铅暴露者卟啉代谢、血压和ALAD基因多态性的研究
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摘要
前言
人类使用铅已有数千年历史。铅中毒也一直伴随着它的使用存在。由于铅的应用非常广泛，对它的研究仍是重金属毒理研究领域中最重要的内容之一。
随着科学技术的进步，铅的生产条件也在不断改进。发达国家由于没有高浓度铅作业环境，铅的流行病学研究多集中于低浓度铅的健康效应上。而在我国，特别是一些中小企业，劳动环境很差，工人仍处在高浓度铅的暴露中，其健康危害是不容忽视的。我们所调查的沈阳冶炼厂，生产铅的技术水平仅为发达国家70年代初的水平，工人作业环境空气中铅的浓度很高。我们选择的低浓度铅暴露人群来自冶炼厂烟波着地点范围内的沈阳低压开关厂，这里的工人们虽未参加铅的作业，却暴露在较高铅浓度的空气环境中。本研究是在此背景下进行的。
量效关系的研究多见于上世纪铅污染的早期。而现在对铅效应指标的分析手段更加准确和敏感，重新评估铅与卟啉代谢产物的量效关系，对于确定铅作业工人铅暴露的可接受上限值和诊断值、开展健康监护和健康诊断以及制定卫生标准有重要意义。
铅对血压的影响目前尚无定论。我国是一个高血压高发国家，控制高血压的流行是卫生工作的重点。铅能否成为高血压的危险因素之一需要澄清。
ALAD基因多态性研究是当前沿对卟啉代谢影响研究的热点。是人类遗传基因对职业或环境因素易感性研究的一个方面。它将对于就业人员的限定和保护高危险人群有重要的作用。
材料与方法
本研究选取沈阳冶炼厂铅生产工段工人150名和沈阳低压开关厂机械
加工和电器维修工段工人70名作为调查对象。均为男性，平均年龄分别为
36．00 t 7．37岁和33．54＊8．49岁。问卷调查项目主要以”沈阳市接触铅
作业工人健康检查表”为基础，并增加了一些症状、既往病史、家族史、吸烟
史、饮酒史、疗养史、驱铅治疗情况和工人在作业场所的卫生习惯等项目。
作业现场空气铅浓度来自于调查前后两厂环保科的监测结果。取调查对象
外周血SInl，分别测定其血铅人LA－D门一氨基乙酸雨酸脱水酶XALA－P
（血浆8一氨基乙酸丙酸XALA－U（尿5一氨基乙酸雨酸＊Hi（血容积）和
Hb（血红素厂并对受试者的血压进行了测定。在230名样本中选择出11
名血铅浓度较低，ALA－D值下降幅度大的个体作为敏感人群进行ALA－
D基因多态性分析。
血铅采用无火焰原子分光光度计法、ALA－D为比色法、ALA－P和
ALA—U为高压液相色谱法。采用 CY．XJll．300台式血压计测定血压。对
敏感人群的血样分离白细胞，提取DNA，通过特定引物，进行PCR扩增。凝
胶电泳，与标准markers比较鉴别ALA－D基因型。采用SPSS10．0统计软
件对上述实验结果进行统计分析，对各指标进行相应的ANOVA分析／检
验、相关、回归分析《‘检验和多元回归分析。
结 果
调查研究结果表明：ALAD在血铅浓度为15－20pg／dl时开始出现有
统计意义的下降、而 ALA－P人LA－U均在 20 pg／dl时出现显著上升。血
铅与 LOG川 ALAD、LOG＊ALA－P和 LOG＊ALA－U相关系数分别是一0·
893刀．853、0．867，直线回归方程为 y二 0．4055－0．olslX、y二 0．2748＋ 0．
0221x、y二一03417 十0．olglx。血铅与＊和 Hb未表现有明显相关关系。
血铅与空气铅之间有良好的相关关系，r＝0．802。空气铅与 LOG；／LAD。
LOG＊LOG＊ALA－P、LOG＊ALA－U和Hi的相关系数分别为一0．778、0．
725、0．760和一0．152，直线回归方程为 十二0．1155－0．6187x、＋＝0．6427＋
0．7343x、y＝－0．0397＋0．6570x和 y＝47．5429－0．8279 x。SBP和 DBP
在血铅浓度为40 pg／dl开始显著上升。血铅和空气铅与DBP的相关系数
分别是 0．187和 0．191。舒张压达 ＞90nunHg时在血铅 ＞20ug／dL人群中
发生率显著增加。采用 backward法进行多元回归分析表明，影响收缩压主
·2·
要因素是血铅、家族史和年龄；舒张压则是空气铅浓度、工龄、吸烟和饮酒。
对选择的 11例敏感人群的 ALAD基因多态性分析未见有 ALADI－2和
ALADZ上型基因携带者。
讨 论
末梢血红细胞ALAD的活性作为反映铅接触最敏感指标而广泛被采
用。但它的血铅阈值尚无明确结论。我们调查的结果表明ALAD下降的阈
值是在15－20收dl。在各种文献报道中这一数值处于中等水平。导致血
铅阈值研究结果的不一致性，有可能通过分析调查对象、作业环境、实验方
法和研究年代的差异得到解读。
铅损伤时叶琳代谢中间产物ALA在血液和尿中增加。我们采用较精
确和特异的荧光高压液相色谱法得出ALA－P和ALA－U的血铅阈值均是
20卜少d。我们测定的血铅阈值基本上是两个工厂人群血铅的分界。对于
ALA－U而言，它与ALAD不同，血铅的阈值基本上存在于较高铅暴露环境
的人群，而非对照人群。因为，ALA－U不仅是反映铅暴露，它的量的多少
意味着铅对叶琳代谢影响的程度，是铅损伤的效应指标。在我们研究的对
象中，有的名工人 ALA－U值大于或等于 6mg／L，
Preface
Human beings have used lead for thousand years, along with it is lead intoxication. Because of its wild use, research of lead intoxication stills plays an important role in heavy metal toxicology.
