a-b4d5-b03d6976fe4b-F009.png
html/hncl/CJEM2019068/alternativeImage/7f94a3a5-665a-420a-b4d5-b03d6976fe4b-F010.png
html/hncl/CJEM2019068/alternativeImage/7f94a3a5-665a-420a-b4d5-b03d6976fe4b-F011.png

图1 TNT中毒研究的历史进程

Fig.1 Evolvement of TNT poisoning research

图2 三种典型炸药分子的结构示意图 -- a. nitroaromatic compound

Fig.2 Molecular structure diagrams of three types of typical explosives. -- a. nitroaromatic compound

图2 三种典型炸药分子的结构示意图 -- b. nitramine compound

Fig.2 Molecular structure diagrams of three types of typical explosives. -- b. nitramine compound

图2 三种典型炸药分子的结构示意图 -- c. nitrate compound

Fig.2 Molecular structure diagrams of three types of typical explosives. -- c. nitrate compound

表1 典型炸药及其代谢物对哺乳动物细胞的体外半致死浓度(LC50)

Table 1 LC50 values of typical explosives and their metabolites on mammalian cellsμmol·L-1

表2 典型炸药及其代谢物对费氏弧菌的半数效应浓度(EC50)[18]

Table 2 EC50 values of typical explosives and their metabolites on Vibrio fischeri[18]μmol·L-1

表4 典型炸药及其代谢物对线蚓(Ench. crypticus)的EC50毒性数[3]

Table 4 EC50 values of typical explosives and their metabolites on Ench. Crypticus[3]

图3 常见含能材料对哺乳动物(大鼠)急性毒性数[24]

Fig.3 LD50 values of typical explosives and their metabolites on mammal (rat)[24]

表3 国内TNT中毒流行病学调查结果统[31]

Table 3 Statistics on the domestic epidemiological survey result of TNT poisoning [31]

图4 部分单电子酶活性中心结构

Fig.4 Structure diagrams of the active centers of four single electron enzymes

图5 TNT代谢物与血红蛋白形成加合物反应路径

Fig.5 The mechanism of the reaction of TNT metabolites and hemoglobin forming adduct

Scheme 1 The mechanism of the reaction of TNT metabolites and the thiol group[54]

Scheme 2 The mechanism of DNA damage induced by free radical

Scheme 3 The mechanism of free radical generation induced by TNT[62]

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EM=Energetic material, Repr=Juvenile production, SSL=Sassafras sandy loam soil

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