镉、砷对肾脏的联合毒性研究
摘要
目的 本研究通过流行病学调查和动物实验，探讨镉、砷对环境与职业镉、
砷接触人群以及镉、砷染毒动物肾脏损伤的联合毒作用特点，进行剂量-效应关
系分析，同时对镉、砷接触人群肾功能损害的基准剂量及其可信限下限（BMD
和BMDL，以确定毒作用的阈剂量或浓度）进行估算，为制订镉、砷联合作用
卫生标准、环境质量标准以及预防其对人体健康的损害提供毒理学依据。
方法 人群研究：选择砷污染地区人群、镉污染地区人群以及职业镉、砷
接触人群为调查对象；动物研究：给大鼠饮用水染毒，根据析因实验设计染毒剂
量（用不同浓度的镉、砷进行剂量组合）。接触标志物为尿镉（UCd）、尿砷（UAs），
效应标志物有反映肾小管损害的尿β 2-微球蛋白（Uβ 2-MG）和尿N-乙酰-β-D-氨
基葡萄糖苷酶（UNAG）；反映肾小球损害的尿白蛋白（UALB）；以及尿金属硫
蛋白（UMT），并对大鼠肾组织金属硫蛋白-1（MT-1）、金属硫蛋白-2（MT-2）
基因的表达进行了探讨。
结果 人群资料显示不同污染地区调查对象的体内镉、砷负荷与环境镉、
砷污染程度呈正相关；污染地区调查对象尿镉、尿砷水平与对照组比较差异具有
统计学意义（P<0.01）。不同污染地区调查对象的体内镉、砷负荷与肾功能异常
（尿蛋白或尿酶排泄增加）检出率间呈正相关；污染区居民Uβ 2-MG、UNAG、
UALB和UMT水平均显著高于对照区，且与镉、砷接触（尿镉、尿砷）有着明
显的剂量-效应关系。镉、无机砷（In-As，环境和职业无机砷接触）均可导致肾
小管重吸收和/或肾小球滤过功能障碍，镉主要引起肾小管的损伤，无机砷主要
引起肾小球的损伤；镉、无机砷对肾功能的联合毒性表现为相加或协同效应，具
有统计学意义（P＜0.05和P＜0.01）；镉、有机砷（Or-As，环境有机砷接触）对
肾功能的联合毒性无明显相加效应，有机砷对镉的肾毒性有一定的抑制作用。基
准剂量和敏感标志物方面，不同研究对象之间有一定差异。对于无机砷污染区接
触人群，发生肾功能损害的尿砷BMDL 值为96.12 μg/gCr，尿镉BMDL 值为
1.06μg/gCr，UALB可作为评价无机砷接触为主人群肾功能改变的敏感生物指标；
对于镉污染区接触人群，尿镉的BMDL 值为5.17μg/gCr，尿砷的BMDL 值为
175.84μg/gCr，Uβ 2-MG可作为评价镉接触为主人群肾功能改变的敏感生物指标。
镉、无机砷职业接触人群发生肾功能损害的尿镉BMDL 值为1.74μg/gCr，尿砷
I
复旦大学博士生毕业论文 镉、砷对肾脏的联合毒性研究 中文摘要
BMDL 值为37.45μg/gCr；UNAG 和UMT 可作为评价镉、无机砷接触职业人群
肾功能改变的敏感生物指标。动物实验表明：镉、无机砷染毒剂量与体内镉、砷
负荷（包括血液、尿液和肾组织）呈正相关，均具有统计学意义（P＜0.01），镉、
砷负荷与肾功能效应指标间有着明显的剂量-效应关系。镉、无机砷对肾功能的
联合毒性也表现为相加或协同效应，具有统计学意义（P＜0.05和P＜0.01）。尿
镉、尿砷的BMDL 值分别为1.60μg/gCr和71.63mg/gCr，尿镉BMDL 值与人群
研究的BMDL 值接近，而砷由于种属多样性和代谢多样性，大鼠尿砷的BMDL
值远远大于人群研究的BMDL 值。各剂量组大鼠肾组织MT-1、MT-2基因表达
随着染毒剂量的增加而上升，?