Producing conditions of lead are advancing as the development of science. Lacking of high - concentration lead environment makes the epidemic researches of developed countries pay more attention on healthy effect induced by lead of low -concentration. But in China, especially for small enterprises, the working condition is terrible, so the healthy risk caused by exposed to high - concentration lead can't be ignored at all. Investigation of Shenyang Smelting Factory which technology is only equal to the early 70'slevel in developed countries, in-dicat that the lead concentration in working environment is very high. Workers in Shenyang Low - Pressure Switch Factory were studied as a group exposed to low - concentration lead, who were exposed the smoke from Smelting Factory. Though they didnt take part in the smelting work, they were worked in high -concentration air. This study is based on this background.
Dose - effect relation can be seen in the early stage of lead intoxication, with the more exact and sensible analyzing methods. The revaluing the dose -effect relation between lead and porphyrin metablism is very important to defining the up - limit and diagnosis of " lead worker" and it is good for healthy care, healthy diagnosis and drafting healthy standards.
We dont know exactly how much lead can effect blood pressure. China is under high - rate hypertension, and it is very important to prevent hypertension
from prevalence. Whether lead can cause hypertension still needs more evidences.
Research of ALAD genetic polymorphism is the key - point of lead influence to porphyrin metablism, Also, it is another aspect of the sensitivty of human gene to occupational and environmental factor. This is important to definition of employees and high - risk group.
Material and Methods
In this research, we chose 150 workers from Smelting Factory and 70 workers from Switch Factory as object, all were males and average ages were 36. 00 ±1.31 and 33.54±8.49. The questionnaire were based on " Questionnaire of Worker Exposed to lead in Shenyang" , added some symptoms, medical record, family history, smoking history, drinking history, recuperation and chelating lead and health custom of worker in working places. We detected lead in blood, ALAD,ALA - P,ALA -U, Ht and Hb in 5ml peripheral blood. We also detected the blood pressure of the objects. As susceptive group we chose 11 low -blood - lead and larger decreasing ALAD values objects in 230 samples to analyze ALAD gene polymorphism.
We used no - flame atom absorption spectrophotometer, colorimeter and HPLC to detect blood lead, ALAD, ALA - P and ALA - U, and used CY. XJl 1. 300 blood - Pressure meter to detect blood pressure, separated the WBC of sensible group, extracted DNA and then made PCR amplify by specific primer. We compared ALAD genotype to the standard marker after making gel - e-lectrophoresis, analyzed these results by SPSS10.0, then did ANOVA analyzed, t - test, correlation, regression, x2 ~test and multiple - regression.
Results
