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有机磷酸酯（organophosphate esters，OPEs）阻燃剂是使用最为广泛的有机磷阻燃剂[1]，兼有增塑功能和润滑效果[2]，广泛应用于工程塑料、聚氨酯泡沫塑料、树脂以及电子设备、家装饰品、纺织品和涂料等产品[3-4]。随着溴系阻燃剂（brominated flame retardants, BFR）主要是多溴二苯醚（polybrominated diphenyl ethers, PBDEs）从2004年开始逐步在全球限制使用，OPEs阻燃剂作为其优秀替代品，在产量和用量上正快速增长[5-6]。2005年欧盟OPEs的用量达8.5万吨，2011年用量为50万吨，2015年约为68万吨[7]；而中国OPEs的消费量在2011年达到10万吨，并以每年15%的速率增长[5]。
OPEs阻燃剂是磷酸上的H被3个取代基团取代的产物。根据取代基的不同，OPEs可分为3类：氯代、烷烃类和芳基类OPEs。不同理化性质影响OPEs的环境行为和生物毒性[8]。OPEs属于添加型阻燃剂，对材料的物理机械性能影响较小[9]，兼有增塑功能和润滑效果[2]，广泛应用于工程塑料、聚氨酯泡沫塑料、树脂以及电子设备、家装饰品、纺织品和涂料等产品[3-4]。OPEs主要以物理添加方式进入到材料中，在产品的生产、使用、处理和回收的过程中，容易通过挥发、溢出或磨损等方式释放到环境介质中[3]，具有一定的环境持留性。OPEs已在大气[10-16]、灰尘[16-20]、水体[21-24]、沉积物[25-26]、土壤[26-27]和食物[26, 28]等环境介质中被检出。毒理学研究表明，OPEs具有免疫毒性、内分泌干扰效应、生殖毒性和神经毒性并具有致癌作用[6, 29-31]。
作为一类新兴环境污染物，OPEs可通过皮肤接触、灰尘摄入、呼吸和饮食等途经进入人体，对人类健康造成潜在危害[32]。OPEs在人群中暴露情况及其可能引起的各种不良健康效应受到广泛关注[33]。当前研究主要集中于孕妇人群OPEs暴露对后代生长发育的影响[34-36]。也有研究报道，OPEs暴露与人群甲状腺肿瘤发生有关联[37]。甲状腺激素和甲状腺激素受体分布于全身脏器和细胞，对于调控个体生长发育和维持机体新陈代谢起着重要作用。考虑到OPEs具有内分泌干扰效应，OPEs暴露的甲状腺毒性研究日益受到学术界关注。鉴于当前有关OPEs的研究报道集中于环境赋存、环境行为和生态毒理学[38-39]，而对于OPEs的人群暴露及甲状腺毒性的综述报道较少，本文基于国内外最新研究进展，对常见OPEs阻燃剂的人群暴露及其甲状腺毒性分别进行综述。
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人体可通过呼吸道吸入、经口摄入和皮肤吸收等途经暴露于OPEs[24, 40-41]。据估算，人类大概有70%—90%的时间是在室内中度过，材料和商品中OPEs的释放首先影响室内环境进而扩散到室外，室内环境中OPEs的浓度水平是室外环境的几百倍，室内空气和灰尘的污染可通过吸入、手口接触和皮肤吸收等多种途径影响到人们。故空气、灰尘吸入以及皮肤暴露于灰尘被认为是室内环境OPEs首要暴露途径[42]。具有挥发性的磷酸三苯酯(triphenyl phosphate, TPHP)、磷酸三丁酯(tri-n-butyl phosphate, TnBP)、磷酸三（丁氧基乙基）酯(tributoxyethyl phosphate , TBOEP)、磷酸三（2-氯乙基）酯(tri(2-chloroethyl) phosphate, TCEP)、磷酸三乙酯(triethyl phosphate, TEP)和磷酸三(2-氯异丙基)酯(tris(1-chloro-2-propyl) phosphate，TCIPP)易以蒸气形式存在大气或者吸附在大气颗粒物上，是室内空气和灰尘中常见OPEs类型。其中，TCEP具有较高化学稳定性，是道路灰尘的主要检出物，比起主要通过灰尘摄入的TBOEP和TPHP，空气吸入是主要途径[43]。氯代OPEs具有高持久性，对降解具有相对稳定性，可在一段时间内在室内环境中聚集，其中TCIPP检出率最高，其吸入暴露远远超过消化道吸收途径[43]。与灰尘有关的OPEs对人类来说具有相当大的威胁，因为它们可以通过空气吸入、摄入重新悬浮的灰尘颗粒、皮肤吸收和手口接触而误食等多种方式联合暴露。
