Review: effect of environmental cadmium pollution on human health

doi:10.4236/health.2009.13026

Paper Menu >>

Journal Menu >>

Vol.1, No.3, 159-1

doi:10.4236/health.2009.13026

SciRes

66 (2009) Health

Review: effect of environmental cadmium pollution

on human health

Jing-Xiu Han1, Qi Shang1, Yu Du2

1Department of Epidemiology and Health effects, Institute for Environmental Health and Related Product Safety, Chinese Center for

Disease Control and Prevention, 29 Nanwei Road, Beijing, 100050, China; Corresponding author: sqyoux@yahoo.com.cn (Qi Shang)

2Yuzhong district centre for disease control and prevention, Chongqing Municipality

Received 14 August 2009; revised 1 September 2009; accepted 2 September 2009.

ABSTRACT

Based on the available data obtained from the

population investigating, the authors reviewed

research articles of the study on analytical me-

thods and exposure levels of cadmium (Cd) in

population, the injury of target organ, the evol-

vement of sensitive index for surveillance, the

study on effects of human disease and death for

environmental Cd exposure, and the study on

priority surveillance of human health risk.

Keywords: Cadmium Pollution; Population

Investigation; Disease Surveillance; Renal Damage

1. INTRODUCTION

Cadmium (Cd) is a toxic heavy metal which can be

accumulated in human body and environment long-term.

The health risks of environmental Cd pollution have

caused the concern all over the world since the “itai-itai”

disease caused by chronic Cd poisoning appearing in

Japan in 1950’s. Series of criteria and guidelines have

been developed in many countries and international orga-

nizations to guide the study on health effect of Cd po-

llution. Cd has been ranked at the sixth of toxic subs-

tances for significant human health hazard by U.S Poison

and Disease Registry [1]. At the same time, this element

has been a focus of study on environmental pollution in

the United Nations Environment Programs and the Inter-

national Commission on Occupational Health. It was also

put on a priority position of the study on food contami-

nation in the World Health Organization [2]. Cd pollution

of industrialization began in the early 1960’s in China and

then many studies on popular health effects of environ-

mental Cd pollution have been carried out in 1980’s and

early of 1990’s. It was estimated that the total area

polluted by Cd in China is more than 11000 hectares, and

there were 11 provinces and municipalities, 25 territories

production Cd-polluted rice (Cd concentration 1.32~5.43

mg/kg) (Ministry of Farming Animal Husbandry and Fish-

eries, Beijing, Internal report, 1980). Annual amount of Cd

with industrial waste discharged into the environment was

more than 680 tons [3,4]. Unfortunately, there were few

researches of Cd pollution on human health effects after

the 1990s in China besides some follow up investigations

of resident’s health effects which were carried out only in a

few contaminated areas. It is these studies that showed the

Cd-polluted actives have not been efficiently dealt with over

last 20 years in China, and the health risk of residents living

in contaminated areas has been becoming more serious

than those in the 1980’s [5-8]. The environmental Cd

exposure occurs mainly in Japan and China. In other

countries, the intensity and duration of Cd exposure and the

injury occurring in populations are in a relatively low level,

with little related literature reported [9,10].

Population expositing to environmental pollutants has

a general character of low-dose, long-term, and chronic

poisoning, which will cause two different kinds of

chronic health effects, damage of target organs and non-

specific changes for population such as weakness, ease to

suffering from illness and rise of morbidity and mortality

etc. In this paper, the information from population-based

study on human health effects of environmental Cd pollu-

tion was reviewed.

2. TARGET ORGANS DAMAGE OF

ENVIRONMENTAL Cd EXPOSURE

Main work of study on popular health effects caused by

environmental Cd pollution can be divided into different

scopes: target organ (kidney, bone, prostate, etc.) damage,

biomonitoring, dose-response relationship, investigation

of exposure level, mortality, and survival analysis [11].

There were some studies on mortality and survival analy-

sis in recent years in China [8].

2.1. Target Organ Damage and

Biomonitoring

Based on results of toxicological studies, the researches

J. X. Han et al. / HEALTH 1 (2009) 159-166

160

on human specific-injury caused by Cd exposure have

focused on injury biomonitoring of bones and urogenital

system. The main researches were early screening for the

early sensitive biomonitoring indices, monitoring and

evaluation of target organ damage, and study on the dose-

response relationship between Cd exposure and health da-

mage indices. There were a lot of early indices of kidney

damage applied in the popular surveys. Some were related

to body burden of Cd exposure, such as blood Cd (B-Cd)

and urinary Cd (U-Cd); some were sign of bone injury,

such as bone mineral density (BMD), urine calcium, urine

phosphorus, urine or serum alkaline phosphatase (U-, B-

ALP), urine hydroxyproline (U-HOP), and so on. Index

commonly used to show Cd accumulation level in renal

cortex and the whole body was U-Cd. There are generally

two different kinds of groups of biomonitoring indices for

renal tubular dysfunction and renal tubular pathological

damage: urine protein and urine enzyme. The former included

urineβ2-micro-globulin (Uβ2-MG), α1-microglobulin (Uα1-

MG), retinolbinding protein (U-RBP), metallothionein (U-

MT), albumin (U-ALB), amino acids, and so on. The latter

were urine N-acetyl-β-D-glucosaminidase (U-NAG), alka-

line urine (U-ALP), and γ-glutamyltranspeptidase enzyme

(γ-GT), etc [5,9,12]. Urine enzyme was mainly from renal

tubular epithelial cell, therefore, changes of enzyme

activity in urine had been considered as representative

indicator of renal tubular injury comparing with urinary

protein serving as tubular re-absorption dysfunction indi-

cator. However, the most commonly used indices were

U-Cd, Uβ2-MG, and U-NAG (U-NAG applying in 3 ways:

