【作者】 叶怀庄；

【导师】 陈坤；

【作者基本信息】 浙江大学 ， 公共卫生， 2009， 硕士

【摘要】 A研究背景乳腺癌是危害女性健康的主要恶性肿瘤之一。WHO资料显示全世界每年约120万妇女发生乳腺癌,51.7万妇女死于乳腺癌;北美、北欧是乳腺癌的高发地区,其发病率约为亚、非、拉美地区的4倍。卫生部统计提示我国乳腺癌发病率正以每年3%～5%的速度递增,发病年龄逐渐年轻化,尤以沪、京、津及沿海地区为显著。病因学探索揭示乳腺癌发病与许多因素相关,包括遗传/家族因素、生殖/内分泌因素、生活/行为因素和环境因素等。同时也发现乳腺癌发病率能归因于已知危险因素尚不到50%,如性别、高龄、初潮年龄早、绝经年龄晚、高龄初产以及家族一级亲属患乳腺癌史等。因此,越来越多的目光投向环境因素,即环境污染物与乳腺癌之间的关系,希望环境污染物能阐明尚未能解释的那部分乳腺癌病因。乳腺是多种内分泌激素的靶器官,如雌激素、孕激素、泌乳素等。目前认为乳腺癌的发病机制主要与体内雌激素代谢有关。环境雌激素样活性物质,通过模拟内源性雌激素的作用,或者干扰雌激素代谢途径,从而促进乳腺癌等的发生。乳腺癌其它相关危险因素的促癌机制也与此有关。研究发现多氯联苯（PCBs）和有机氯农药（OCPs）等环境有机物污染物,具有类雌激素样活性,可能增加与雌激素代谢密切相关疾病的风险,2001年被联合国环境署列入了《持久性有机污染物的斯德哥尔摩公约》。调查显示长期暴露于低浓度环境有机氯污染物,人群的乳腺癌发生率增加,尤其是绝经前妇女。但也有研究未发现乳腺癌与环境有机氯相关的证据。我国当前的相关研究主要集中在环境PCBs和OCPs残留水平的监测等,以个体暴露水平为基础的人群调查资料尚不足,因此有必要开展系统的流行病学研究。B研究目的本研究初步评价我国人群血清有机氯污染物的暴露水平及其影响因素,探索有机氯污染物暴露与乳腺癌发病风险的关系,揭示乳腺癌病因因素中的一个方面,以期进一步阐明乳腺癌的病因和发病机理,为乳腺癌的预防和控制积累人群研究的数据。C研究方法本研究以自然人群为基础,选择了浙江省嘉善县2005年1月至2007年5月新发的、经病理确诊的女性原发性乳腺癌病例78例,以及依据调查时间、居住地点、年龄与病例匹配的原则确定的对照72例。在征得本人同意并签署知情同意书的前提下,收集了研究对象的一般情况、饮食习惯、生活方式、疾病史、生殖内分泌因素等相关资料,采集了相应的血液标本,运用液相微萃取-气相色谱-电子捕获检测技术,分析了150份血清样品中PCBs、六六六（HCH）及滴滴涕（DDT）等13种有机氯污染物指标的含量,并比较它们在病例组和对照组之间的差异。D研究结果（1）研究对象有机氯残留量检测结果。PCBs检出率,病例组和对照组分别为96.2%～100%和91.7%～100%;HCH及DDT检出率均为100%;PCBs、HCH、DDT总含量的中位数分别为1.3974、0.6514、0.9544ng/ml和0.7883、0.5569、0.5959ng/ml。经K-S正态性检验,检测结果呈明显的偏态分布（p＜0.001）。因此,采用秩和检验的方法比较13种有机氯残留量的组间差异。其中,病例组PCB101、PCB118、PCB138、PCB153、PCB180、总PCBs和β-HCH、p,p’-DDE、总DDT的残留量明显高于对照组（p＜0.01）;总HCH、p,p’-DDT高于对照组（p＜0.05）。（2）有机氯暴露与乳腺癌发生危险度估计。按照对照组血清有机氯残留量的上四分位数(P₇₅),将研究对象划分为高、低2个暴露水平。采用x²检验比较组间的有机氯暴露情况,其中病例组PCB118、PCB138、PCB153、PCB180总PCBs和β-HCH、总HCH、p,p’-DDE的暴露率高于对照组,差异有统计学意义（x²为5.713～11.92 1,p＜0.05或p＜0.01）。控制了年龄、BMI、职业、文化程度后,分别对各类有机氯暴露率进行单因素Logistic回归分析,发现部分有机氯指标与乳腺癌的发生呈正相关,包括PCB118、PCB138、PCB153、PCB180、总PCBs和β-HCH、总HCH、p,p’-DDE（OR＞2,p＜0.05或p＜0.01）。结合文献报道、专业知识以及指标间的相关性分析结果,决定挑选年龄、乳腺良性疾病史、哺乳史等作为协变量,进行有机氯暴露与乳腺癌发生的多因素模型分析。在进出模型的α=0.10水平上,通过逐步回归,最终能够保留在乳腺癌多因素模型的只有8个有机氯污染物指标,按OR值由大到小顺序排列,分别为PCB138、总PCBs、PCB153、β-HCH、PCB118、P,P’-DDE、PCB180、总HCH。综合本研究和文献结果,提示PCB138、PCB153和β-HCH、p,p’-DDE可用于PCBs和OCPs的暴露评价。E研究结论本研究以病例-对照研究为手段,通过78例女性乳腺癌患者和72例对照的调查资料分析,得出如下结论:（1）研究对象血清中PCBs和OCPs检出率均较高,病例组残留量高于对照组;（2）有机氯暴露可能与乳腺癌有关,暴露水平越高,发生乳腺癌的危险性越大;（3）结果提示PCB138、PCB153和β-HCH、p,p’-DDE可分别作为PCBs和OCPs暴露效应的评价指标。更多还原