经膳食和饮水摄入是人体OPEs暴露另一个重要途径[45]。食物中OPEs有两种来源方式[46-47]。一是环境介质中OPEs通过食物链进入食物。Zhang等在中国北部湾某海鲜养殖场的池水、沉积物、饲料和养殖物均检测出11种OPEs，且发现OPEs在沉积物、饲料和养殖物中平均浓度呈递增趋势，提示OPEs可在食物链中迁移并在生物体内富集[48]。Wang等在肉类、海鲜、乳制品、谷物、食用油和食品包装上均检出15种OPEs，其中肉类ΣOPEs（Median：6.76 ng·g −1ww）和海鲜（Median：7.11 ng·g −1 ww）的检出浓度最高；肉类占成人OPEs膳食摄入总量的47%，而乳制品占儿童OPEs膳食摄入总量的52%[49]。Ding等分析中国东部某城市的鸡肉、猪肉、鱼类、蔬菜、豆制品、谷物和蛋类等食品样品[50]，其中10种OPEs的总残留浓度为1.1—9.6 ng·g −1 fw（鲜重），谷物是城乡居民膳食OPEs的主要来源（占总膳食的55.5%—62.5%）且残留水平高（4.9 ng·g −1 fw）。二是食物在生产、加工和储存过程被包装材料中OPEs污染。尽管不同国家人群经食物摄入OPEs类型存在较大差异，但是作为食品包装材料成分的EHDPP，在世界各国的加工食品中被普遍检出。对于婴幼儿来说，母乳是一个重要的食物暴露源，在多个亚洲和欧洲国家哺乳期的妇女母乳中均有检出芳基类和烷基类OPEs[51-52]。
皮肤直接接触含OPEs的水或者产品也是人体暴露OPEs途经之一。皮肤吸收一般通过监测经擦拭皮肤的湿巾纸中OPEs含量来评估分析，TCEP、TCIPP和磷酸三（1,3-二氯异丙基）酯(Tris(1,3-dichloroisopropyl) phosphate, TDCIPP)被证实可经皮肤吸收暴露[53-54]，而且疏水性较强的化合物皮肤吸收可能会时间滞后[55]。TDCIPP、TCEP和TPHP在擦拭皮肤的湿巾中检出率超90.6%，被发现可能存在手口接触摄入和皮肤吸收途径暴露[56-57]。一些研究发现，从51名加拿大妇女的手、手机和家庭粉尘中检出OPEs能够解释其尿液OPEs总浓度8%—33%的变异[58]，3名美国成年人手中TDCIPP和TPHP浓度与尿样代谢产物具有统计学关联[56] ，而26名美国妇女通过指甲油暴露于TPHP，这说明成年人可通过手口接触和皮肤接触暴露于OPEs。
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生物监测是OPEs人群内暴露监测主要实施手段。尿液是最常用的评估人体OPEs内暴露的生物材料。体内和体外实验证实， OPEs在体内容易通过I相和II相代谢反应形成有机磷酸二酯(di-OPEs)从尿液排出[59]，故国内外许多研究将人体尿液中di-OPEs 作为暴露标志物，用来评估人体OPEs内暴露[29, 60]（见表1）。除了尿液，血液和羊水也被用于监测di-OPEs的生物材料。Hou等分析尿液和匹配的血液后发现，除了BCIPP和di-o-cresyl phosphate（DoCP），其余di-OPEs（如DnBP、DiBP、BBOEP、BCEP、BDCIPP、DPHP和BEHP等）在尿液中检出频率和浓度均高于血液样本，而相对于全血，血清样本中所有9种目标di-OPEs的检出频率和浓度均较低[61]。Bai等在我国汕头某电子垃圾地区的孕妇尿液及配对的羊水中均检出DnBP （GM: 2.9 ng·mL−1, 1.3 ng·mL−1）和DPHP （GM: 0.94 ng·mL−1, 0.12 ng·mL−1），且尿液样本浓度比羊水样本高2倍以上[62]。另一方面，有机磷酸三酯(tri-OPEs)也被作为暴露标志物，用于评估人体OPEs内暴露。血样样本应用最多，其次是母乳（见表2）。头发中OPEs被认为是来自空气和灰尘的外暴露和内暴露的组合。Kucharska等分析48个母亲和54个子女的头发和尿液样本，发现头发可作为OPEs暴露评估的指示材料[63]。Ding等分析我国华东地区50份人体胎盘样本，检出率最高的是TCEP，其次是TBOEP和TPHP，tri-OPEs检出量（34.4—862 ng·g−1 lw）比多溴二苯醚（PBDEs）检出浓度高一个数量级，这是第一次研究胎盘中OPEs暴露[64]。
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人群OPEs暴露存在明显地域差异。以DPHP为例，澳大利亚人浓度水平高达63400 pg·mL−1[65]，其次是挪威成年人(24000 pg·mL−1) [66]。中国和美国人群普遍检出DPHP，但是美国人浓度水平(8150 pg·mL−1)要高于中国人(1200 pg·mL−1) （见表1）。就OPEs类型而言，世界各国人群普遍暴露于芳基类和含氯类OPEs。章涛等研究了中国14个省市普通人群和儿童尿样中8种OPEs代谢产物，发现中国居民普遍暴露于OPEs，在10个省、市中人群暴露以氯代OPEs为主，4个地区以非氯代OPEs暴露为主[29]。Ding等检测成年人尿液OPEs代谢产物水平，结果显示一般成年人均暴露于多种氯代OPEs，尤其是磷酸二(1,3-二氯异丙基)酯[Bris(1,3-dichloroisopropyl) phosphate, BDCIPP] 暴露水平高(6200 pg·mL−1)，远高于DPHP含量水平(400 pg·mL−1) [67]；Petropoulou等检测美国成年人尿液中4种OPEs代谢物含量水平，发现3种氯代OPEs，尤其是磷酸二（2-氯乙基）酯[Bri(2-chloroethyl) phosphate, BCEP]暴露水平较高，约为DPHP含量水平的2倍[80]。Su等检测加拿大成年人尿液也发现3种氯代OPEs，其中磷酸二(2-氯乙基)酯[Bis(2-chloroethyl) phosphate, BCEP] 的浓度水平最高(12330 pg·mL−1)，接近DPHP含量水平的10倍[69]。但是，澳大利亚成年人尿液样本中DPHP含量水平(63400 pg·mL−1)远高于含氯类OPEs(660 pg·mL−1) [65]。烷基类OPEs暴露仅见中国人群报道最多，其次是美国和挪威人群(见表1)。