The research indicated that ALAD had statistic decreasing when the lead concentration of blood was 15 -20μg/dl and ALA - P, ALA - U was at 20μg/
dl, the concentration increased. Correlation coefficient of blood lead and LOG10 ALAD, LOG10ALA - P, and LOG10ALA - U are -0. 893,0. 853,0. 867. Its liner regression were y = 0. 4055 - 0. 018x, y = 0. 2148 + 0. 0221x, y = - 0. 3417 +0. 019Ix. But there was no obvious relationship between blood lead and Ht, Hb. Good correlation coefficient existed in blood lead and air lead, r=0. 802. Correlation coefficient of air lead and LOG10ALAD, LOGGIA - P, and LOG10ALA - U and Ht were - 0.778,0.725 ,0. 760 and - 0.152,liner regression regulation were y =00. 1155 -0. 6187x, y =0. 6427 +0.7343x, y = -0. 0397 +0.6570x and y =47. 5429 -0. 8279x. Obvious increasing SBP,
人类使用铅已有数千年历史。铅中毒也一直伴随着它的使用存在。由于铅的应用非常广泛，对它的研究仍是重金属毒理研究领域中最重要的内容之一。
随着科学技术的进步，铅的生产条件也在不断改进。发达国家由于没有高浓度铅作业环境，铅的流行病学研究多集中于低浓度铅的健康效应上。而在我国，特别是一些中小企业，劳动环境很差，工人仍处在高浓度铅的暴露中，其健康危害是不容忽视的。我们所调查的沈阳冶炼厂，生产铅的技术水平仅为发达国家70年代初的水平，工人作业环境空气中铅的浓度很高。我们选择的低浓度铅暴露人群来自冶炼厂烟波着地点范围内的沈阳低压开关厂，这里的工人们虽未参加铅的作业，却暴露在较高铅浓度的空气环境中。本研究是在此背景下进行的。
量效关系的研究多见于上世纪铅污染的早期。而现在对铅效应指标的分析手段更加准确和敏感，重新评估铅与卟啉代谢产物的量效关系，对于确定铅作业工人铅暴露的可接受上限值和诊断值、开展健康监护和健康诊断以及制定卫生标准有重要意义。
铅对血压的影响目前尚无定论。我国是一个高血压高发国家，控制高血压的流行是卫生工作的重点。铅能否成为高血压的危险因素之一需要澄清。
ALAD基因多态性研究是当前沿对卟啉代谢影响研究的热点。是人类遗传基因对职业或环境因素易感性研究的一个方面。它将对于就业人员的限定和保护高危险人群有重要的作用。
材料与方法
本研究选取沈阳冶炼厂铅生产工段工人150名和沈阳低压开关厂机械
加工和电器维修工段工人70名作为调查对象。均为男性，平均年龄分别为
36．00 t 7．37岁和33．54＊8．49岁。问卷调查项目主要以”沈阳市接触铅
作业工人健康检查表”为基础，并增加了一些症状、既往病史、家族史、吸烟
史、饮酒史、疗养史、驱铅治疗情况和工人在作业场所的卫生习惯等项目。
作业现场空气铅浓度来自于调查前后两厂环保科的监测结果。取调查对象
外周血SInl，分别测定其血铅人LA－D门一氨基乙酸雨酸脱水酶XALA－P
（血浆8一氨基乙酸丙酸XALA－U（尿5一氨基乙酸雨酸＊Hi（血容积）和
Hb（血红素厂并对受试者的血压进行了测定。在230名样本中选择出11
名血铅浓度较低，ALA－D值下降幅度大的个体作为敏感人群进行ALA－
D基因多态性分析。
血铅采用无火焰原子分光光度计法、ALA－D为比色法、ALA－P和
ALA—U为高压液相色谱法。采用 CY．XJll．300台式血压计测定血压。对
敏感人群的血样分离白细胞，提取DNA，通过特定引物，进行PCR扩增。凝
胶电泳，与标准markers比较鉴别ALA－D基因型。采用SPSS10．0统计软
件对上述实验结果进行统计分析，对各指标进行相应的ANOVA分析／检
验、相关、回归分析《‘检验和多元回归分析。
结 果
调查研究结果表明：ALAD在血铅浓度为15－20pg／dl时开始出现有
统计意义的下降、而 ALA－P人LA－U均在 20 pg／dl时出现显著上升。血
铅与 LOG川 ALAD、LOG＊ALA－P和 LOG＊ALA－U相关系数分别是一0·
893刀．853、0．867，直线回归方程为 y二 0．4055－0．olslX、y二 0．2748＋ 0．
0221x、y二一03417 十0．olglx。血铅与＊和 Hb未表现有明显相关关系。
血铅与空气铅之间有良好的相关关系，r＝0．802。空气铅与 LOG；／LAD。
LOG＊LOG＊ALA－P、LOG＊ALA－U和Hi的相关系数分别为一0．778、0．
725、0．760和一0．152，直线回归方程为 十二0．1155－0．6187x、＋＝0．6427＋
0．7343x、y＝－0．0397＋0．6570x和 y＝47．5429－0．8279 x。SBP和 DBP
在血铅浓度为40 pg／dl开始显著上升。血铅和空气铅与DBP的相关系数
分别是 0．187和 0．191。舒张压达 ＞90nunHg时在血铅 ＞20ug／dL人群中
发生率显著增加。采用 backward法进行多元回归分析表明，影响收缩压主
·2·
要因素是血铅、家族史和年龄；舒张压则是空气铅浓度、工龄、吸烟和饮酒。
对选择的 11例敏感人群的 ALAD基因多态性分析未见有 ALADI－2和
ALADZ上型基因携带者。
讨 论
末梢血红细胞ALAD的活性作为反映铅接触最敏感指标而广泛被采
用。但它的血铅阈值尚无明确结论。我们调查的结果表明ALAD下降的阈
值是在15－20收dl。在各种文献报道中这一数值处于中等水平。导致血
铅阈值研究结果的不一致性，有可能通过分析调查对象、作业环境、实验方
法和研究年代的差异得到解读。
铅损伤时叶琳代谢中间产物ALA在血液和尿中增加。我们采用较精
确和特异的荧光高压液相色谱法得出ALA－P和ALA－U的血铅阈值均是
20卜少d。我们测定的血铅阈值基本上是两个工厂人群血铅的分界。对于
ALA－U而言，它与ALAD不同，血铅的阈值基本上存在于较高铅暴露环境
的人群，而非对照人群。因为，ALA－U不仅是反映铅暴露，它的量的多少
意味着铅对叶琳代谢影响的程度，是铅损伤的效应指标。在我们研究的对
象中，有的名工人 ALA－U值大于或等于 6mg／L，
Preface
Human beings have used lead for thousand years, along with it is lead intoxication. Because of its wild use, research of lead intoxication stills plays an important role in heavy metal toxicology.