A-isozyme, B-isozyme and total NAG, renal tubular epi-

thelial cells are rich in B-NAG), among which good

correlations have been observed. Early sensitivity of urinary

enzymes or urine protein reported in many literatures. It is a

result of the survey reported by different authors carrying

out at different Cd exposure stages, different accumulating

Cd exposure level causing different health effects. Analyz-

ing the progress of chronic Cd poisoning, the urinary protein

mainly from the serum did not increase significantly when

there was no renal glomerulus and re-absorptive in the

early stage. In this period, phenomena of Cd nephrotoxic

was a rise in U-Cd and urinary enzymes. With the

increase in Cd exposure level, U-Cd, urine enzyme and

urine protein would be synchro-increasing, it was a sign

of renal tissue injury with renal dysfunction. The renal

tubular injury induced by environmental Cd exposure was

irreversible even after soil replacement in Cd-polluted rice

paddies [13-15]. In the late stage of Cd exposure, it would

be seen that U-Cd and urinary protein increased sharply

with urinary enzyme active reducing. Therefore, in practice,

application of specific biomonitoring indicators and result

analysis should consider the levels of U-Cd and cumu-

lative Cd exposure of population in different con-

taminated areas [16,17]. It was estimated based on litera-

tures that some of above indicators appearing in the urine

in correspondence to 24-hour urinary Cd concentrations

were: Ca: 1.9μg, U-NAG: 2.74μg, U-RBP: 2.87μg, Uβ2-MG:

3.05μg, amino acids: 4.29μg. In addition, when U-Cd

began to rise abnormally, the other biomarks would be at

the levels of: U-NAG: 2.74μg, U-RBP: 338μg, Uβ2-MG:

283μg [10]. If an individual has synchronized with

increasing in the levels of U-Cd, Uβ2-MG and U-NAG

over national standard value, it would mean that the

individual’s health had been severely damaged suffering

from environmental Cd pollution. And if there were 10%

individuals with severe health damage in a contaminated

area at the same time, it would be judged to be a

contaminated area with popular health damage according

to the health standards of China [18]. Government should

take action to control environmental pollution and prevent

residents in the area from Cd health damage.

The first change of biomark index corresponding to

environmental Cd exposure was the increase of U-Cd.

When the level of U-Cd arrived at approximately 2.5～5.0μg/g,

the indices of renal dysfunction and renal tubular injury

began to change [19-22]. However, some researchers [8,23,

24] calculated benchmark doses (BMDs) of U-Cd and their

95% lower confidence bounds (BMDLs) for renal effects

of Cd in a population with low environmental exposure.

Yasushi et al. [23] obtained BMDs of U-Cd were lower

than the critical concentrations previously reported. For

both NAG and protein HC, the BMDs (BMDLs) of U-Cd

were 0.5-1.1 (0.4-0.8) μg/L (adjusted for specific gravity of

1.015 g/ml) and 0.6-1.1 (0.5-0.8) μg/g creatinine. But

considering age effect, it was important to establish the

threshold level of Cd exposure at each age [14,15]. In the

late of chronic Cd poisoning, with U-Cd and Uβ2-MG

significantly increasing [25-27], the bone injury indicators

and U-ALB were expected to show a significant change.

Usually, bone damage was a delayed sign of severe chronic

Cd poisoning. Population-based studies [28-31] showed an

association between osteoporosis and low-level environment-

tal Cd exposure. Cd can cause bone demineralization, either

through direct bone damage or indirectly as a result of renal

dysfunction. Result of a study [32] indicated that excretion

of urinary Vitamin D-binding protein (DBP, which binds,

transports and activates vitamin D, plays a major role in

calcium homeostasis and bone turnover) in urine may be

linked to renal tubular dysfunction and possibly bone

lesions in the inhabitants of Cd-polluted areas. Nordburg

et al. [33,34] reported that the BMD decrease in post-

partum women with raised levels of U-Cd or B-Cd, and

BMD decrease in men with increased levels of B-Cd in

Asia excluding Japan. Kido’s [35] studies had shown that

the urinary indicators of renal function (β2-MG) and in-

dicator of Cd exposure in male and female were negatively

correlated with the central part of the second metacarpal

BMD. Cd induced the disorders of normal osteoblasts and

bone metabolism through disrupting calcium messenger

system, led to osteomalacia, increased the dissolution of

J. X. Han et al. / HEALTH 1 (2009) 159-166

161

calcium, decreased BMD, and caused osteoporosis [36].

Environmental Cd exposure may also be associated with

increased risk of dental caries in deciduous teeth of

children [37].

Jin et al. [38,39] had reported prostate damage induced

by Cd, but little information was provided in population

research.