人群OPEs暴露特征与年龄、职业密切相关。Hu等在评估中国广州地区经呼吸道摄入（室内和室外环境）的OPEs暴露风险时发现，成年人是危害熵（Hazard Quotient，HQ）和终身致癌风险（Incremental life cancer risk，ILCR）最高的人群，紧接着是青少年和儿童，最低的为老年人[98]。但是，van den Eede等分析澳大利亚居民尿样中9种di-OPEs，结果显示，di-OPEs浓度水平与年龄呈负相关，且儿童中DPHP和BDCIPP的浓度显著高于成人水平，提示儿童是某些类别OPEs的高暴露人群[65]。Chen等检测中国儿童尿液OPEs代谢产物，结果发现BCEP的检出率和浓度最高，而DPHP次之，说明中国儿童以氯代和芳基类OPEs暴露为主[73]。Cequier等发现挪威子女尿液中4种二烷基和二芳基有机磷酸（Dialkyl and diaryl phosphates, DAPs）的浓度远高于母亲，提示当地儿童对于烷基OPEs和芳基OPEs的暴露比较敏感[93]。针对孕妇人群，Hoffman等分析美国孕妇尿液，结果显示DPHP与BDCIPP检出率相同（97.4%）[81]，前者含量水平略高于后者；而Feng等检测我国孕妇尿液，发现BDCIPP检出率仅17%而DPHP全部可检出，两者含量水平分布相近[74]。Shi等分析某电子垃圾回收处理场附近成年工人和儿童尿液标本，结果显示，儿童有比成人更低的di-OPEs暴露水平，提示成年人的职业OPEs暴露风险不容忽视[23]。
OPEs在过去数十年在产量和用量上正快速增长，大量的研究数据表明人群暴露的形势越来越严峻，暴露的OPEs种类越来越多，浓度值也呈现递增趋势。Hoffman等收集了近10年本实验室进行的14项关于OPEs的流行病学研究发现[99]，尿液种TDCIPP的代谢产物BDCIPP自2002年起始呈急剧增长态势，仅2014—2015年比过去10年浓度水平增长15倍之多，TPHP的代谢产物DPHP也增速迅猛。随着暴露量增加，对人群健康危害问题迫切需要关注。
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目前大部分研究，都以美国国家环境保护局（U.S. Environmental Protection Agency, USEPA）建立的人体暴露评估模型[100]和已有的文献[26, 101-102]中获得参数，以计算OPEs的暴露量，具体计算公式如下：
呼吸吸入途径：EDIA=CAir×IR×IEF/BW
式中，EDIA为空气中 OPEs通过呼吸的日摄入量估算值，ng·kg−1·d−1bw；CAir为空气（气态和颗粒态）中OPEs浓度，ng·m−3；IR为室内空气日吸收速率，m3·d−1；IEF为日暴露比率，无量纲； BW为体重，kg。
经口摄入途径：EDID=CDust×IR×IEF/BW
式中，EDID为粉尘中 OPEs通过经口摄入的日摄入量估算值，ng·kg−1·d−1bw；CDust为粉尘中OPEs浓度，ng·g−3； IR为粉尘中OPEs日吸收速率，g·d−1； IEF为日暴露比率，无量纲；BW为体重，kg。
皮肤吸收途径：EDIDA = 10×CDust×BSA×SAS×ABS×IEF/BW
式中，EDIDA为灰尘中OPEs通过皮肤吸收的日摄入量估算值，ng·kg−1·d−1bw； BSA为暴露在环境中的皮肤面积，m2； SAS为皮肤对灰尘的吸附系数，mg·cm−2·d−1； ABS为皮肤对灰尘中OPEs的吸收系数，无量纲。
OPE的环境持留性和食物链的生物放大效应不如PBDEs强烈，但OPEs在世界范围内被持续大量使用，OPEs在人群膳食中普遍存在。人平均每日摄入量DI计算公式如下：
式中，Ci为食品中OPEs的中位浓度；CFi为食品每日消耗量（中位数），ng·kg−1· d−1bw
评估人群OPEs暴露风险的危险熵值（Hazard quotient, HQ）计算公式如下：
其中，RfD用于描述每种OPEs的参考剂量(Reference dose, RfD)，既往文献[102-107]中和USEPA（2017年）修订提供相关毒理学参数（见表3）。当HQ≥1时，认为具有健康风险。每种OPEs的HQ总和为危险指数（Hazard index，HI），计算公式如下：
Li等[103]完善了OPEs的风险评估模型，提出计算通过摄入和皮肤接触暴露于室内灰尘中OPEs的慢性摄入量（Chronic daily intake, CDI）公式如下：
其中，CDIingestion为室内灰尘的摄入相关的每日摄入量[mg·(kg·d)−1]，CDIdermal contact为皮肤接触灰尘摄入相关的每日摄入量[mg·(kg·d)−1]，Ci为某种OPEs浓度（mg·kg −1），IR为室内灰尘的摄入率（mg·d −1），ED为持续暴露时间（a），EF为暴露频率（d·a-1），CF为转换因子（0.01 g·mg −1），SA为与灰尘接触的皮肤表面积（cm2），AF为皮肤黏附因子（mg·m−2）。
