摘要
二噁英类化合物(dioxins,或PCDD/Fs)是指多氯代二苯并二噁英(poly-chlorinated dibenzo-p-dioxins, PCDDs)和多氯代二苯并呋喃(polychlorinateddibenzofurans, PCDFs)，属于持久性有机污染物（persistent organic pollutants, PoPs），具有持久性、生物蓄积性、半挥发性和高毒性的特点。最常见的二噁英类化合物是2,3,7,8-位氯原子取代的二噁英类同类物，包括7种四～八氯代二苯并二噁英类化合物和10种四～八氯代二苯并呋喃，共17种，其中，四氯代二苯并二噁英（2,3,7,8-TCDD）毒性最大，被誉为世纪之毒。
二噁英类化合物几乎全部来自工业生产活动，存在燃烧、高温和含氯化合物的相关生产行业都可能产生二噁英，如化工生产的杂质与副产物(多氯联苯、氯碱工业、五氯酚和染料工业等)；废物焚烧生活垃圾、医疗废物，金属熔炼与加工（钢铁生产和金属热处理）；电子垃圾拆解；造纸和纸浆漂白过程；汽车尾气排放；稻杆焚烧等。我国目前二噁英的排放主要来自金属冶炼行业。
研究表明，二噁英可以产生广泛的毒性作用，包括对多器官、多系统的毒性及致癌性。1997年国际癌症中心（IARC）将二噁英中毒性最强的2,3,7,8-TCDD划分为人类一级致癌物。有关二噁英致人群健康效应的研究已引起广泛关注。为了保障人体健康，世界多个国家先后对二噁英制定了控制标准，即人日容许摄入量(Tolerable DailyIntake,简称TDI)。WHO于2005年将二噁英的TDI重新修订为1-4pgTEQkg-1d-1。然而从目前的研究结果看，二噁英导致人群癌症的报道很有限，还需要进一步的评估。
到目前为止，检测二噁英类化合物的方法也在不断进步和完善中，如生物学法、酶联免疫法和化学分析法等，以毒性当量为浓度单位。每种方法都具有各自的优势与不足，为满足不同的检测需求提供了更多选择的空间。但我国目前还没有生产场所二噁英类化合物测定的标准方法。
铸造过程被认为是我国二噁英类化合物排放的主要工业源之一，但目前对其生产过程中产生的二噁英类化合物的研究还很少，本研究目的是：（1）发展和规范铸造行业生产环境中二噁英类化合物的测定方法，分析生产过程中产生的二噁英类化合物的浓度水平和特征；（2）评估铸造工人和附近居民的二噁英个体外暴露水平；（3）探讨二噁英暴露与铸造工人恶性肿瘤死亡的关联。本研究共分为以下三大部分：
第一部分汽车铸造厂生产环境的二噁英类化合物的测定与分析
第一节HRGC/HRMS法测定铸造厂二噁英类化合物
本节通过采集铸造厂生产车间和厂外环境的空气和积尘样品，建立一套适用于检测和分析职业环境中产生二噁英类化合物的浓度和特征的分析方法，进而评价该铸造厂二噁英类化合物的污染水平以及对周围环境的影响。
采集熔化炉、浇注、造型一线工种和控制室外及门口等辅助工种的空气和积尘样品，经加标、抽提、净化和浓缩后，用HRGC/HRMS法进行定性和定量的分析。该铸造厂生产车间的空气中二噁英类化合物浓度为0.36-2.25pg WHO-TEQ Nm-3(平均1.01pg WHO-TEQ Nm-3)，是厂外空气中二噁英类化合物浓度的1.16-7.26倍。车间内积尘中二噁英类化合物的浓度为3.34-18.64pg WHO-TEQ g-1(平均8.25pg WHO-TEQg-1)，厂外积尘中二噁英类化合物的浓度比车间内多个采样点积尘中二噁英类化合物的浓度要高。铸造过程中产生的二噁英类化合物以高氯代同系物为主，其中呋喃类占了绝对比重。2,3,4,7,8-PeCDF是该铸造过程中产生二噁英类化合物的TEQ构成的主要特征性因子。
本部分研究结果表明铸造过程产生的二噁英类化合物已对外环境造成了污染，熔化炉是铸造过程中二噁英类化合物的主要释放源。
第二节利用EROD法测定铸造厂环境样品中的二噁英类化合物浓度
本部分通过建立的EROD生物学法对铸造厂生产过程中产生的二噁英类化合物产生进行测定和分析。
采集铸造厂生产车间内熔化、浇注、造型、清理和制芯几个主要的生产工艺环节的积尘样品和熔化、浇注两处的空气样品，通过索氏抽提，多层色谱柱净化、浓缩和定容后，用EROD法检测。EROD法依据二噁英类化合物对固着细胞EROD酶活力的特定的刺激作用原理，通过测定细胞EROD酶活力反映二噁英类化合物的危害水平。
熔化和浇注两工种积尘中二噁英类化合物浓度较高（分别为28.79pgTEQ/g和13.58pgTEQ/g），造型和清理次之，制芯工种积尘中二噁英类化合物浓度低于检测限；通风除尘器口处积尘中二噁英类化合物残留浓度高于上述五个工种积尘中的二噁英类化合物浓度。熔化和浇注两个工种其空气中二噁英类化合物的浓度分别为3.89pgTEQ/m3和2.19pgTEQ/m3。本部分研究结果也表明熔化工种是铸造过程中二噁英类化合物的主要释放源，相比化学法，EROD法更适用于快速筛检职业环境样品中的二噁英类化合物。
