Vol.1, No.3, 159-1
Copyright © 2009 Openly accessible at http://www.scirp.org/journal/HEALTH/
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.
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
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.
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
Based on results of toxicological studies, the researches
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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 2.55.0μg/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
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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
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
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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
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 diabetes: 1.24 (95%CI:
1.06~1.45) and 1.45 (95%CI: 1.07~1.97) [2]. Early
diabetes (IFG) and type 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
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
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special-effects, in a long time, yet few investigations on
the change of popular mortality and morbidity of environ-
mental Cd exposure.
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.
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.
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