2.2. Estimation of Cd Intake Level

Early research on the population Cd intake levels mainly

focused on estimating daily intake. It was a static mode

and just got a cross-sectional data at surveying day. This

method could not get accumulation exposure level, a very

important data to observe and research a relationship

between Cd intake and chronic health damage. For this

reason, many people used total intake (or the cumulative

intake) to find out the relationship between accumulative

Cd intake and health chronic injury as well as key point of

chronic damage at different total intake level, which

would be corresponding to different degree of health

injury [40,41]. Japanese scholars reported their result that

they used the data of daily intake level multiplying by

total exposure days to estimate population total intake

level [42-44]. This method did not consider a difference in

food intake levels at different age stages, generally, and

the amount estimated in this method might be greater than

actual intake level. There were some scholars who cal-

culated the Cd total intake through way of estimating the

cumulative rice consumption. Two different methods

were accepted to estimate the cumulative rice consum-

ption. One method is that total rice consumption was

calculated using consumption in various age groups,

which was estimated based on the curve equation of daily

average rice consumption in various age groups [40], the

another way, which used coefficient to estimate, the total

rice con- sumption was reckoned according to various

coefficients of various age groups. The coefficients were

set as follows, 0~9 age group: 0.413, 10~19 age group:

0.885, 20~59 age group: 1, and age group beyond 60:

0.823 [41]. Two kinds of methods both considered the

differences in dietary consumption in children and elder

population, and the calculated results were also similar

(estimated Cd intakes for the 45-year-old group are

161mg and 166mg, respectively). Chiyoda [45] used

urine protein and urine sugar as biomonitoring indicators,

and estimated that the allowed total intake of Cd in

Japanese was less than 1.58g in their life. Due to the lack

of continuous monitoring data, the estimating value of

population total intake was a relative result, it would be

mainly applied in evaluating the group exposure, and

considered only as a reference value when used to

identify the health damage of individual [40].

2.3. Dose-Response Relationship

on Cd Exposure

It has been possible to link the total Cd intake with

population health damage dynamically by calculating

accumulative Cd intake so that a regress formula could be

gotten between population health damage degree and Cd

exposure dose. The result of digitizing health damage

degree makes it possible to compare all of information

from different authors’ studies in a dosage scale. Health

damage degree corresponding to different accumulative

exposure dose could also be used to predict the tendency

of population health damage caused by Cd exposure

which based on the data of environmental monitoring or

biomonitoring. A large number of articles had reported

the dose-response relationship between the total Cd

exposure and biomonitoring indicator of popular health

injury, and explored the level of Cd exposure associated

with the degree of health injury. These reports about

dose-response relationship focused on the association

between Cd exposure and indicators of renal injury, such

as: U-Cd and Uβ2-MG, U-NAG, U-RBP, and so on. The

estimation of total exposure level laid basis on the unit of

population group, which corresponded to the incidence of

abnormal value of a variety of monitoring indicators, the

occurrence of specific chronic diseases, such as fracture

morbidity and mortality of “itai-itai” disease. Some

authors had used U-Cd as indicator of Cd exposure to that

of responsive renal injury indicator to calculate relation-

ship between exposure and response, and observe deve-

lopment trend and degree of renal injury [46-48].

Japanese scholars also used Cd concentration of rice in

different regions, corresponding to incidence of abnormal

monitoring indicators, to calculate dose-response rela-

tionship. Nevertheless, this method which only provided

a relationship between different exposure level and index-

es of popular health damage just was a static model of

dose-response relationship.

2.4. Mortality and Survival Analysis of

Population Exposed to Environmental Cd

Mortality of people exposed to environmental Cd had

been reported in China and Japan. Kawana [49] reported

the mortality rate of “itai-itai” disease was 72.6 % (50.4%

in control group) from 1967 to 1982, the average survival

time was 76.4 year-old (control group: 78.3 year-old) with

statistically significant differences. Kobayashi [50] had

studied on relationship between the level of urine calcium

and life expectancy, as well as the number of female

pregnancy and childbirth associating with popular morta-

lity. He found that the lower urine calcium, the shorter

life-span. But popular mortality was not associated with

the number of pregnancy and childbirth. Death analysis in

Japan mainly adopted a method of following-up observa-

tion [51,52]. Based on the biomonitor data from past

population-based survey, they collected the data of death

records from Cd contaminated areas and analyzed morta-

lity and survival time to observe the changes of popular

renal injury indicators, such as U-Cd, Uβ2-MG, U-RBP

and so on, in the areas where populations had exposed to

J. X. Han et al. / HEALTH 1 (2009) 159-166

162

environmental Cd at different levels. Different from common

disease surveillance, there was no cause-specific death or

disease-specific mortality reported in those reports. Since

the discovery of itai-itai disease, Japanese scholars had

observed and studied on the damage of the death in

Cd-exposure population. The studies had shown that

higher volume of Cd in rice caused population higher Cd

exposure, and then could induce population to have a

series of health effects, such as more severe renal injury,

higher mortality, shorter survival time, and more unfavorable

the prognosis [48,50,53-56]. Even if zinc-Cd smelters

closed, historical environmental contamination remained a

persistent source of exposure. Environmental exposure to

Cd increased total, and noncardiovascular mortality in a

continuous fashion without threshold [57,58]. One study

[59] found that environmental Cd exposure was asso-

ciateed with an increasing risk of all cause, cancer, and

cardiovascular disease mortality among men, but not among

women. Additional efforts are warranted to fully explain

gender differences on the impact of environmental Cd

exposure.