非致癌风险评估基于危险系数（HI）和危险熵值（HQ），对于通过意外摄入和皮肤接触暴露于多种OPEs的风险，计算公式如下：
致癌风险的计算公式如下：
SFO为经口风险斜坡因子（oral cancer slope factor, SFO）
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环境污染物的甲状腺毒性通常指污染物通过改变甲状腺及其所分泌的甲状腺激素水平而产生的生物毒性。甲状腺激素在促进生长发育和调控产热及物质代谢方面起重要作用，又在调节人体中枢神经系统发育和维持神经系统功能等方面发挥至关重要的作用。甲状腺受神经-内分泌系统共同调节，与下丘脑和垂体构成下丘脑-垂体-甲状腺轴(hypothalamus-pituitary-thyroid axis, HPT) 体系，并通过HPT轴对甲状腺激素稳态进行动态调节。OPEs暴露引起甲状腺毒性，其对HPT轴体系可能的作用模式(mode of action, MOA)包括：①OPEs直接作用于甲状腺组织，产生甲状腺腺体损伤，即暴露-甲状腺组织-肿瘤；②OPEs影响控制递送甲状腺激素到靶细胞或组织的蛋白，或者干扰肝脏代谢和胆汁排泄，影响甲状腺激素的合成、转运、结合和代谢等过程，从而干扰甲状腺激素内环境的稳态，继而改变循环血中甲状腺激素水平，导致产生不良健康效应，即暴露-激素稳态-效应。
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OPEs暴露对甲状腺的损伤主要表现在甲状腺组织形态学的改变和甲状腺肿瘤的发生。已有动物实验显示，给SD大鼠每天染毒TDCPP（80 mg·kg−1 bw），12个月和24个月后雌性和雄性大鼠均出现甲状腺重量增加，而且雌性大鼠的甲状腺腺瘤发生率提高，甲状滤泡旁细胞瘤发生率也略微上升；给F-344大鼠每周5 d染毒TCEP（88 mg·kg−1 bw），103周后雄性大鼠的甲状腺滤泡腺瘤发生率略有上升[31]。一项人群流行病学研究发现，人暴露于室内灰尘中高浓度TCEP与甲状腺乳头状癌发生呈正关联[OR=2.42（1.10, 5.33）, P=0.03]，而暴露于室内灰尘中高浓度TPHP仅与较低恶性程度的人甲状腺乳头状癌发生呈正关联[OR=3.63（1.26, 10.4）, P<0.05][106]。但是，另一项人群病例-对照研究显示，尿液中DPHP、BCIPP、BDCIPP、BCIPHIPP等di-OPEs浓度水平与人甲状腺癌患病风险无关联[37]。可见，研究结论存在不一致。
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通过影响THP轴来改变生物体甲状腺激素稳态是OPEs暴露产生不良健康效应重要作用模式。这里的甲状腺激素包括3,5,3′,5′-四碘甲状腺原氨酸,即甲状腺素（Thyroxine, T4）、3,5,3′-三碘甲状腺原氨酸（3,5,3′-triiodothyronine, T3）、促甲状腺激素释放激素（Thyortropin releasing hormone, TRH）、促甲状腺激素（Thyroid stimulating hormone, TSH）、血清游离3,5,3′,5′-四碘甲状腺原氨酸,即甲状腺素（free thyroxine, fT4）和游离3,5,3′-三碘甲状腺原氨酸（free 3,5,3′-triiodothyronine, fT3）、血清总3,5,3′,5′-四碘甲状腺原氨酸（total thyroxine, tT4）和总3,5,3′-三碘甲状腺原氨酸（total 3,5,3′-triiodothyronine, tT3）等。关于OPEs暴露对于各种生物体甲状腺激素水平的影响目前仍然存在较大的争议（表4）。
斑马鱼是研究最多的受试生物。将斑马鱼胚胎暴露于不同浓度的TDCPP，结果发现，仔鱼T4的含量显著降低，而T3含量升高[107]；但是将斑马鱼暴露于TPHP，仔鱼体内T3和T4含量均显著增加[111]。较低剂量TBOEP（0— 2000 μg·L−1）暴露也显著增加了斑马鱼仔鱼体内T3和T4的含量，会使斑马鱼胚胎畸形率增加，发育延缓及心率降低[109]。OPEs暴露还表现出性别差异。雌性斑马鱼对TDCPP暴露敏感，能在脑组织蓄积TDCPP；长期暴露于低浓度TDCPP会改变雌性鱼体中枢神经系统基因表达，导致神经行为毒性作用[113]。最近研究发现，将斑马鱼暴露于TDCPP和TPHP在14d后，雄鱼血浆T3和T4水平显著降低而雌鱼升高，这与暴露改变了HPT轴相关基因表达有关；TDCPP和TPHP暴露引起雄鱼脑组织中促肾上腺皮质激素释放激素(Corticotropin-releasing hormone, CRH)和TSH转录水平上调，但是雌鱼体内CRH和TSH表达下调；同时雄鱼的甲状腺和肝脏组织中甲状腺球蛋白(Thyroglobulin, Tg) 和脱碘酶(Deiodinase type 2, DIO2)表达下调[111]。