第三节生物学方法与化学方法结果的比对研究
本节通过对用EROD和HRGC/HRMS两种方法检测的二噁英类化合物结果进行比对分析，探讨两种方法的适用性。对两次采样中采集的熔化和浇注两个工种积尘和空气样品的检测数据进行分析。结果显示用EROD法检测二噁英类化合物的结果普遍高于用HRGC/HRMS法检测结果，两者呈现出了很好的相关性(R2=0.94)，表明两种方法具有一定的可比性，并可以满足不同的职业卫生检测需求。
第二部分铸造工人与附近居民二噁英类化合物个体外暴露量的评估
本部分通过铸造厂车间内及厂外空气中二噁英类化合物浓度的检测结果，对铸造厂工人和附近居民的二噁英类化合物个体外暴露量进行初步评估。
在熔化、浇注和造型三个一线工种中，熔化工人每日经由呼吸途径摄入的二噁英类化合物个体外暴露量最高。一线工人在一天工作时间内经由呼吸途径摄入的二噁英类化合物暴露量是居民每日经由呼吸途径摄入的二噁英类化合物暴露量的1.14～9.43倍。推算的厂外附近居民每日总的二噁英类化合物暴露水平结果表明，儿童每公斤体重二噁英类化合物暴露量大约是成人的两倍，超过了WHO对二噁英类化合物制定的TDI上限。
本部分研究结果提示：该铸造厂产生的二噁英对铸造工人和附近居民构成了威胁，应加强工人的防护并严格控制二噁英向外界的排放。
第三部分铸造工人恶性肿瘤死亡的队列内病例对照研究
本部分通过对铸造工人队列的研究，探讨二噁英类化合物暴露与工人恶性肿瘤死亡之间的关联。
以该铸造厂1980至1985年在册且工作1年以上的工人建立队列，队列共计3529人，自1980年追访至2005年底，死因信息来自职工医院病例和职工丧葬记录，职业史信息来自工厂工资名册。以全国居民1980至2005年年龄别疾病平均死亡率为参照，计算第一死因的标化死亡比（standardized mortality ratio, SMR）及其95%可信区间（confidence interval, CI）。
结果显示恶性肿瘤为该铸造工人的第一位死因，与全国平均水平比较，恶性肿瘤的死亡率明显升高(SMR=1.70,95%CI=1.35-2.13)，尤其是肺癌(SMR=2.13,95%=1.58-2.88)和肝癌(SMR=1.71,95%CI=1.21-2.42)。将121例（男95例）恶性肿瘤死亡者，按性别、出生年以1:3的比例在该队列人群中配对照共363例。将铸造工种按二噁英浓度水平划分为高、中、低（或无）三个暴露级别。Cox比例风险模型结果显示，工人恶性肿瘤死亡风险与二噁英暴露之间存在显著的剂量-反应关系，差异有统计学意义（P＜0.01），其中高二噁英暴露组工人的恶性肿瘤死亡风险是低（或无）二噁英暴露组工人恶性肿瘤死亡风险的2.44倍（95%CI:1.38-4.32）。
本部分研究显示，铸造过程中产生的二噁英是主要的职业致癌物，长期二噁英暴露可能与工人恶性肿瘤死亡率增高有关。
综上所述，本研究通过建立的EROD生物学法和HRGC-HRMS化学法对某汽车铸造厂生产过程中二噁英类化合物的浓度水平及其指纹特征等进行了检测和分析，并且该铸造厂生产过程中产生的二噁英对外界环境造成了污染。结合建立的该铸造厂工人的研究队列，来评价职业二噁英暴露与工人健康危害的关系。通过铸造厂队列内病例对照研究发现二噁英暴露与铸造工人恶性肿瘤死亡风险存在剂量反应关系。
尽管我们先后两次对该铸造厂生产过程产生的二噁英进行采样检测，更多的采样将有助于评价不同工种二噁英的浓度水平及变化情况，此外，对铸造厂中可能引起肿瘤高发的其它混杂因素还需做进一步分析。
Dioxins (polychlorinated dibenzo-p-dioxins and of polychlorinated dibenzofurans,PCDD/Fs) are persistent organic pollutants (PoPs). They have persistent, bioaccumulative,semi-volatile and highly toxic characteristics. The common dioxins are at least the2,3,7,8chlorinated dioxins and furans, referring to seven dioxin congeners and ten furan congeners.The most toxic congener was2,3,7,8-tetrachlorodibenzop-dioxin (TCDD), which is known as thepoison of the century.