Producing conditions of lead are advancing as the development of science. Lacking of high - concentration lead environment makes the epidemic researches of developed countries pay more attention on healthy effect induced by lead of low -concentration. But in China, especially for small enterprises, the working condition is terrible, so the healthy risk caused by exposed to high - concentration lead can't be ignored at all. Investigation of Shenyang Smelting Factory which technology is only equal to the early 70'slevel in developed countries, in-dicat that the lead concentration in working environment is very high. Workers in Shenyang Low - Pressure Switch Factory were studied as a group exposed to low - concentration lead, who were exposed the smoke from Smelting Factory. Though they didnt take part in the smelting work, they were worked in high -concentration air. This study is based on this background.
Dose - effect relation can be seen in the early stage of lead intoxication, with the more exact and sensible analyzing methods. The revaluing the dose -effect relation between lead and porphyrin metablism is very important to defining the up - limit and diagnosis of " lead worker" and it is good for healthy care, healthy diagnosis and drafting healthy standards.
We dont know exactly how much lead can effect blood pressure. China is under high - rate hypertension, and it is very important to prevent hypertension
from prevalence. Whether lead can cause hypertension still needs more evidences.
Research of ALAD genetic polymorphism is the key - point of lead influence to porphyrin metablism, Also, it is another aspect of the sensitivty of human gene to occupational and environmental factor. This is important to definition of employees and high - risk group.
Material and Methods
In this research, we chose 150 workers from Smelting Factory and 70 workers from Switch Factory as object, all were males and average ages were 36. 00 ±1.31 and 33.54±8.49. The questionnaire were based on " Questionnaire of Worker Exposed to lead in Shenyang" , added some symptoms, medical record, family history, smoking history, drinking history, recuperation and chelating lead and health custom of worker in working places. We detected lead in blood, ALAD,ALA - P,ALA -U, Ht and Hb in 5ml peripheral blood. We also detected the blood pressure of the objects. As susceptive group we chose 11 low -blood - lead and larger decreasing ALAD values objects in 230 samples to analyze ALAD gene polymorphism.
We used no - flame atom absorption spectrophotometer, colorimeter and HPLC to detect blood lead, ALAD, ALA - P and ALA - U, and used CY. XJl 1. 300 blood - Pressure meter to detect blood pressure, separated the WBC of sensible group, extracted DNA and then made PCR amplify by specific primer. We compared ALAD genotype to the standard marker after making gel - e-lectrophoresis, analyzed these results by SPSS10.0, then did ANOVA analyzed, t - test, correlation, regression, x2 ~test and multiple - regression.
Results
The research indicated that ALAD had statistic decreasing when the lead concentration of blood was 15 -20μg/dl and ALA - P, ALA - U was at 20μg/
dl, the concentration increased. Correlation coefficient of blood lead and LOG10 ALAD, LOG10ALA - P, and LOG10ALA - U are -0. 893,0. 853,0. 867. Its liner regression were y = 0. 4055 - 0. 018x, y = 0. 2148 + 0. 0221x, y = - 0. 3417 +0. 019Ix. But there was no obvious relationship between blood lead and Ht, Hb. Good correlation coefficient existed in blood lead and air lead, r=0. 802. Correlation coefficient of air lead and LOG10ALAD, LOGGIA - P, and LOG10ALA - U and Ht were - 0.778,0.725 ,0. 760 and - 0.152,liner regression regulation were y =00. 1155 -0. 6187x, y =0. 6427 +0.7343x, y = -0. 0397 +0.6570x and y =47. 5429 -0. 8279x. Obvious increasing SBP,
引文
1． 野本昭三 生体内微量金属 微量金属 临床检查法。透析 1988;25:817-823,
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3． Tomokuni K, Ichiba M, Hirai Y. High-sensitive determination of 8-aminolevulinic acid (ALA) in serum or plasma. Porphyrins, 1992,1;299-304．
4． Tomokuni K, Ichiba M, Hirai Y. Measurement of urinary 8-aminolevulinic acid (ALA) by fluorometric and colorimetric methods. Ind Health, 1992, 30:119-128．
5． Sakurai H, Sugita M. Tsuchiya K. Biological response and subjective symptoms in low level lead exposure. Anch Environ Health. 1974． 29． 157-163．
6． Tola S. The. effect of lead blood concentration. Age, sex, and time of exposure upon erythrocyte 8-aminolevulinic acid dehydratase activity. Work Environ Health 1973． 10． 26-35．
7． Haeger-Aronsen B. An assessment of laboratory tests used to monitor the exposure of lead workers. Br J Ind Med 1971． 28． 52-58．
8． Hernberg S, Nikkanen J. Enzyme inhibition by lead under normal urban conditions Lancet 1970． 1． 63-64．
9． Nordman CH. Hernberg S. Blood lead levels and erythrocyte 8-aminolevulinic acid dehydrase activity of selected population groups in Heisinki. Scand J Work Environ Health 1975． 1． 219-232．