就鸟类而言，TDCIPP处理组中鸡胚血清fT4含量显著降低[112]，TEP处理组呈现类似结果[113]，但是在TCIPP处理组中血清fT4水平没有显著变化。在哺乳动物实验研究中，TDCIPP暴露显著上调了大鼠的脱碘酶(Deiodinase type 1, DIO1)、甲状腺素运载蛋白(Transthyretin, TTR)、甲状腺激素清除酶(Udp-glucuronosyltransferase-1A6, UGT1A6)以及甲状腺激素合成相关基因(NIS, TPO及Tg)的表达，引起大鼠血清中T3的浓度显著升高，但不影响tT4和fT4的含量，这提示TDCIPP暴露能影响HPT轴体系中与甲状腺激素的合成、转运、代谢以及清除、反馈等蛋白的基因表达，从而导致甲状腺功能紊乱[117]。
相对于传统的整体生物实验，离体生物实验使暴露后效应变化更容易判别与获取。体外细胞研究表明，将大鼠垂体瘤细胞(Rat pituitary cell lines, GH3)暴露于一定剂量的TPHP，处理48 h后在TPHP暴露组中促甲状腺释放激素基因的表达显著增加；进一步用TPHP处理大鼠甲状腺囊泡细胞(Thyroid follicular cell lines, FRTL-5)24 h后，TPHP暴露组中钠碘转运体(Sodium iodide symporter, NIS)及甲状腺过氧化物酶基因(Thyroid peroxidase, TPO)的表达显著增加，这说明TPHP直接作用于脑垂体细胞及甲状腺滤泡刺激甲状腺激素的合成。
OPEs暴露可能还通过干扰生长激素或性激素水平，间接发挥发育毒性效应。一项动物试验显示，将斑马鱼幼鱼暴露于环境相关剂量的TDCIPP（6300 ng·L−1）在120 d后，雌性斑马鱼的体长变短、体指数和性腺指数均显著下降，并引起生长激素/胰岛素样生长因子（GH/IGF）轴相关基因表达下调，后者显著影响幼体生长[115]。
甲状腺激素主要是通过细胞中甲状腺激素受体(Thyroid hormone receptor, TR)发挥作用。人的TR由TRα和TRβ两个基因编码，产生TRα1、α2、TRβ1、β2等异构体。在T3作用下，TR与称作T3依赖性辅激活蛋白的蛋白结合促进转录，在T3不存在的情况下与协同抑制因子结合，发挥抑制目的基因转录活化的作用。陆美娅等通过TRβ介导的报告基因实验检测发现，9种OPEs（TBP、TCP、TPP、TBOEP、TCEP、TDCIPP、TCIPP、TBPP和TEHP）均无激动活性，而其中4种则表现出显著的抗甲状腺激素效应，活性的大小顺序为TCP>TBP>TCIPP>TDCIPP；分子对接结果表明，OPEs甲状腺激素活性的强弱程度，取决于它和TRβ不同的结合方式，结构中含有苯环、卤素及短链的OPEs可能更容易表现出拮抗效应[116]。Ren等通过体外细胞增殖实验和荧光素酶报告基因实验，评估了4种OPEs(TMP、TEP、TCEP和TDCIPP)对TRα/β活性的影响，发现TDCPP能够更有效地结合配体结合区(ligand-binding domain，TRβ-LBD)，对TRβ产生明显的拮抗活性[123]。Zhang等通过荧光素酶报告基因发现4种OPEs(TDCIPP、TCIPP、TnBP和TMPP)对TRβ活性有拮抗作用，且拮抗作用逐渐增强，即拮抗活性TDCIPP<TCIPP<TnBP <TMPP [118]。目前人群流行病学研究资料十分有限。Preston等分别在同年的1、6、12月检测了51名成年人尿液中DPHP浓度和血液甲状腺功能相关激素，发现DPHP的浓度与血清中FT4、TT3和TSH没有显著相关性，仅与TT4水平升高相关[84]。Meeker等也发现室内灰尘中TDCPP的浓度与男性血液fT4的浓度呈显著负相关[87]。另一项研究检测男性尿液中TDCIPP、TPHP及其代谢产物BDCIPP和DPHP，发现尿液中BDCIPP和DPHP的浓度与血清中TT3含量呈正相关，而且尿液中BDCIPP浓度与体内TSH的含量呈正相关[119]，而与血清fT4没有显著相关。
甲状腺激素是维持胎儿和新生儿正常生长发育的关键激素。OPEs暴露通过改变甲状腺激素水平，间接产生发育神经毒性作用[35]。人群流行病学研究发现，美国孕妇尿液中TPHP浓度每增加10倍，出生后7岁儿童的IQ减少2.9分（CI:−6.3, 0.5）以及学习记忆减少3.9分（CI:−7.3—−0.5）[36]；中国孕妇尿液中DPHP高负荷水平与女性新生儿低出生体重风险有显著的相关性（P
<0.05）；这些提示TPHP/DPHP暴露可能会影响子代神经发育以及产生出生缺陷[34]。 -
迄今为止，关于OPEs的人群暴露特征及其甲状腺毒性的相关研究受到热切关注，未来亟需研究和解决的问题和挑战有：
（1）人群OPEs暴露评估方法比较单一。大部分人群暴露研究来自点尿样，易受采样时间、污染物代谢动力学差异等因素影响，造成暴露评估不确定性较高。OPEs体内代谢过程复杂，一些羟基化代谢产物例如4-OH-TPHP已被报道[123]，且一些OPEs例如TCEP在体内代谢效率较低，更多以原型形式排泄[52]，仅用di-OPEs作为尿液暴露标志，容易低估人群暴露风险，需要筛选新型暴露生物标志和合适的生物监测手段，以便真实全面地反映OPEs的人体负荷水平。另外，环境介质中OPEs赋存水平研究较多，但人群OPEs内暴露特征研究较少，而涉及OPEs内外暴露关联的研究鲜见报道，在完成定量检测的同时也要合理建立内外暴露剂量之间的关系，需开展生理毒物代谢动力学（PBTK）模型研究。