Dioxins are generated almost entirely from industrial activities. The industriesinvolving combustion and high temperature can generate dioxins. Common industries areimpurities and byproducts of chemical production (PCBs, chlor-alkali industry,pentachlorophenol and dye industry, etc.); waste burning, including garbage and medicalwaste; metal smelting and processing (steel production and metal heat treatment);disassembly of electronic waste; paper and pulp bleaching process; vehicle exhaustemissions; rice straw burning, and so on. Today in our country, dioxins emissions aremainly from metal smelting industries.
Previous studies indicated that dioxins may produce a wide spectrum of adverse healtheffects, including toxicity and carcinogenicity to multiple organs and tissues. Amongdioxins,2,3,7,8-TCDD, the most toxic congener of dioxins had been designated as a Group1carcinogen by IARC in1997. The studies on dioxins related with human adverse healtheffects have caught widespread concern. To protect human health, many countries all overthe world had developed a control standard for dioxins, namely tolerable daily intake (TDI). The TDI for dioxins was newly revised at1-4pgTEQkg-1d-1by WHO in2005. However, theresults of current researches showed that cancers from dioxins on human beings were verylimited and need further evaluation.
So far, the detection methods for dioxins have also been improved continuously, suchas the biological method, enzyme-linked immunosorbent assay and chemical analysis. Eachmethod has its own advantages and disadvantages, which provide more choices to meetdifferent detection needs. However, there is no standard method to determine dioxins inwork sites in our country.
The foundry process is considered to be one of the main dioxin emissions sourcesfrom industrial production in our country, but researches on dioxins emissions from suchprocesses are still limited. The objectives of this study were to (1) develop and regulate themethods to determine dioxins in foundry process, to analyze the concentrations andcharacteristics of dioxins;(2) to estimate personal dioxins for exposure workers andsurrounding residents;, and (3) to explore association between dioxins exposure and cancermortality among workers. There are the following three parts in this study.
Part Ⅰ Determination and analysis of dioxins in production environment of oneautomobile foundry factory
Section I HRGC/HRMS method for determining dioxins in productionenvironment of the foundry factory
This objective of this section was to determine and analysis the concentrations andcharacteristics of dioxins generated from foundry process by collecting air and dust samplesin and outside the foundry workshop, and to evaluate dioxins levels in the foundry factoryand their contaminations on surrounding environment.
Air and settling dust samples were collected from front-line job categories includingmelting, casting, modeling and assistant job categories including technical andadministrative staff and entrance guard. After adding internal standard, extraction,purification and concentration, the extracts were analyzed by HRGC/HRMS qualitativelyand quantitatively. The dioxins concentrations of air in workplace ranged0.36-2.25pgWHO-TEQ Nm-3(average1.01pg WHO-TEQ Nm-3), which were1.16-7.26times higher than those outside the factory. The dioxins concentrations of settling dust in workplaceranged3.34-18.64pg WHO-TEQ g-1(average8.25pg WHO-TEQ g-1), which were lowerthan those just outside the factory (average16.13pg WHO-TEQ g-1). For concentrations,higher chlorinated congeners prevailed in dioxins, especially furans congeners; for TEQs,2,3,4,7,8-PeCDF was the main characteristic factor of dioxins in foundry process.
The results showed that the dioxins generated from foundry production processcontaminated surrounding environment, and the melting furnaces were the main source ofdioxins emissions in foundry process.
Section II EROD method for determining dioxins in production environment ofthe foundry factory
This objective of this section was to determine and analyze dioxins generated infoundry process by biological method of EROD.