10． Wada,O. Yano,Y Ono,T and Toyokawa,K The dignosis od different degrees of lead absorption; In special reference to choice and evaluation of various parameters indicative of an increased lead absorption. Ind. Health. 1973． 11． 55-61．
11． Zielhuis RL. Second international workshop permissible levels for occupational exposure to inorganic lead. Int Arch Occup Environ Health 1977． 39． 59-72．
12． Schiele R. Schaller KH. Diagnostic criteria of increased lead absorption in occupational medcine. J Clin Chem Clin biochem. 1978． 16． 181-197．
13． Abdulla M. Svensson S. Hager-Aronsen BC. Antagonistic effects of zinc and alminum on lead inhibition of 8-aminolevulinic acid dehydratase . Arch Envrion Health 1979． 34． 464-469．
14． 森田杨子,阪井公 荒井俊一, 产业医学 1993． 35． 112-118．
15． Selander S. Cramer K. Interrelationship between lead poisoning in children. New Engl J Med 1973． 289． 1016-1018．
16． Tsuchiya K. Lead , Handbook on the Toxicology of Metals edited tby Frib-erg L, Nordberg GF,Vouk KB,Elsevier, North Holland Biomedical Press, Amsterdam , 1 979 . 45 1-484．
17． WHO. Recommended health-based limits in occupational exposure to heavy metals. 1980． 36-80．
18． Hernberg S. Nikkanen J. 8-aminolevulinic acid dehydrase as a measure of lead exposure. Arch Environ Health 1970． 21． 140-145．
19． Chisolm JJ, Mellits ED. Barett MB. Interrelationships among blood lead concentration , quantitative daily ALA-U and urinary lead output following calcium EDTA , effect and dose-response relationship of toxic metals , edited by Nordberg GF, Elsevier Sci Publishing Co, Amsterdam, 1976． 416-433．
20． Baloh RW. Laboratory diagnosis of increased lead absorption. Arch Environ Health 1974． 28． 198-208．
21． 森田杨子，阪井公，荒井俊一， 测定，保存条件榫两测定值比较，产业医学，1993，35，638-539．
22． Neri, L. C. Hewitt, D. and Orser, B. Blood lead and blood pressure : analysis of cross-sectional and longitudinal data from Canada. Environ.
Health Perspect. 1988. 78. 123-126.
23. Beattie,A. D. Moore, M.R. Devenay, W.T. Miller, H.R. and Goldbirg, A. Environmemal lead pollution in an urban soft water area. Brit. Med. J. 1972.2.491-493.
24．細田加那江，樱井治彥，大前和幸，镰仓光宏，左藤敏彥。血中δ-酸早期铅影响指标有用性。产业医学1989．31．240-241．
25．森田阳子，阪井公，荒井俊一，低浓度铅暴露指标血浆中δ-酸血中δ-酸脱水酵素活性关系 日本卫生学杂志，1994．49．180．
26. Zielhuis RL. Dose -response relationship for inorganic lead. I. Biochemical and haematological responses. Int Arch Occup Environ Health. 1975.35.1-18.
27．武林亨，大前和幸，细田加那江，铅暴露指标δ-酸血清分画定量．产业医学，1992．34．857．
28．王簃兰 劳动卫生学(第三版)人民卫生出版社北京p41．
29．原田章等 铅健康诊断方 全国劳働卫生团体连合会东京1990 p176．
30. Hager-Aronsen B, Abdulla M Fristedt BL. Effect of lead on δ-aminolevulinic acid dehydrase activity in red blood celsls. Arch Environ Health 1971.23. 440-445.
31. Ushio K , Sakai t, Yanagihara S, et al. Properties of A1AD (δ-aminolevulinic acid dehydrase) and the evaluation of lead exposure using heat activation. Jpn J Ind Health . 1975.17. 475-482.
32．阪井公，牛尾耕一，竹内幸子，低浓度铅被暴露者的ALAD全活性(Zn+DTT回复活性)残存活性率．日本灾害杂志，1987．35．525-530．
33．新沼幸子，阪井公，柳原进铅作业者血球亚铅值他生体指标关系，日本灾害杂志，1982．30．816-824．
34. Sakai T, Ushio K. A simplified method for determining erythrocyte pyrami-
ding 5'-nucleotidase (P5N) activity by HPLC and its value in monitoring lead exposure. Br. J Ind Med 1986． 43． 839-844． 1993． 2． 109-112．
36． Morita Y, Araki S,Sakai T,et al. Determination of deta-aminolevulinic acid in plasma using high-Performance liquid chromatogtaphy : a sensitive indicator of lead effects. Ind Health 1994． 32． 85-96．
37． Hernberg S. Biochemical, subclinical and clinical responses to lead and their relation to different exposure levels, as indication by the concentration of lead in blood. 1976, Elsevier Scientific Publishing Company, Amsterdam. B15404-415 .
38． Tola S. The effect of blood lead concentration, age, sex and time of exposure upon erythrocyte d-aminolevulinic acid dehydratase activity. Work Environ Health, 1973 ,10:26．
39． Legge,T. M. and Goadlby,K. W. Lead poisoning and lead absorption, Arnold, London,1912．
40． Oliver, T. Lead Poisoning, H. K. Lewis, London, 1914．
41． Aub,J. C, Fairhall, L. T, Minot, A. S. et al. Lead poisoning, Medicine Monographs 7． 265p, The Williams and Wilkins, Baltimore, 1926．
42． Teleky,L A note on blood pressure in lead poisoning, j. Ind Hyg 1937． 19． 1-5．
43． Calvery,A. M Chronic effects of ingested lead and arsenc, JAMA111． 1938． 1722-1729．
44． Fishbarg,A. M Hypertension and nephritis, Lea and Febiger,Philadelphia, 1939．
45． Harlan,W. Landis, J. Schmouder, R. et al. Blood lead and blood pressure. JAMA. 1985,253:530-534．
46． Moreau,T. Hannaert, P. Orssaud,G. et al. Influence of membrane sodium transport upon the ralation between blood pressure in general population. Environmental Health Perspect. 1988 78:45-51．
47． Beevers,D. G. Cruickshank,J. K. Yeoman, W. B. Carter, G. F. Goldberg, A. and Moore, M. R. Blood-lead and cadmium in human hypertension. J. Environ. Pathol. Toxicol. 1980． 4． 251-260．
48． Britten, R. H. and Thompson, A. A Health study on ten thousandmale industrial worker, statistical analysis of surveys in ten industries, Public health Bulletin. U. S. Government Printing Office, Washington, D. C. 1926． 162,170p.