（2）OPEs暴露对哺乳动物甲状腺内分泌系统危害的研究非常有限。目前动物试验研究的暴露途经单一，暴露剂量一般较高。而人类可从多种媒介中暴露于低浓度的OPEs。因此，需要关注不同暴露途径，如灰尘吸入、皮肤接触暴露等，在长期低剂量下，同时考虑不同暴露敏感期，以准确评估OPEs的甲状腺毒性。
（3）甲状腺毒性作用机制研究有待深入探究。目前研究的观察指标仅是甲状腺激素的升高或者下降，以及相关的HPT轴调控基因表达改变等，缺少对OPEs暴露与甲状腺肿瘤发生的分子机制深入探究。需要深入研究OPEs暴露影响子代甲状腺内分泌系统的作用机制，从而阐释OPEs暴露对儿童神经发育毒性作用机制。
（4）OPEs与其他污染物的相互作用报道较少。OPEs在环境中并不是单一存在的，由于具有环境持久性和高生物蓄积性，PBDEs以及有相似结构的PCBs在我国仍然广泛存在于环境中[124]。例如，Hoffman等人同时检测TPHP和BDE-47 [108]。但目前缺乏对OPEs与其他污染物的联合暴露毒性作用的研究，尤其是模拟真实环境下低浓度、长时间、联合暴露毒效应的研究。
（5）有关OPEs环境污染的人体健康危害流行病学研究缺乏。当前，我国关于OPEs健康风险评估研究更多在环境赋存水平检测，反映人体暴露水平的数据有限，更缺乏探究健康危害的人群流行病学研究数据。对于这样一种在我国使用量正日益增大的新型环境污染物，亟待深入开展OPEs的人群流行病学研究，对于准确评估我国人群OPEs暴露的潜在健康风险具有重要意义。目前OPEs现有的毒理学数据尚不完全，应填补暴露和风险评估之间的空白，高度重视相关风险管理、制定环境安全阈值，出台政策法规以限制部分OPEs的过度使用，保护人类健康和环境的可持续发展。
（6）OPEs具有可降解性，在评价膳食暴露时，应将烹饪方式也纳入考量，若能在同一队列中分析膳食暴露和OPEs及其代谢产物，也须制定符合中国国情的健康指导值，有助于理解不同OPEs人体负荷的暴露途径。
有机磷酸酯阻燃剂的人群暴露和甲状腺毒性的研究进展
A review of organophosphate esters (OPEs): Human exposure and toxicities in thyroid
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摘要: 有机磷酸酯（organophosphate esters，OPEs）是使用最为广泛的有机磷阻燃剂，并兼具增塑剂、消泡剂和萃取剂等功能，被广泛用于电子产品、建筑材料和塑料材料等中，导致其在环境介质中普遍存在，对生态系统和人体健康构成巨大威胁。作为一种新型环境污染物，OPEs的人群暴露特征和生物毒性成为环境健康领域的研究热点。本文系统综述了OPEs的人群暴露特征和甲状腺毒性的研究进展，最后对存在的问题和未来研究方向进行了分析和展望。Abstract: Organophosphate esters (OPEs) are the most widely used organophosphorus flame retardant and has the functions of plasticizer, defoamer and extractant, added in electronic products, building materials and plastic materials, etc. The widespread use of OPEs has resulted in their ubiquitous occurrence in environmental media, which pose a threat to both ecosystems and human health. As a type of emerging environmental pollutants, human exposure to OPEs and related toxicity have become a research hotpot in the field of environmental health. In this paper, the research progresses on the population exposure to several kinds of OPEs and its toxicities in thyroid system were summarized. Finally, the gaps in our knowledge of human exposure assessment and thyroid toxicity of OPEs were highlighted and critical directions for future studies were proposed.