Objective：The combined nephrotoxicity of cadmium (Cd) and arsenic (As) and
an assessment of the dose response relationships between Cd and As co-exposure and
renal dysfunction have been studied in both the populations environmentally or
occupationally co-exposed to Cd and As and experimental animals. The benchmark
dose (BMD) and the lower confidence limit on the benchmark dose (BMDL) of urinary
cadmium (UCd) and arsenic (UAs) were estimated. It could provide toxicological data
from humans and animals to formulate the health standard for As and Cd co-exposure.
Methods：The concentration UAs and UCd were used as exposure biomarkers.
Urinary β 2-microglobulin (Uβ 2-MG), N-acetyl-β-glucosaminidase (UNAG), albumin
(UALB) and metallothionein (UMT) were determined as biomarkers of renal
dysfunction. Using semi-quantitative RT-PCR, gene expression of MT-1 and MT-2 in
renal cortex were assayed.
Results：There were significant differences in UCd and UAs concentration
between residents living in the polluted areas and the control area, and these differences
were related to the extent of co-exposure to Cd and As. It was also obvious that the
levels of Uβ 2-MG, UNAG, UALB and UMT in the exposed groups were significantly
higher than that in the control group (P<0.01). The dose response relationships between
Cd and As co-exposure and renal adverse effects was found. Cd and inorganic arsenic
(In-As，in environment and workplace) can cause renal dysfunction including in both
glomerulus and tubules. The tubular damage was caused by mostly Cd exposure and
the glomerular damage was by mostly In-As exposure. The combined nephrotoxicity of
Cd and In-As were additive and/or synergistic effect. But there has not combined effect
between Cd and organic arsenic (Or-As，in seafood) and Or-As may restrain
nephrotoxicity of Cd during the long-term and co-exposure of Or-As and Cd in humans.
The BMDL of UAs and UCd for a 10% level of risk above the background level were
estimated as 96.12μg/g creatinine and 1.06μg/g creatinine for general population
mainly In-As exposed. In such case, UALB may be as a sensitive biomarker for those
III
复旦大学博士生毕业论文 镉、砷对肾脏的联合毒性研究 英文摘要
people mainly exposed to In-As. For general population mainly Cd exposed, the BMDL
of UCd and UAs for a 10% level of risk above the background level were estimated as
5.17μg/g creatinine and 175.84μg/g creatinine and Uβ 2-MG may be as sensitive
biomarker. For workers occupationally co-exposed to Cd and In-As, the BMDL of
UCd and UAs for a 10% level of risk above the background level were estimated as
1.74μg/g creatinine and 37.45μg/g creatinine and UNAG and UMT may be as sensitive
biomarkers. In animal study, the BMDL of UCd and UAs was estimated as 1.60μg/g
creatinine and 71.63mg/g creatinine, respectively. There were significant differences in
gene expression of MT-1 and MT-2 in renal cortex from rats with drinking water
containing Cd and/or In-As and these differences were related to the extent of intake of
Cd and In-As.