Dust samples were collected at melting furnaces, casting, modeling, fettling and coremaking in several main job categories in the foundry production workshops, and two sitesof air samples were collected at melting furnaces and casting. Samples were extracted bySoxhlet extractions, purified through multi-layer chromatography column, and thendetermined by EROD method after enrichment and constant volume. EROD method wasbased on the principle that dioxins can stimulate EROD activity of fixed cell particularly,and the risk level of dioxins was reflected by measuring the EROD activity.
For settling dust samples, high concentrations of dioxins were in melting furnaces andcasting (28.79pgTEQ/g and13.58pgTEQ/g, respectively), followed by modeling andfettling; the concentration of dioxins in core making process was below the detection limit;the concentration of dioxins in ventilation dust collectors was higher than those at abovefive job categories. For air samples, the concentrations of dioxins at melting furnaces andcasting were3.89pgTEQ/m3and2.19pgTEQ/m3, respectively. The results also showed thatmelting furnaces was the main source of dioxins emissions in foundry process, andcompared with chemical method, the EROD method was more applicable to screen dioxinsin occupational and environmental samples rapidly.
Section III Comparison of the results between EROD and HRGC/HRMSmethods
The objective of this section was to discuss the applicability of EROD andHRGC/HRMS methods by comparing the results of dioxins. Data of dust and air samplescollected in melting and casting job categories were analyzed. The results showed that theconcentrations of dioxins determined by EROD method were generally higher than thoseby HRGC/HRMS method, showing a good correlation (R2=0.94), which manifested therewas a certain comparability between two methods.And these two methods combined canmeet different inspection requirements for occupational health.
Part Ⅱ Personal exposure assessment of dioxins for foundry workers andnearby residents
The objective of this part was to assess personal external exposure levels of dioxins forfoundry workers and nearby residents preliminarily on the basis of air concentrations ofdioxins inside and outside the factory.
Among melting, casting and modeling job categories, intake of dioxins via respiratorypathway during working time one day for melting workers was the highest. Intake ofdioxins via respiratory pathway during working time one day for front-line workers were1.14～9.43times for those for residents all day long. Moreover, total daily intake of dioxinsfor residents showed that intake of dioxins for children per kilogram body weight was abouttwice that for adults, and had exceeded the upper limit value of TDI established by WHOfor dioxins.
The results of this part suggested that dioxins generated from this foundry factory posethreats to the foundry workers and nearby residents, therefore, the protection measures forworkers should be strengthened and dioxins emissions should be controlled strictly.
Part Ⅲ Nested case-control study of cancer mortalityamong foundry workers
The objective of this part was to evaluate the relation between dioxins exposure andcancer mortalities among workers by a cohort study of foundry workers.
A retrospective study with a cohort of3529subjects employed during1980to1985and had worked for more than one year in this foundry factory was conducted. The cohortwas followed from beginning of1980up till the end of2005. The causes of deathinformation was collected from medical and funeral records in hospitals. The occupationalhistory was recorded from registers of the factory. The SMRs and95%CI were calculatedfor the first cause of death by using1980-2005Chinese national age-specific mortality ratesas reference.
Cancer was the leading cause of death among foundry workers. When compared withthe national average mortality, mortality from all cancers (SMR=1.70,95%CI=1.35-2.13),especially from lung cancer (SMR=2.13,95%=1.58-2.88) and liver cancer(SMR=1.71,95%CI=1.21-2.42) was significantly increased. A nested case-control study of121cancer deaths (male,95cases) and363controls was initiated from the cohort study.According to the air concentrations of dioxins, job categories in foundry process weredivided into high, medium, and low (or no) dioxins exposure levels. Cox proportionalhazards model results showed that there was a dose-response relation between cancermortality risk for workers and dioxins exposure with statistically significant (P<0.01), andcancer mortality for high dioxins exposure group was2.44times more than that for low (orno) dioxins exposure group (95%CI:1.38-4.32).
The results of this part showed that dioxins generated from in foundry process werethe main occupational carcinogens, and long-term dioxins exposure may have relation withhigh cancer mortality among workers.
In summary, this study detected and analyzed the concentrations and fingerprintcharacteristics of dioxins generated from one automobile foundry production process bybiological methods (EROD) and chemical methods (HRGC/HRMS). The dioxins generatedfrom producing processes also polluted the surrounding environment. We established acohort to evaluate adverse health effects from occupational dioxins expoaure amongworkers. A dose-response relationhisp between dioxins exposure and cancer mortalityamong foundry workers was observed by a nested case-control study in this foundry.
Although we conducted determination twice in the foundry factory, more samplingwould be help to evaluate dioxin concentrations and changes in different work sites.Moreover, other confounding factors that may cause cancer should be studied in future.
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