49． Dreessen, W. C. Edwards,T. I. Reinhart,W. H. et al. The control of the lead hazards in the storage battery industry , Public Health Services Bulletin 1941． U. S. Government Printing Office, Washington, D. C. 1926． 262p.
50． Parkinson, D. K. Hodgson, M. J. Bromet, E. J et al. Occupational lead exposure and blood pressure. Brit. J. Ind. Med. 198744:744-748．
51． Battistuzzi,G. Petrucci,R. Silagni, L. Urbani,FR and Caiola,S. 8-amin-olevulinic acid dehydrase: a new genetic polymorphism in man. Ann. Hum Genet. 1981． 45． 223-229．
52． Schwarz, BS. Lee,BK. Stewart, W. Ahn KD. Springer, K. and Kelsey, K. Associations ofδ-aminolevulinic acid dehydrase genotype with plant, exposure duration, and blood lead zinc protoporphrin level in Korean lead worker. Am J epidemiol. 1995． 142． 738-745．
53． 吴胜虎，沈晓明，颜崇淮，等，应用ALAD基因型筛查儿童铅毒性易感 人群的研究。中华儿科杂志 , 2000 38(7) 435-438．
54． Wetmur, JG. Lehnet G. Desnick, RJ. The delta-aminolevulinic acid dehydrase polymorphism: higher blood lead levels in lead workers and environmentally exposure children with the 1-2 and 2-2 isozymes. Environ. Res. 1991． 56． 109-119．
55． Smith, CM. Wang X, Hu H. et al. A polymorphism in the delta-aminolevulinic acid dehydrase gene may modify the pharmacokinetics and toxicity of lead. Environ. Health Perspect. 1995． 103． 248-253．
56． Wetmur, JG. Kaya AH. Plewinska, M. and Desnick, RJ. Molecular characterization of the humanδ-aminolevulinic acid dehydrase2 ( ALAD2 ) al-
lele : implications for molecular screening of individuals for genetic sus-ceotibility ti lead poisoning. Am J Hum Genet. 1991． 49． 757-763．
57． Astri, KH. Bishop, DF. Wetmur, JR. Kaul, B. Davidow, B. and Desnic RJ-δ-aminolevulinic acid dehydrase isozyme and lead toxicity. Ann NY Acad Sci.1987． 514． 23-29．
58． Fleming, DE. Chettle, DR. Wetmur, JR. et al. Effect of the delta-aminolevulinic acid dehydrase polymorphism on the accumulation of lead in bone and blood in lead smelter worker. Environ. Res. 1998． 77． 49-61．
59． Alexander BH et al. Interaction of blood lead and delta-aminolevulinic acid dehydrase genotype on markers of heme synthesis and sperm production in lead smelter worker. Environ Health Perspect. 1998 104． 213-216．
60． Schwartz, BS. Lee, BK. Stewart, W. Sithisarankul , P. Strickland, PT. Ahn , KD. And Kelsey , K. delta-aminolevulinic acid dehydrase genotype modifies four hour urinary lead excretion after oral administration of dimer-captosuccinic acid. Occup Environ Med. 1997． 54． 241-246．
61． 高万珍，李竹，王振刚，δ-氨基乙酰丙酸脱水酶与铅中毒的关系，国外 医学卫生分册，1997 24(6) 345-348．
62． 郑玉新，宋文佳，王雅文等 ALAD基因多态性与铅致神经毒效应关系的 研究，中国公共卫生2000 16(10) 908-910．
2． Tomokuni K. Comparison of the activity values of delta-aminolevulinic acid dehydratase in human erythrocytes, as measured by three different methods. Jpn J Hyg, 1981,35 :864．
3． Tomokuni K, Ichiba M, Hirai Y. High-sensitive determination of 8-aminolevulinic acid (ALA) in serum or plasma. Porphyrins, 1992,1;299-304．
4． Tomokuni K, Ichiba M, Hirai Y. Measurement of urinary 8-aminolevulinic acid (ALA) by fluorometric and colorimetric methods. Ind Health, 1992, 30:119-128．
5． Sakurai H, Sugita M. Tsuchiya K. Biological response and subjective symptoms in low level lead exposure. Anch Environ Health. 1974． 29． 157-163．
6． Tola S. The. effect of lead blood concentration. Age, sex, and time of exposure upon erythrocyte 8-aminolevulinic acid dehydratase activity. Work Environ Health 1973． 10． 26-35．
7． Haeger-Aronsen B. An assessment of laboratory tests used to monitor the exposure of lead workers. Br J Ind Med 1971． 28． 52-58．
8． Hernberg S, Nikkanen J. Enzyme inhibition by lead under normal urban conditions Lancet 1970． 1． 63-64．
9． Nordman CH. Hernberg S. Blood lead levels and erythrocyte 8-aminolevulinic acid dehydrase activity of selected population groups in Heisinki. Scand J Work Environ Health 1975． 1． 219-232．