砷接触人群以及镉、砷染毒动物肾脏损伤的联合毒作用特点，进行剂量-效应关
系分析，同时对镉、砷接触人群肾功能损害的基准剂量及其可信限下限（BMD
和BMDL，以确定毒作用的阈剂量或浓度）进行估算，为制订镉、砷联合作用
卫生标准、环境质量标准以及预防其对人体健康的损害提供毒理学依据。
方法 人群研究：选择砷污染地区人群、镉污染地区人群以及职业镉、砷
接触人群为调查对象；动物研究：给大鼠饮用水染毒，根据析因实验设计染毒剂
量（用不同浓度的镉、砷进行剂量组合）。接触标志物为尿镉（UCd）、尿砷（UAs），
效应标志物有反映肾小管损害的尿β 2-微球蛋白（Uβ 2-MG）和尿N-乙酰-β-D-氨
基葡萄糖苷酶（UNAG）；反映肾小球损害的尿白蛋白（UALB）；以及尿金属硫
蛋白（UMT），并对大鼠肾组织金属硫蛋白-1（MT-1）、金属硫蛋白-2（MT-2）
基因的表达进行了探讨。
结果 人群资料显示不同污染地区调查对象的体内镉、砷负荷与环境镉、
砷污染程度呈正相关；污染地区调查对象尿镉、尿砷水平与对照组比较差异具有
统计学意义（P<0.01）。不同污染地区调查对象的体内镉、砷负荷与肾功能异常
（尿蛋白或尿酶排泄增加）检出率间呈正相关；污染区居民Uβ 2-MG、UNAG、
UALB和UMT水平均显著高于对照区，且与镉、砷接触（尿镉、尿砷）有着明
显的剂量-效应关系。镉、无机砷（In-As，环境和职业无机砷接触）均可导致肾
小管重吸收和/或肾小球滤过功能障碍，镉主要引起肾小管的损伤，无机砷主要
引起肾小球的损伤；镉、无机砷对肾功能的联合毒性表现为相加或协同效应，具
有统计学意义（P＜0.05和P＜0.01）；镉、有机砷（Or-As，环境有机砷接触）对
肾功能的联合毒性无明显相加效应，有机砷对镉的肾毒性有一定的抑制作用。基
准剂量和敏感标志物方面，不同研究对象之间有一定差异。对于无机砷污染区接
触人群，发生肾功能损害的尿砷BMDL 值为96.12 μg/gCr，尿镉BMDL 值为
1.06μg/gCr，UALB可作为评价无机砷接触为主人群肾功能改变的敏感生物指标；
对于镉污染区接触人群，尿镉的BMDL 值为5.17μg/gCr，尿砷的BMDL 值为
175.84μg/gCr，Uβ 2-MG可作为评价镉接触为主人群肾功能改变的敏感生物指标。
镉、无机砷职业接触人群发生肾功能损害的尿镉BMDL 值为1.74μg/gCr，尿砷
I
复旦大学博士生毕业论文 镉、砷对肾脏的联合毒性研究 中文摘要
BMDL 值为37.45μg/gCr；UNAG 和UMT 可作为评价镉、无机砷接触职业人群
肾功能改变的敏感生物指标。动物实验表明：镉、无机砷染毒剂量与体内镉、砷
负荷（包括血液、尿液和肾组织）呈正相关，均具有统计学意义（P＜0.01），镉、
砷负荷与肾功能效应指标间有着明显的剂量-效应关系。镉、无机砷对肾功能的
联合毒性也表现为相加或协同效应，具有统计学意义（P＜0.05和P＜0.01）。尿
镉、尿砷的BMDL 值分别为1.60μg/gCr和71.63mg/gCr，尿镉BMDL 值与人群
研究的BMDL 值接近，而砷由于种属多样性和代谢多样性，大鼠尿砷的BMDL
值远远大于人群研究的BMDL 值。各剂量组大鼠肾组织MT-1、MT-2基因表达
随着染毒剂量的增加而上升，?
Objective：The combined nephrotoxicity of cadmium (Cd) and arsenic (As) and
an assessment of the dose response relationships between Cd and As co-exposure and
renal dysfunction have been studied in both the populations environmentally or
occupationally co-exposed to Cd and As and experimental animals. The benchmark
dose (BMD) and the lower confidence limit on the benchmark dose (BMDL) of urinary
cadmium (UCd) and arsenic (UAs) were estimated. It could provide toxicological data
from humans and animals to formulate the health standard for As and Cd co-exposure.
Methods：The concentration UAs and UCd were used as exposure biomarkers.