【Abstract】 A BackgroundBreast cancer is one kind of the most common malignant cancers that jeopardize women’s health.Datas and materials from the World Health Organization(WHO)have showed that every year in the world there are more than 1,200,000 new cases occur and will cause 517,000 women death.It is estimated that the incidence of breast cancer in north America and northern part of Europe is approximately 4-fold higher compared with the incidence in Asia,Africa and Latin America.China is the country with a relatively low incidence rate,but recently the rate has increased by 3%to 5%annually and the age of onset has inclined to be younger.This condition is especially distinctive in Shanghai,Beijing,Tianjing and China’s coastal area.Etiological study reveals that breast cancer is related with multiple factors including genetic/family factor,genesis/hormone factor,life style/behavior factor and environmental factor.Most epidemiological studies have reported that no more than 50%of breast cancer could be explained by the known factors such as gender,older age, early age in menarche,late age in menopause,older age when primiparity and breast cancer history of first degree relatives.Therefore,more and more focuses are concentrated to environmental factors and researchers hope it will help to illustrate the etiology of breast cancer.Lacteal gland is a target organ of many kinds of hormones such as estrogen, progestin,prolactin et al.Nowadays researchers believe the mechanism of breast cancer is mainly related with estrogen metabolism.Environmental hormone-like active compound will enhance the carcinogenesis of breast cancer through mimicing estrogenic effect or disturbing estrogen metabolism pathway.Other risk factors of the breast cancer share the same mechanism mentioned above.Researchers have reported environmental contaminates such as PCBs and OCPs will probably increase the risk of estrogen metabolism related disease.In the year 2001, these pollutants are registered in the“Stockholm Convention on Persistent Organic Pollutants”by UNEP.Investigations have discovered that long-term exposure to low concentration of environmental organochlorines will increase the incidence of breast cancer,especially in premenopausal women.But there are also researches that found no relationship between breast cancer and organochlorines.In our nation,most researchers pay attention to the monitoring of PCBs and OCPs residual.Materials from population-based studies are still in the shortage,therefore it is worth conducting systematically epidemiological studies to bring new ideas and evidences.B ObjectivesWe will combine both datas from lab and investigation to give a primary assessment of organochlorine exposure-level and the relevant influential factors. Therefore,we can probe and explore the relationship between breast cancer and organochlorines.Moreover,we can offer methods and evidences to the control and prevention of breast cancer and illuminate the etiological factor and mechanism to a further and deeper step. C MethodsOur research is a population-based case-control study.The subjects are all from Jiashan county,Zhejiang province.We have collected a total number of 78 primary female breast cancer cases which are newly-happened and patho-definited.We have got 72 Controls matching with age,investigate time and residence.All the subjects have been informed with the specific purpose of our research and all of them have signed informed consent.Consequently,we have collected datas in general state of health,eating habit,life style,patient history,genesis and endocrine secretion and we have got the blood preparation.As a result,150 portions of plasma are extracted from the blood sample by liquid-phase microextraction.The contents of organochlorines such as PCBs,HCH and DDT are detected and analyzed by gas chromatograpy -elctron capture detector.Statistical analysis is carried out between cases and control groups.D Results(1)Detection rate of PCBs among cases and controls ranges from 96.2%to 100% and 91.7%tol00%respectively.Both the detection rate of HCH and DDT are 100%. The median contents of PCBs,HCH and DDT among cases are 1.3974ng/ml, 0.6514ng/ml and 0.9544ng/ml respectively,while those among controls are 0.7883ng/ml,0.5569ng/ml,0.5959ng/ml respectively.By the Kolmogorov-Smirnov test of normality,the results showed significantly skewed distribution(p＜0.001).Therefore,the differences of 13-kinds organochlorine pollutants between case and control were compared by rank sum test.The plasma content of PCB101,PCB118,PCB138,PCB153,PCB180,total PCBs,p-HCH, p,p’-DDE,total DDT,total HCH and p,p’-DDT among cases are higher than that in controls,the difference has statistical significance.(2)We have divided all the subjects into two levels.The upper quartile of the control group is considered as reference level,the rest belong to exposure level.After adjusting age,BMI,occupation and education factors,logistic regression shows some kind of organchlorines have positive relationship with breast cancer.Reference for both literature report and expertise,several factors are choosen as consideration variables,which was the exposure levels of organic chlorine,age, breastfeeding history,and benign breast history.Statistical Analysis of all variables by multi-factor logtistic regression,in theα-0.10 level,through the stepwise regression, and ultimately able to enter the multi-factor model of breast cancer,were only eight indicators of organochlorine pollutants.Descending order of OR value,it was from PCB138,total PCBs,PCB153,β-HCH,PCB118,P,P’-DDE,PCB180,to total HCH.Comprehensive our research and documentation of the results,suggesting that PCB138,PCB153,andβ-HCH,p,p’-DDE can be used as an indicator to evaluat effects of PCBs and OCPs exposed.E ConclusionWe conclude from the result of the population-based case-control study as followed.(1)Detection rates of PCB and OCPs indexes among all the subjects were higher, respectively.Their contents of plasma among cases were higher than that in controls, the difference has statistical significance.(2)Organochlorine exposure may have possible positive relationship with breast cancer.In our research,we find a positive relationship between breast cancer and PCB138,PCB153,PCB118,PCB180,total PCBs,(3-HCH,p,p’-DDE and total HCH.(3)Literature report have revealed that PCB138 and PCB153 can be used a index for PCBs exposure assessment while P-HCH and p,p’-DDE can be for OCPs.更多还原