10． Wada,O. Yano,Y Ono,T and Toyokawa,K The dignosis od different degrees of lead absorption; In special reference to choice and evaluation of various parameters indicative of an increased lead absorption. Ind. Health. 1973． 11． 55-61．
11． Zielhuis RL. Second international workshop permissible levels for occupational exposure to inorganic lead. Int Arch Occup Environ Health 1977． 39． 59-72．
12． Schiele R. Schaller KH. Diagnostic criteria of increased lead absorption in occupational medcine. J Clin Chem Clin biochem. 1978． 16． 181-197．
13． Abdulla M. Svensson S. Hager-Aronsen BC. Antagonistic effects of zinc and alminum on lead inhibition of 8-aminolevulinic acid dehydratase . Arch Envrion Health 1979． 34． 464-469．
14． 森田杨子,阪井公 荒井俊一, 产业医学 1993． 35． 112-118．
15． Selander S. Cramer K. Interrelationship between lead poisoning in children. New Engl J Med 1973． 289． 1016-1018．
16． Tsuchiya K. Lead , Handbook on the Toxicology of Metals edited tby Frib-erg L, Nordberg GF,Vouk KB,Elsevier, North Holland Biomedical Press, Amsterdam , 1 979 . 45 1-484．
17． WHO. Recommended health-based limits in occupational exposure to heavy metals. 1980． 36-80．
18． Hernberg S. Nikkanen J. 8-aminolevulinic acid dehydrase as a measure of lead exposure. Arch Environ Health 1970． 21． 140-145．
19． Chisolm JJ, Mellits ED. Barett MB. Interrelationships among blood lead concentration , quantitative daily ALA-U and urinary lead output following calcium EDTA , effect and dose-response relationship of toxic metals , edited by Nordberg GF, Elsevier Sci Publishing Co, Amsterdam, 1976． 416-433．
20． Baloh RW. Laboratory diagnosis of increased lead absorption. Arch Environ Health 1974． 28． 198-208．
21． 森田杨子，阪井公，荒井俊一， 测定，保存条件榫两测定值比较，产业医学，1993，35，638-539．
22． Neri, L. C. Hewitt, D. and Orser, B. Blood lead and blood pressure : analysis of cross-sectional and longitudinal data from Canada. Environ.
Health Perspect. 1988. 78. 123-126.
23. Beattie,A. D. Moore, M.R. Devenay, W.T. Miller, H.R. and Goldbirg, A. Environmemal lead pollution in an urban soft water area. Brit. Med. J. 1972.2.491-493.
24．細田加那江，樱井治彥，大前和幸，镰仓光宏，左藤敏彥。血中δ-酸早期铅影响指标有用性。产业医学1989．31．240-241．
25．森田阳子，阪井公，荒井俊一，低浓度铅暴露指标血浆中δ-酸血中δ-酸脱水酵素活性关系 日本卫生学杂志，1994．49．180．
26. Zielhuis RL. Dose -response relationship for inorganic lead. I. Biochemical and haematological responses. Int Arch Occup Environ Health. 1975.35.1-18.
27．武林亨，大前和幸，细田加那江，铅暴露指标δ-酸血清分画定量．产业医学，1992．34．857．
28．王簃兰 劳动卫生学(第三版)人民卫生出版社北京p41．
29．原田章等 铅健康诊断方 全国劳働卫生团体连合会东京1990 p176．
30. Hager-Aronsen B, Abdulla M Fristedt BL. Effect of lead on δ-aminolevulinic acid dehydrase activity in red blood celsls. Arch Environ Health 1971.23. 440-445.
31. Ushio K , Sakai t, Yanagihara S, et al. Properties of A1AD (δ-aminolevulinic acid dehydrase) and the evaluation of lead exposure using heat activation. Jpn J Ind Health . 1975.17. 475-482.
32．阪井公，牛尾耕一，竹内幸子，低浓度铅被暴露者的ALAD全活性(Zn+DTT回复活性)残存活性率．日本灾害杂志，1987．35．525-530．
33．新沼幸子，阪井公，柳原进铅作业者血球亚铅值他生体指标关系，日本灾害杂志，1982．30．816-824．
34. Sakai T, Ushio K. A simplified method for determining erythrocyte pyrami-
ding 5'-nucleotidase (P5N) activity by HPLC and its value in monitoring lead exposure. Br. J Ind Med 1986． 43． 839-844． 1993． 2． 109-112．
36． Morita Y, Araki S,Sakai T,et al. Determination of deta-aminolevulinic acid in plasma using high-Performance liquid chromatogtaphy : a sensitive indicator of lead effects. Ind Health 1994． 32． 85-96．
37． Hernberg S. Biochemical, subclinical and clinical responses to lead and their relation to different exposure levels, as indication by the concentration of lead in blood. 1976, Elsevier Scientific Publishing Company, Amsterdam. B15404-415 .