3. HUMAN NON-SPECIFIC DAMAGE FROM

ENVIRONMENTAL Cd POLLUTION

In addition to target organ damage, there were still some

non-specific impacts of environmental Cd pollution on

the human health. Low IgG level of children with higher

Cd body burden suggested that Cd could affect develop-

ment of children’s immune system. According to the de-

tection of immunoglobulin sub-type, IgG3 was the most

sensitive to the inhibitory effect of Cd, followed by: IgG1,

IgG2, IgM and IgG2a. Therefore, IgG could be used as the

sensitive indicator of immune suppression of children

exposed to Cd [60]. EU Toxicology, Eco-toxicology and

Environmental Science Committee had agreed with the

opine that Cd exposure could have immunosuppressive

effects [61]. Gary [21] reported that the urine Cd in 3 levels

of 0~0.99μg/g Cr (control group), 1.00~1.99μg/g Cr and

≥2μg/g Cr respectively, its OR for the early stage of

diabetes were: 1.48 (95%CI: 1.21~1.82) and 2.05 (95%CI:

1.42~2.95); the OR for type Ⅱ diabetes: 1.24 (95%CI:

1.06~1.45) and 1.45 (95%CI: 1.07~1.97) [2]. Early

diabetes (IFG) and type Ⅱ diabetes had significant dose-

response relationships with urinary Cd concentration, it

suggested that the two kinds of human diseases had

related to the Cd exposure.

Many literatures reported the impact of Cd on human

reproductive system. Falcon [62] reported that pregnant

women exposed to environmental Cd might have an adverse

effect in perinatal period, e.g. fetal growth retardation, low

birth weight, birth deformities and premature. Nishijo et al

[63-65] reported that mothers with higher urinary Cd

concentration would be company with higher levels of Cd

and lower calcium concentration in their breast milk. Cd

exposure may be a possible cause of male infertility. A

significant negative correlation was observed between

serum Cd level and all examined biophysical semen

characteristics except sperm volume [66].

Nishijo et al. [55,67] reported that there were dose-

response relationships between Cd exposure and mortality

risks in both male and female in the Cd contaminated

areas. Chronic exposure to Cd could increase popular

mortality and shorten life expectancy. In recent years, a

15-year-follow-up investigation of 3119 residents living in

Cd polluted area had confirmed that Cd exposure was

associated with popular mortality [55]. Another survey

found the standardized mortality rates of six kinds of

diseases in Cd contaminated areas were higher than non-

contaminated areas, such as cancer, respiratory disease

and cerebrovascular disease. Some population-based studies

reported that Cd exposure was associated with increased

risk of breast and endometrial cancer [68-70]. These

might because that Cd mimicked the function of steroid

hormones [71]. Moreover, data suggested that Cd ex-

posure was associated with increasing testosterone levels

[72]. High testosterone levels have been associated with

the risk of breast cancer. But more experimental and

epidemiological studies are required to establish a cause

and effect association between the metal and hormone

dependent cancers and to verify the mechanism of action.

Cd exposure via inhalation might associate with some

human cancers, but Verougstraete [73] did not think that

it could cause human cancer exposing to environ- mental

Cd. Cd levels in blood were associated with a modest

elevation in blood pressure [74]. A 15-year-follow-up

study found that mortality for heart failure and cerebral

infarction was increased among inhabitants living in a

Cd-polluted area in Japan [54].The incidence of subhealth

state of population in Cd pollution area was higher than

that of people in non-polluted area, such as dizziness

headache, loss of appetite, coughing, shortness of breath,

etc. The morbidity of chronic disease was also significantly

higher than that of people in non-polluted area, such as

stomach and duodenal ulcer, bronchitis, urinary calculi,

and so on. The health status of residents in the polluted

area had been impacted by the environmental Cd pollution,

the infant mortality. The pre-mature deliver rate in the Cd

polluted area was higher than those of control area, and the

spectrum of popular disease and death in polluted area was

significantly high than those of people in control area

[75,76].

Some research data [77] indicated that Cd exposure

could result in pancreatic dysfunction and the effect appeared

at lower urinary Cd level than renal dysfunction. But

more studies were needed to prove it.

The research data on non-specific hazards of environ-

mental Cd pollution was not too much, because the health

effects of population were characterized by target organ

damage in the early stage of chromic Cd poisoning, which

had led main studies focusing on effects of renal injury, a

J. X. Han et al. / HEALTH 1 (2009) 159-166

163

special-effects, in a long time, yet few investigations on

the change of popular mortality and morbidity of environ-

mental Cd exposure.

4. MONITORING AND EARLY WARNING

STUDIES ON POPULATION HEALTH

HAZARDS

Thacker [78] put forward the concept of Environmental

Public Health Surveillance (EPHS) in 1996. The U.S.

Center for Disease Control and Prevention (CDC) has

been laying the groundwork for what was planned to

become a nationwide environmental public health track

network in 2002 for integrating network to assess local

and state data to determine exposures and health effects

linked to environmental hazards. CDC also provided the

EPHS system with a set of environmental public health

indicator (EPHI) in 2003, including: 1) hazard indicators

(Conditions or activities that identify the potential for

exposure to a contaminate or hazardous condition); 2)

exposure indicators (Biological markers in tissue or fluid that

identify the presence of a substance or combination of

substance that could harm an individual); 3) health effect

indicators (Disease or condition that identify an adverse

effects from exposure to a known or suspected environ-

mental hazard); 4) intervention indicators (programs or

official policies that minimize or prevent an environ-

mental hazard, exposure, or health effect). Project-

specific monitoring indicators needed to meet the following

requirements: 1) measurable; 2) trackable over time; 3) based

on demonstrated links between environment and health; 4)

useful and understood by diverse populations; 5) informative

to the public and to responsible agencies; 6) tied to public

health objectives; 7) action-oriented; 8) incorporated in

clear-case definitions [79]. In 2005, the U.S CDC announced

the launch of national network-building projects EPHS.