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表 1 主要di-OPEs的国内外人群平均内暴露水平（pg·mL−1）
Table 1. Typical di- OPEs levels among population reported in various studies worldwide（pg·mL−1）
国家或地区
Sample site年份
Time人群
Population年龄
/岁
Year数量a
n样本类型
Type芳基类
Aryl-烷基类
Alkyl-含氯类
Chlorinated-参考文献
ReferenceDPHP DEP DnBP BEHP BBOEP BCEP BCIPP BDCIPP 中国 2018* 电子拆解工人 — 88 尿液 700 — — — — 1770 N.D. 230 Yan等[70] 垃圾回收厂工人 — 30 尿液 110 — — — — 1440 N.D. 220 2018* 成人 17—87 52 尿液 177 — 230 6760 2650 2570 150 291 Hou等[61] 57 全血 92 — 123 4480 328 <LOQ 370 <LOQ 57 血清 14 — <LOQ 3080 <LOQ <LOQ 121 <LOQ 2016—2017* 成人 — 26 尿液 240 — 48 — 110 — — 230 Tao等[71] 2016—2017 孕妇 — 15 尿液 940
1200*— 2900
2200*— 87 — — 270 Bai等[62] 羊水 120
180*— 1300
1200*— <LOQ — — <LOQ 2016—2017 成人和儿童 4—90 180 尿液 32.4 376 8.04 49.1 69.1 1.73 22.8 5.31 Sun等[61] 2016 儿童 0—5 227 尿液 250 — — — 50 670 810 80 Zhang等[72] 2015 成人 306 尿液 400 — — — 100 1000 200 6200 Ding等[67] 2015* 儿童 6—14 411 尿液 280 — 120 — 50 1040 150 50 Chen等[73] 2015* 怀孕妇女 — 23 尿液 1100 — — — — — — 1200 Feng等[74] 2014 成人和儿童 0.4—87 221 尿液 550 — 290 — 65 720 94 91 Lu等[42] 2014—2016 孕妇 28.8±4.3 113 尿液 220 — — — 50 — — 120 Luo等[34] — 儿童 12—15 306 尿液 420 — — — N.D. 1000 180 6170 丁锦建等[75] 美国 2018 成人 33.8±12 213 尿液 1060 348 16.8 13.4 32.6 354 83.8 414 Wang等[76] 2015 母亲 — 28 尿液 1200 — — — — — — 3300 Butt等[77] 子女 2—70个月 33 尿液 2900 — — — — — — 10900 2015 成人 — 76 尿液 890 — — — — N.D. N.D. 690 Jayatilaka等[78] 2010—2011 消防员 — 146 尿液 2900 — — — — 860 240 3400 2013—2014 母亲 — 22 尿液 1900 — — — — — N.D. 2400 Butt等[79] 子女 — 26 尿液 3000 — — — — — N.D. 5600 2013—2014 儿童 15—18个月 21 尿液 3370 — — — — — — 6810 Thomas等[80] 儿童 — 20 尿液 8150 — — — — — — 2700 — 成人 — 13 尿液 1500 3400 400 2500 Pretropoulou等[68] 2011—2012 孕妇 28—36 39 尿液 1900 — — — — — — 1300 Hoffman等[81] 2011 成人 — 16 尿液 440 — 110 — N.D. 630 N.D. 90 Dodson等[82] 2011 成人 23—46 9 尿液 2974 — — — — — — 410 Cooper等[83] 2010—2011 成人 40±12.7 47 尿液 2990 — — — — — — — Preston等[84] 46 尿液 1800 — — — — — — — 42 尿液 2110 — — — — — — — 2009 成人 49* 29 尿液 — — — — — — — 408 Carignan等[85] 2008* 母亲 32.6±4.1 96 尿液 2500 — — — — — 700 1100 Gibson等[86] 儿童 4.8±0.8 90 尿液 3200 — — — — — 900 2600 2002—2007 成年男性 18—54 61 尿液 310 — — — — — — 130 Meeker等[87] 2000—2001 孕妇 26 310 尿液 930 — — — — — N.D. b 280 Castorina等[88] 澳大利亚 2010—2013 成人和儿童 — 72
23尿液 24400
63400—
——
——
—<LOQ
N.D.—
——
—1000
660van den Eede等[65] 波多黎哥 2011—2015 孕妇 18—40 141 尿液 15100 — — — — 1120 260 1150 Ingle等[89] 加拿大 2014 成人 — 12 尿液 N.D.—
1290— N.D. N.D. N.D. N.D. —12330 N.D. —680 N.D. —1170 Su等[69] 2010—2012 孕妇 18—45 24 尿液 2880 — — — 380 <LOQ <LOQ 270 Kosarac等[90] 挪威 2015* 母亲 32—54 244 尿液 630 — N.D. — N.D. — — 80 Cequier等[91] 子女 6—12 112 尿液 1000 — N.D. — N.D. — — 230 2013—2014* 成人 — 55 头发 24000 — <LOQ — — — — <LOQ Xu等[66] — 61 尿液 610 — 99 — <35 — — 68 a 收集样本数，the number of collected samples； b N.D.：未检出，N.D. this chemical was not detected in all samples； c <LOQ：小于定量限，geometric mean or median concentration was lower than the limit of quantification ； — 没有数据，data unavailable；* 暴露水平为中位数，the concentration was shown by median 
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表 2 主要tri-OPEs的国内外人群平均内暴露水平
Table 2. Typical tri- OPEs levels among population reported in various studies worldwide