38． Tola S. The effect of blood lead concentration, age, sex and time of exposure upon erythrocyte d-aminolevulinic acid dehydratase activity. Work Environ Health, 1973 ,10:26．
39． Legge,T. M. and Goadlby,K. W. Lead poisoning and lead absorption, Arnold, London,1912．
40． Oliver, T. Lead Poisoning, H. K. Lewis, London, 1914．
41． Aub,J. C, Fairhall, L. T, Minot, A. S. et al. Lead poisoning, Medicine Monographs 7． 265p, The Williams and Wilkins, Baltimore, 1926．
42． Teleky,L A note on blood pressure in lead poisoning, j. Ind Hyg 1937． 19． 1-5．
43． Calvery,A. M Chronic effects of ingested lead and arsenc, JAMA111． 1938． 1722-1729．
44． Fishbarg,A. M Hypertension and nephritis, Lea and Febiger,Philadelphia, 1939．
45． Harlan,W. Landis, J. Schmouder, R. et al. Blood lead and blood pressure. JAMA. 1985,253:530-534．
46． Moreau,T. Hannaert, P. Orssaud,G. et al. Influence of membrane sodium transport upon the ralation between blood pressure in general population. Environmental Health Perspect. 1988 78:45-51．
47． Beevers,D. G. Cruickshank,J. K. Yeoman, W. B. Carter, G. F. Goldberg, A. and Moore, M. R. Blood-lead and cadmium in human hypertension. J. Environ. Pathol. Toxicol. 1980． 4． 251-260．
48． Britten, R. H. and Thompson, A. A Health study on ten thousandmale industrial worker, statistical analysis of surveys in ten industries, Public health Bulletin. U. S. Government Printing Office, Washington, D. C. 1926． 162,170p.
49． Dreessen, W. C. Edwards,T. I. Reinhart,W. H. et al. The control of the lead hazards in the storage battery industry , Public Health Services Bulletin 1941． U. S. Government Printing Office, Washington, D. C. 1926． 262p.
50． Parkinson, D. K. Hodgson, M. J. Bromet, E. J et al. Occupational lead exposure and blood pressure. Brit. J. Ind. Med. 198744:744-748．
51． Battistuzzi,G. Petrucci,R. Silagni, L. Urbani,FR and Caiola,S. 8-amin-olevulinic acid dehydrase: a new genetic polymorphism in man. Ann. Hum Genet. 1981． 45． 223-229．
52． Schwarz, BS. Lee,BK. Stewart, W. Ahn KD. Springer, K. and Kelsey, K. Associations ofδ-aminolevulinic acid dehydrase genotype with plant, exposure duration, and blood lead zinc protoporphrin level in Korean lead worker. Am J epidemiol. 1995． 142． 738-745．
53． 吴胜虎，沈晓明，颜崇淮，等，应用ALAD基因型筛查儿童铅毒性易感 人群的研究。中华儿科杂志 , 2000 38(7) 435-438．
54． Wetmur, JG. Lehnet G. Desnick, RJ. The delta-aminolevulinic acid dehydrase polymorphism: higher blood lead levels in lead workers and environmentally exposure children with the 1-2 and 2-2 isozymes. Environ. Res. 1991． 56． 109-119．
55． Smith, CM. Wang X, Hu H. et al. A polymorphism in the delta-aminolevulinic acid dehydrase gene may modify the pharmacokinetics and toxicity of lead. Environ. Health Perspect. 1995． 103． 248-253．
56． Wetmur, JG. Kaya AH. Plewinska, M. and Desnick, RJ. Molecular characterization of the humanδ-aminolevulinic acid dehydrase2 ( ALAD2 ) al-
lele : implications for molecular screening of individuals for genetic sus-ceotibility ti lead poisoning. Am J Hum Genet. 1991． 49． 757-763．
57． Astri, KH. Bishop, DF. Wetmur, JR. Kaul, B. Davidow, B. and Desnic RJ-δ-aminolevulinic acid dehydrase isozyme and lead toxicity. Ann NY Acad Sci.1987． 514． 23-29．
58． Fleming, DE. Chettle, DR. Wetmur, JR. et al. Effect of the delta-aminolevulinic acid dehydrase polymorphism on the accumulation of lead in bone and blood in lead smelter worker. Environ. Res. 1998． 77． 49-61．
59． Alexander BH et al. Interaction of blood lead and delta-aminolevulinic acid dehydrase genotype on markers of heme synthesis and sperm production in lead smelter worker. Environ Health Perspect. 1998 104． 213-216．
60． Schwartz, BS. Lee, BK. Stewart, W. Sithisarankul , P. Strickland, PT. Ahn , KD. And Kelsey , K. delta-aminolevulinic acid dehydrase genotype modifies four hour urinary lead excretion after oral administration of dimer-captosuccinic acid. Occup Environ Med. 1997． 54． 241-246．
61． 高万珍，李竹，王振刚，δ-氨基乙酰丙酸脱水酶与铅中毒的关系，国外 医学卫生分册，1997 24(6) 345-348．
62． 郑玉新，宋文佳，王雅文等 ALAD基因多态性与铅致神经毒效应关系的 研究，中国公共卫生2000 16(10) 908-910．