Combining with population disease information, EPHS

would help to assess hazard factors in the environment,

the main exposure routes, the health effects of population

and time trends through monitoring environmental

harmful factors, investigating the exposure routes and

identifying people at risk, timely releasing and delivering

relevant information to help high-risk people to avoid the

exposure to hazard factors and reducing the incidence of

chronic diseases in population. Its basic object was to

realize the integration of disease and death data monitor-

ed continuously and routinely with the occasional pro-

fessional investigation of environmental risk factors and

the individual-based population health evaluation data.

EPHS was different from any other existing monitoring

system. Its characteristics included: identify the health

effect trend of population exposed to environmental risk

factors based on the routine analysis of data on population

disease and death; determine the environmental risks and

population health status through professional targeted

research [80]. The raise of EPHS concept was the over-

throw of conventional route of monitoring and early

warning study on population health risks. It was com-

bined with environmental benchmark dose exposure and

referred to the EAI (environmental accident index) in-

dicators. The integration of environmental hazard surveys

monitoring data and human disease surveillance data pro-

vided scientific opportunities for the development of

population health hazard monitoring and early warning

system studies. EPHS was expected to be an ideal

technical platform, which was able to integrate all kinds

of disease control tasks and disciplines in the field of

environmental health and combine the main tasks of CDC

at all levels.

5. RESEARCH OBJECTIVES

IN THE FUTURE

It is very important to explore the risk factor for “Itai-Itai”

disease exposed to environmental Cd continuously in

long time and at high level, which has already existed in

China [81]. It is not time to say stop, although great ach-

ievement has been made in study on health effect of

exposure to environmental Cd. There is a lot of work

needed to do for realizing Cd health risk well in the future.

The main research objects should focus on: 1) continue to

conduct follow-up study on health hazards of all kinds of

people, evaluate the population Cd exposure and the

severity of health damage related, and analyze its trend; 2)

concern about the human disease and death impact due to

Cd exposure, collect and screen the information of popu-

lation disease and death closely related to Cd exposure,

and study the link and dose-response relation-ship between

kidney damage and Cd exposure; 3) establish human health

hazard monitoring and early warning network of Cd exposure

in the framework of environmental public health monitoring;

4) implement prevention and intervention research on

population health hazards of environmental Cd exposure

to reduce the risk of population Cd exposure and health

injury related.

REFERENCES

[1] ATSDR (Agency for Toxic Substances and Disease

Registry). (1997) Toxicological Profile for Cadmium

(Update).

[2] WHO (1989), Cadmium. Evaluation of certain additives

and contaminants Geneva: WHO.

[3] Q. H. Kong, (2001) Human health effects for environ-

mental cadmium pollution. Journal of Zhejiang Academy

of Medical Sciences, 12(1), 1-2.

[4] J. Z. Geng, (1993) Environment and Health. Huaxia

Publishing House, First Edition, 447.

[5] G. Nordberg, T. Jin, and Q. Kong, (1997) Biological

monitoring of cadmium exposure and renal effects in a

population group residing in a polluted area in China. Sci.

J. X. Han et al. / HEALTH 1 (2009) 159-166

164

Total Environ., 16, 199-114.

[6] J. Q. Li, X. Y. Chen, Y. J. Tang, et al., (2001) Environ-

mental Cadmium Pollution and the Effect on Population

Health. China Public Health, 17(3), 196-198.

[7] T. Y. Jin, Q. H. Kong, T. T. Ye, et al., (2002)

Environmental Epidemiology: Human Health Impacts

Caused by Cadmium. Journal of Labour Medicine, 9(1),

10-16.

[8] T. Jin, X. Wu, Y. Tang, et al., (2004) Environmental

epidemiological study and estimation of benchmark dose

for renal dysfunction in a cadmium-polluted area in China.

Biometals, 17(5), 525-30.

[9] R. Dianne and J. William, (1999) Heavy metal poisoning

and its laboratory investigation. Ann Clin Biochem, 36,

267-300.

[10] EPA, (1999) Toxicological review, Cadmium and Com-

pounds (CAS No. 7440-43-9).

[11] M. M. Zhai and Q. Shang, (2007) Reseach advance of

environmental cadmium exposure on human health

damage. Journal of Hygiene Research, 36(2), 255-257

(Chinese).

[12] T. Kido, E. Kobayashi, M. Hayano, et al., (1995) Sig-

nificance of elevated urinary human intestinal alkaline

phosphatase in Japanese people exposed to environmental

cadmium. Toxicol Lett., 80(1-3), 49-54.

[13] K. Etsuko, S. Yasushi, H. Ryumon, et al., (2008) Serial

changes in urinary cadmium concentrations and degree of

renal tubular injury after soil replacement in cadmium-

polluted rice paddies. Toxicology Letters, 176, 124-130.

[14] E. Kobayashi, Y. Suwazono, M. Dochi, et al., (2008)

Estimation of benchmark doses as threshold levels of

urinary cadmium, based on excretion of beta2-micro-

globulin in cadmium-polluted and non-polluted regions in

Japan. Toxicol Lett., 179(2), 108-12.