Urinary β 2-microglobulin (Uβ 2-MG), N-acetyl-β-glucosaminidase (UNAG), albumin
(UALB) and metallothionein (UMT) were determined as biomarkers of renal
dysfunction. Using semi-quantitative RT-PCR, gene expression of MT-1 and MT-2 in
renal cortex were assayed.
Results：There were significant differences in UCd and UAs concentration
between residents living in the polluted areas and the control area, and these differences
were related to the extent of co-exposure to Cd and As. It was also obvious that the
levels of Uβ 2-MG, UNAG, UALB and UMT in the exposed groups were significantly
higher than that in the control group (P<0.01). The dose response relationships between
Cd and As co-exposure and renal adverse effects was found. Cd and inorganic arsenic
(In-As，in environment and workplace) can cause renal dysfunction including in both
glomerulus and tubules. The tubular damage was caused by mostly Cd exposure and
the glomerular damage was by mostly In-As exposure. The combined nephrotoxicity of
Cd and In-As were additive and/or synergistic effect. But there has not combined effect
between Cd and organic arsenic (Or-As，in seafood) and Or-As may restrain
nephrotoxicity of Cd during the long-term and co-exposure of Or-As and Cd in humans.
The BMDL of UAs and UCd for a 10% level of risk above the background level were
estimated as 96.12μg/g creatinine and 1.06μg/g creatinine for general population
mainly In-As exposed. In such case, UALB may be as a sensitive biomarker for those
III
复旦大学博士生毕业论文 镉、砷对肾脏的联合毒性研究 英文摘要
people mainly exposed to In-As. For general population mainly Cd exposed, the BMDL
of UCd and UAs for a 10% level of risk above the background level were estimated as
5.17μg/g creatinine and 175.84μg/g creatinine and Uβ 2-MG may be as sensitive
biomarker. For workers occupationally co-exposed to Cd and In-As, the BMDL of
UCd and UAs for a 10% level of risk above the background level were estimated as
1.74μg/g creatinine and 37.45μg/g creatinine and UNAG and UMT may be as sensitive
biomarkers. In animal study, the BMDL of UCd and UAs was estimated as 1.60μg/g
creatinine and 71.63mg/g creatinine, respectively. There were significant differences in
gene expression of MT-1 and MT-2 in renal cortex from rats with drinking water
containing Cd and/or In-As and these differences were related to the extent of intake of
Cd and In-As.
引文
1. IPCS. Environmental Health Criteria. V224：Arsenic and Arsenic Compounds
（second edition）. International Programme on Chemical Safety. Geneva. World
Health Organization. 2001
2. Chen CJ，Hsueh YM，Chiou HY，et al. Human carcinogenicity of inorganic
arsenic. In：Arsenic-Exposure and Health Effects(eds Abernathy CD, Calderon
RL and Chappell WR)，London: Chapman & Hall，1997:232-242
3. U.S.EPA. Risk assessment forum. Special report on ingested inorganic arsenic:
skin cancer, nutrition essentiality. US Environmental Protection Agency,
Washington DC. 1988
4. Enterline PE. Estimating cancer risks from air arsenic exposure using data on
copper smelter workers. In：Arsenic- Exposure and Health Effects(eds Abernathy
CD, Calderon RL and Chappell WR), London: Chapman & Hall；1997: 227-231
5. Hopenhayn-Rich. C., Smith. A. H., Biggs. M. L. Lung and kidney cancer
mortality associated with arsenic in drinking water in Córdoba, Argentina. Int. J.
Epidemiology. 1998, 27:561-569
6. 荀黎红.地方性砷中毒与人体多系统损害的研究进展.国外医学医学地理分
册,1998,19(4): 145-148、156.