国家或
地区
Sample
site年份
Time年龄
/岁
Year数量a
n类型
Type芳基类
Aryl-烷基类
Alkyl-含氯类
Chlorinated-单位
Unit参考文献
ReferenceTPHP TMPP EHDPP TEP TnBP TEHP TBOEP TCEP TCIPP TDCIPP 中国 2019 29—94 232 血浆 N.D. b 0.79 0.72 1.1 N.D. N.D. — — N.D. — µg·L−1 Li等[92] 56 血浆 6.01 N.D. N.D. 0.16 0.88 N.D. — — N.D. — µg·L−1 2018* 17—87 57 全血 0.366 — 1.100 0.432 0.176 <0.145 0.164 <0.194 <0.166 <0.393 ng·mL−1 Hou等[62] 57 血清 <0.307 — 0.933 0.196 0.154 <0.145 0.209 <0.194 1.05 <0.393 ng·mL−1 52 尿液 <0.061 <0.002 <0.016 0.075 <0.006 <0.091 0.038 <0.039 <0.033 <0.079 ng·mL−1 2018 22—88 89 血清 10.2 — — — 10.3 — — 227 1.0 — ng·g−1 lwd Gao等[93] 2015 — 9 血清 <4.2 — — — 3.4—
46.5— — 248.6—958.2 — — ng·g−1 lw Li等[94] 2013* 18—87 99 血液 0.35 — 0.85 0.15 N.D. N.D. 0.05 0.1 0.05 N.D. ng·mL−1 Ya等[95] 2012* 20—50 257 全血 0.43 0.09 1.22 0.49 37.8 0.04 0.54 <0.31 0.71 N.D. ng·mL−1 Zhao等[96] 2005* 18—37 50 胎盘 15.1 — N.D. 10.2 N.D. N.D. 16.7 142 — N.D. ng·g−1lw Ding等[64] 挪威 2012 32—56 48 头发 52 — 27 — 22 12 65 72 — 30 ng·g−1 Kucharska
等[64]6—12 54 头发 63 — 21 — 11 8 318 59 — 美国 2009—
201219—40 100 母乳 0.149 0.021 0.022 0.350 0.539 0.245 1.44 0.036 0.221 — ng·mL−1 Ma等[97] 日本* 2009—
201125—42 20 母乳 1.4 N.D. N.D. N.D. 0.39 — 0.24 0.14 — N.D. ng·g−1 lw Kim等[51] 菲律宾* 2008 17—45 41 母乳 19 2.3 N.D. N.D. 1.5 — N.D. 42 — N.D. ng·g−1 lw 越南* 2008 21—34 26 母乳 4.9 0.28 N.D. N.D. 2.0 — N.D. N.D. — N.D. ng·g−1 lw 瑞典* — — — 母乳 8.5 — 6.5 — 12 — 4.7 4.9 — 4.3 ng·g−1 lw Sundkvist
等 [52]a 收集样本数，the number of collected samples； b N.D.：未检出，N.D. this chemical was not detected in all samples； c <LOQ：小于定量限，geometric mean or median concentration was lower than the limit of quantification ；d lw: lipid weight ；— 没有数据，data unavailable；* 暴露水平为中位数，the concentration was shown by median.
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表 3 OPEs毒理学参数
Table 3. Toxicological parameters of OPEs
RfD[41]a RfD[104] a RfD[100] a SFO[100]b GIABS[100]c ABS[102]d TMP — — 0.01 0.02 1 0.1 TnBP 0.0024 0.024 0.01 0.009 1 0.1 TCIPP 0.008 0.008 0.01 — 1 0.1 TCEP 0.0022 0.0022 0.007 0.020 1 0.1 TDCIPP 0.0015 0.0015 0.02 — 1 0.1 TBOEP 0.0015 0.0015 — — — — TDBPP — — — 2.300 1 — TEHP — — 0.1 0.0032 1 0.1 TPHP 0.007 0.007 — — — — TMPP 0.0013 0.0013 0.02 — — — DMMP — — 0.06 0.001 1 0.1 a 为参考剂量（ng·kg−1·d−1bw）；b 经口风险斜坡因子[1/（ng·kg−1·d−1bw）]；c 胃肠道吸收因子；d 皮肤吸附分数.
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表 4 OPEs暴露与甲状腺激素水平的变化
Table 4. OPEs exposure and changes in thyroid hormone levels
出版时间
Time目标化合物
Compound研究对象
Subject研究结果
Result染毒情况
Dose参考文献
Reference2013 TDCPP 斑马鱼 仔鱼T4↓T3↑ 10—600 μg·L−1, 144 h Wang等[107] 2015 TDCPP 斑马鱼 F0代雌鱼T3↓T4↓
F1代T4↓0—100 μg·L−1，6 个月 Wang等[110] 2015 TPHP 斑马鱼 仔鱼T3↑T4↑ 40—500 μg·L−1, 7 d Kim等[108] 2017 TBOEP 斑马鱼 仔鱼T3↑T4↑ 0—2000 μg·L−1, 144 h Liu等[109] 2019 TDCPP, TPP 斑马鱼 T3↓T4↓(雄鱼), T3↑T4↑(雌鱼) 0—1000 μg·L−1, 14 d Liu等[111] 2013 TCIPP 鸡胚 fT4↓ 0—51600 ng·g−1, 22 d Farhat等[112] 2013 TDCIPP 鸡胚 fT4→ 0—45000 ng·g−1, 22 d Farhat等[112] 2014 TEP 鸡胚 fT4↓TT4→ 8—241500 ng·g−1, 22 d Egloff等[113] 2016 TDCIPP 大鼠 T3↑TT4→ fT4→ 50—250 mg·kg−1, 21 d Zhao等[114] 2010 TDCPP 室内灰尘 fT4↓（男性） — Meeker等[120] 2013 TDCIPP、TPHP、BDCIPP、DPHP 男性尿液 TT3↑TSH↑fT4→ — Meeker等[119] 2017 DPHP 人尿液 TT4↑FT4→TT3→TSH→ — Preston等[84]
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