[15] E. Kobayashi, Y. Suwazono, R. Honda, et al., (2008)

Serial changes in urinary cadmium concentrations and

degree of renal tubular injury after soil replacement in

cadmium- polluted rice paddies. Toxicol Lett., 176(2),

124-30.

[16] H. Nakadaira and S. Nishi, (2003) Effects of low-dose

cadmium exposure on biological examinations. Sci. Total

Environ., 308, 49-62.

[17] K. Nogawa, T. Kido, and Z. A. Shaikh, (1992) Dose-

response relationship for renal dysfunction in a population

environmentally, Cadmium in the Human Environment.

IARC, 311-318.

[18] Criteria to determine health hazard district caused by

environmental cadmium pollution (1998) GB/T, 17221.

[19] L. Jarup and C. G. Elinder, (1994) Dose-response

relations between urinary cadmium and tubular protei-

nuria in cadmium-exposure workers. Am J. Ind. Med., 26,

757.

[20] Oo, Y., E. Kobayashi, K. Nogawa, Y., et al., (2000) Renal

effects of cadmium intake of a Japanese general popu-

lation in two areas unpolluted by cadmium. Arch. Environ.

Health, 55, 98-103.

[21] I. Masayuki , E. Takafumi , M. Jiro , et al., (2005) The

threshold cadmium level that causes a substantial increase

in ß2-microglobulin in urine of general populations. Exp.

Med., 205, 247-261.

[22] M. Ikeda, T. Ezaki, J. Moriguchi, et al., (2005) The thre-

shold cadmium level that causes a substantial increase in

beta2-microglobulin in urine of general populations.

Tohoku J. Exp. Med., 205(3), 247-61.

[23] S. Yasushi, S. Salomon, V. Marie, et al., (2006)

Benchmark dose for cadmium-induced renal effects in

humans. Environ Health Perspect, 114(7), 1072-1076.

[24] E. Kobayashi, Y. Suwazono, M. Uetani, et al., (2006)

Esti- mation of benchmark dose as the threshold levels of

urinary cadmium, based on excretion of total protein,

beta2-microglobulin, and N-acetyl-beta-D-glucosemini-

dase in cadmium nonpolluted regions in Japan. Environ.

Res., 101(3), 401-6.

[25] T. Y. Jin and X. W. Wu, (2003) Application of Benchmark

Dose (BMD) in an Epidemiological Study on a General

Population Environmentally Exposed to Cadmium. Jour-

nal of Labour Medicine, 20(5), 335-337.

[26] X. W. Wu, T. T. Ye, T. Jin, et al., (1997) Dose-response

relationship between cadmium and renal dysfunction in a

general population. Journal of Shanghai Medical (Univer-

sity), 24(1), 41-44 (Chinese).

[27] Q. Shang and S. W. Cai, (1988) Urinary N-acetyl-β-D-

gluco-saminidase and early renal damage, Foreign

Medical Science-Section Hygiene, 3, 149-153 (Chinese).

[28] J. A. Staessen, H. A. Roels, D. Emelianov, T. Kuznetsova,

L. Thijs, J. Vangronsveld, et al., (1999) Environmental

exposure to cadmium, forearm bone density, and risk of

fractures: prospective population study. Lancet, 353,

1140-1144.

[29] R. Honda, I. Tsuritani, Y. Noborisaka, H. Suzuki, M.

Ishizaki, and Y. Yamada, (2003) Urinary cadmium

excretion is correlated with calcaneal bone mass in

Japanese women living in an urban area. Environ. Res, 91,

63-70.

[30] G. Zhu, H. Wang, Y. Shi, S. Weng, T. Jin, Q. Kong, et al.,

(2004) Environmental cadmium exposure and forearm

bone density. Biometals, 17, 499-503 (Chinese).

[31] M. G. Carolyn, S. K. John, and R. M., (2008) Jaymie

Urinary cadmium and osteoporsis in U.S. women ≥50

years of age: NHANES 1988-1994 and 1999-2004.

Environ. Health Perspect, 116(10), 1338-1343.

[32] M. Uchida, H. Teranishi, K. Aoshima, et al., (2007)

Elevated urinary levels of vitamin D-binding protein in

the inhabitants of a cadmium polluted area, Jinzu River

basin, Japan. Tohoku J. Exp. Med., 211(3), 269-74.

[33] G. Nordberg, T. Y. Jin, A. Bernard, et al., (2002) Low

bone density and renal dysfunction following environ-

mental cadmium exposure in China. Ambio, 31(6),

4782481.

[34] A. Agneta, B. Per, L. Thomas, et al., (2006) Cadmium-

induced effects on bone in a population-based study of

women. Environ. Health Perspect, 114(6), 830-834.

[35] T. Kido, K. Nogawa, R. Honda, et al., (1990) The asso-

ciation between renal dysfunction and osteopenia: in

environmental cadmium-exposed subjects. Environ. Res.,

51, 71-82.

[36] T. Alfvdn, C. G. Elinder, M. D. Carlsson, et al., (2000)

Low-level cadmium and osteoporosis. J. Bone Miner Res.,

15, 1579-1586.

[37] A. Manish, W. Jennifer, S. Joel, et al., (2008) Association

of Environmental Cadmium Exposure with Pediatric

Dental Caries. Environ. Health Perspect, 116(6), 821-825.

[38] T. Jin, G. Nordberg, X. Wu, et al., (1999) Urinary

N-acetyl-β-D-glucosaminidase isoenzymes as biomarker

J. X. Han et al. / HEALTH 1 (2009) 159-166

165

of renal dysfunction caused by cadmium in general

population. Environ. Res., 81, 167.