7. Liu. J., Liu. Y., Goyer. R. A., et al. Metallothionein-I/II null mice are more
sensitive than wild-type mice to the hepatotoxic and nephrotoxic effects of
chronic oral or injected inorganic arsenicals. Toxicological. Sci. 2000, 55:
460-467
8. Vahter. M. Genetic polymorphism in the biotransformation of inorganic arsenic
and its role in toxicity. Toxicology. Lett. 2000,112-113: 209-217
9. Hirata. M., Tanaka. A., Hisanaga. A., et al. Effects of glutathione depletion on
the acute nephrotoxic potential of arsenite and on arsenic metabolism in
hamsters. Toxic. Appl. Pharma. 1990, 106:469-481.
10. Falkner. K. C., McCallum. G. P., Bend. J. R., et al. Effects of acute sodium
arsenite administration on the pulmonary chemical metabolizing enzymes,
- 108 -
复旦大学博士生毕业论文 镉、砷对肾脏的联合毒性研究 综述
cytochrome P-450 monooxygenase, NAD(P)H: quinone acceptor oxidoreductase
and glutathione S-transferase in guinea pig: comparison with effects in liver and
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mechanism of liver and kidney to arsenic exposure and its relation to dietary
protein deficiency. Environ. Toxic. Pharma. 2000, 8:227-235
12. Liu. J., Liu. Y., Habeebu. S. M., et al. Chronic combined exposure to cadmium
and arsenic exacerbates nephrotoxicty, particularly in metallothionein-I/II null
mice. Toxicology. 2000, 147: 157-166
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学杂志. 1998; 32(2): 76-78
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Chapman & Hall，1997:124-134
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微量元素与健康研究. 2000;17(2): 21-22
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protein deficiency. Environ. Toxic. Pharma. 2000, 8:227-235
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复旦大学博士生毕业论文 镉、砷对肾脏的联合毒性研究 综述
in rat tissues by a mechanism independent of glutathione levels. Environ. Health.
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（second edition）. International Programme on Chemical Safety. Geneva. World
Health Organization. 2001
2. Chen CJ，Hsueh YM，Chiou HY，et al. Human carcinogenicity of inorganic
arsenic. In：Arsenic-Exposure and Health Effects(eds Abernathy CD, Calderon
RL and Chappell WR)，London: Chapman & Hall，1997:232-242
3. U.S.EPA. Risk assessment forum. Special report on ingested inorganic arsenic:
skin cancer, nutrition essentiality. US Environmental Protection Agency,
Washington DC. 1988
4. Enterline PE. Estimating cancer risks from air arsenic exposure using data on
copper smelter workers. In：Arsenic- Exposure and Health Effects(eds Abernathy
CD, Calderon RL and Chappell WR), London: Chapman & Hall；1997: 227-231
5. Hopenhayn-Rich. C., Smith. A. H., Biggs. M. L. Lung and kidney cancer
mortality associated with arsenic in drinking water in Córdoba, Argentina. Int. J.
Epidemiology. 1998, 27:561-569
6. 荀黎红.地方性砷中毒与人体多系统损害的研究进展.国外医学医学地理分
册,1998,19(4): 145-148、156.
7. Liu. J., Liu. Y., Goyer. R. A., et al. Metallothionein-I/II null mice are more
sensitive than wild-type mice to the hepatotoxic and nephrotoxic effects of
chronic oral or injected inorganic arsenicals. Toxicological. Sci. 2000, 55:
460-467
8. Vahter. M. Genetic polymorphism in the biotransformation of inorganic arsenic
and its role in toxicity. Toxicology. Lett. 2000,112-113: 209-217
9. Hirata. M., Tanaka. A., Hisanaga. A., et al. Effects of glutathione depletion on
the acute nephrotoxic potential of arsenite and on arsenic metabolism in
hamsters. Toxic. Appl. Pharma. 1990, 106:469-481.
10. Falkner. K. C., McCallum. G. P., Bend. J. R., et al. Effects of acute sodium
arsenite administration on the pulmonary chemical metabolizing enzymes,
- 108 -
复旦大学博士生毕业论文 镉、砷对肾脏的联合毒性研究 综述
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