[39] B. Shlomo, Z. Xiang, S-T, et al., (2008) Transcriptome

Analyses in Normal Prostate Epithelial Cells Exposed to

Low-Dose Cadmium: Oncogenic and Immunomodu-

lations Involving the Action of Tumor Necrosis Factor.

Environ. Health Perspect, 116(6), 769-776.

[40] Q. Shang and S. W. Cai, (1993) Relationship between

cadmium intake and renal damage in cadmium-con-

taminated area population. J. Environ. Health, 10(5),

193-196.

[41] S. Cai, L. Yue, T. Jin, et al., (1998) Renal dysfunction

from cadmium contamination of irrigation water: dose-

response analysis in a Chinese population. Bulletin, 76(2),

153-159.

[42] K. Nogawa, R. Honda, R. Tsuritani, et al., (1989) A dose

response analysis of cadmium intake limit. Environ. Res.,

48(1), 7-16.

[43] E. Kobayashi, Y. Okubo, Y. Sowazonu, et al., (2002)

Association between urinary calcium excretion level and

mortality in inhabitants of the Jinzu river basin area of

Japan. Biolog Trace Elem Res., 89(2), 145-154.

[44] N. Hiroto and N. Hiroto, (2003) Effects of low-dose

cadmium exposure on biological examinations. The

Science of the Total Environment, 308, 49-62.

[45] N. Chiyoda, E. Kobayashi, Y. Okubo, et al., (2003)

Allowable level of lifetime cadmium intake calculated

from the individuals in the Jinzu river basin of Japan.

Biolog Trace Elem Res., 96(1-3), 9-20.

[46] W. Curtis, M. Sara, C. Dave, et al., (2002) Effects of

exposure to low levels of environmental cadmium on

renal biomarkers. Environ. Health Perspect, 110, 151-155.

[47] D. K. T. Laura, H. Susan, N. Mark,et al., (2009) Early

Kidney Damage in a Population Exposed to Cadmium and

Other Heavy Metals. Environ. Health Perspect, 117(2),

181-184.

[48] H. Nakagawa, M. Nishijo, Y. Morikawa, et al., (1993)

Urinary beta-2-microglobulin concentration and Mortality

in a cadmium-polluted area. Arch. Environ. Health, 48,

428-435.

[49] S. Kawano, H. Nakagawa, Y. Okumura, et al., (1986)

Amortality study of patients with Itai-Itai disease. Environ.

Res., 40(1), 98-102.

[50] E. Kobayashi, Y. Okubo, Y. Suwazono, T. Kido, et al.,

(2002) Dose-response relationship between total

cadmium intake calculated from the cadmium concen-

tration in rice collected from each household of farmers

and renal dysfunction in inhabitants of the Jinzu River

basin, Japan. J. Appl. Toxicol, 22, 431-436.

[51] K. Etsuko, O. Yasushi, S. Yasushi, et al., (2002) Associ-

ation between total cadmium intake calculated from the

cadmium concentration in household rice and mortality

among inhabitants of the cadmium-polluted Jinzu River

basin of Japan. Toxicology Letters, 129, 85-91.

[52] I. Teruhide, K. Etsuko, O. Yasushi, et al., (2001) Associ-

ation between cadmium concentration in rice and mor-

tality in the Jinzu River basin, Japan. Toxicology, 163,

23-28.

[53] H. Nakagawa, M. Nishijo, Y. Morikawa, et al., (1993)

Urinary beta-2-microglobulin concentration and Morta- lity

in a cadmium-polluted area. Arch. Environ. Health, 48,

428-435; K. Matsuda, E. Kobayashi, Y. Okubo, et al. (2003)

Total cadmium intake and mortality among residents in the

Jinzu river basin, Japan. Arch. Environ. Health, 58(4),

(http://www.findarticles.com/p/articles/mi_m0907/is_4_5

8/ai_111732609/pg_3).

[54] M. Nishijo, Y. Morikawa, H. Nakagawa, et al., (2006)

Causes of death and renal tubular dysfunction in residents

exposed to cadmium in the environment. Occupat Environ.

Med., 63, 545-550.

[55] M. Nishijo, H. Nakagawa, Y. Morikawa, et al., (1999)

Relationship between urinary cadmium and mortality

among inhibitions living in a cadmium polluted area in

Japan. Toxicol Lett., 108, 321-327.

[56] M. Nishijo, H. Nakagawa, Y. Morikawa, et al., (1999)

Mortality of inhibitions in cadmium area: 15 year follow-

up. Occupational and Environmental Medicine, 52, 181-

184.

[57] T. S. Nawrot, E. Van Hecke, L. Thijs, et al., (2008)

Cadmiumrelated mortality and long-term secular trends in

the cadmium body burden of an environmentally exposed

population. Environ. Health Perspect, 116(12), 1620-8.

[58] S. N. Tim, V. H. Etienne, T. R. Lutgarde, et al., (2008)

Cadmium-Related Mortality and Long-Term Secular

Trends in the Cadmium Body Burden of an Environ-

mentally Exposed Population. Environ. Health Perspect,

116(121), 1620-1628.

[59] M. Andy, M. Paul, K. S. Ellen, et al., (2009) Cadmium

levels in urine and mortality among U.S. Adult. Environ.

Health Perspect, 117(2), 190-196.

[60] B. Ritz，J. Heinrich，M. Wjst，et al., (1998) Effect of cad-

mium body burden on immune response of school child-

ren, Archives of Environmental Health,

(http://www.findarticles.com/p/articles/mi_m0907/is_n4_

v53/ai_21017752/pg_6).

[61] Scientific Committee on Toxixcity, Ecotoxicity and the

Environ- ment (CSTEE) (2004), Opinion on the results of

the Risk Assessment of: Cadmium Metal Human Health,

CAS-No.: 7440-43-9, EINECS-n: 231-152-8, Cadmium

Oxide Human Health, CAS-No.: 1306-19-0, EINECS-n:

215-146-2, Brussels, C7/VR/csteeop/Cdmet-oxhh/0801

04D/.

[62] M. Falcon, P. Vinas, E. Osuna, et al., (2002) Environ-

mental exposure to lead and cadmium measured in human

placenta. Arch Environ. Health, 57(6), 598-602.

[63] M. Nishijo, H. Nakagawa, R. Honda, et al., (2002) Effects

of maternal exposure to cadmium on pregnancy outcome

and breast milk. Occupat Environ. Med., 59, 394-397.

[64] A. Fischer, R. Georgieva, V. Nikolova, J. Halkova, A.

Bainova, V. Hristeva, D. Penkov, and D. Alandjiisk, (2003)

Health risk for children from lead and cadmium near a

non-ferrous smelter in Bulgaria. Int. J. Hyg. Environ.

Health, 206, 25-38.

[65] H. Epstein, J. Dejmek, P. Subart, N. Viternovaa, and R. J.

Saraam, (2000) Trace metals and pregnancy outcome in

the Czech Republic. Env. Epidemiol. Toxicol, 2(1), 13-19.

[66] O. Akinloye, A. O. Arowojolu, O. B. Shittu, et al., (2006)

Cadmium toxicity: a possible cause of male infertility in

Nigeria Reprod Biol., 6(1), 17-30.

[67] M. Kaori, K. Etsuko, O. Yasushi, et al., (2003) Total cad-

mium intake and mortality among residents in the Jinzu

River Basin, Japan. Arch. Environ. Health, 58(4),

218-222.

J. X. Han et al. / HEALTH 1 (2009) 159-166

166

[68] J. A. McElroy, M. M. Shafer, A. Trentham-Dietz, J. M.

Hampton, and P. A. Newcomb, (2006) Cadmium

exposure and breast cancer risk. J. Natl. Cancer Inst., 98,

869-873.

[69] A. Akesson, B. Julin, and A. Wolk, (2008) Long-term

dietary cadmium intake and postmenopausal endometrial

cancer incidence: a population-based prospective cohort

study. Cancer Res., 68, 6435-6441.

[70] A. Agneta, J. Bettina, and W. Alicja, (2008) Long-term

Dietary Cadmium Intake and Postmenopausal

Endometrial Cancer Incidence: A Population-Based

Prospective Cohort Study. Cancer Res., 68(15), 6435-41.

[71] B. Celia, D. D. Shailaja, B. S. Geoffrey, et al., (2009)

Cadmium-a metallohormone? Toxicol Appl Pharmacol ,

238(3), 266-271.

[72] C. Nagata, Y. Nagao, C. Shibuya, et al., (2005) Urinary

cadmium and serum levels of estrogens and androgens in

postmenopausal Japanese women. Cancer Epidemiol Bio-

markers Prev., 14(3), 705-8.

[73] V. Verougstraete, D. Lison, and P. Hotz, (2003) Cadmium,

lung and prostate cancer: A systematic review of recent

epidemiological data. J. Toxicol Environ. Health Part B:

Critical Reviews, 6(3), 227-256.

[74] T. P. Maria, N. A. Ana, M. C. Ciprian, et al., (2008)

Cadmium Exposure and Hypertension in the 1999-2004

National Health and Nutrition Examination Survey

(NHANES). Environ. Health Perspect, 116(1), 51-56.

[75] S. Y. Wu, J. Tian, T. S. Zhou, et al., (2003) Analysis on

resident's spectrum of disease and death in cadmium-

polluted area. China Public Health, 19(1), 29-30

(Chinese).

[76] S. Y. Wu, J. Tian, M. Z. Wang, et al., (2004) Effect of

cadmium pollution on sub-health state and chronic

diseases. China Public Health, 20(9), 1053-1054.

[77] L. J. Lei, L. Chen, T. Y. Jin, et al., (2007) Estimation of

benchmark dose for pancreatic damage in cadmium-

exposed smelters. Toxicol Sci., 97(1), 189-195.

[78] S. Thacker, D. Stroup, R. Parrish, et al., (1996) Surveill-

ance in environmental public health: issues, systems, and

sources. Am. J. Public Health, 86(5), 633-638.

[79] U.S.CDC, Environmental public health indicators, U.S.

CDC，ECEH, EHHE, (2003),

(http: // www. cdc. gov/ nceh/divisions/ehhe.htm).

[80] B. Ritz, I. Tager, and J. Balmes, (2005) Can lessons from

public health disease surveillance be applied to Environ-

mental public health tracking? Environ. Health Perspect,

113, 243-249.

[81] Q. Shang, M. M. Zhai, L. S. Yao, et al., (2009) A

following up survey on cadmium level in rice in a

contaminated area, Jiangxi province. J. Hygiene Research,

38(3), 296-298 (Chinese).