Relationship between environmental exposure to cadmium and bone metabolism in a non-polluted area of Japan
Environ Health Prev Med
Relationship between environmental exposure to cadmium and bone metabolism in a non-polluted area of Japan
Mitsuru Osada 0 1 2
Takashi Izuno 0 1 2
Minatsu Kobayashi 0 1 2
Minoru Sugita 0 1 2
0 M. Kobayashi Laboratory of Public Health Nutrition, Department of Food Science, Faculty of Home Economics, Otsuma Women's University , Tokyo , Japan
1 T. Izuno Bureau of Social Welfare and Public Health, Tokyo Metropolitan Government , Tokyo , Japan
2 M. Osada (&) M. Sugita Department of Environmental and Occupational Health, Toho University School of Medicine , 5-21-16 Omori-nishi, Ota-ku, Tokyo 143-8540 , Japan
Objectives The purpose of this study was to investigate the effects of environmental low-grade cadmium exposure on bone in the population of a non-polluted area. We investigated the relationship between environmental cadmium exposure (via rice intake) and bone metabolism in middle-aged and elderly women living in a non-polluted area in Japan. Methods Four hundred and twenty-nine women over the age of 39 years (54.6 ± 9.1 years; arithmetic mean ± SD) participated in this study in 2003. We investigated blood and urine, and rice intake, and performed ultrasonic bone evaluation, and obtained individual information about the subjects' health. Multiple regression analysis was performed in the statistical analysis. Results The arithmetic mean of cadmium content in rice was 70.8 ± 44.7 lg/kg (AM ± SD). The geometric mean of daily cadmium intake (Cd intake) from rice calculated based on food consumption data was 9.12 lg/day (GSD 2.33). The geometric means of serum and urine cadmium concentrations were 1.57 lg/l (GSD 2.11) and 1.93 lg/g creatinine (cr.) (GSD 2.05), respectively. Multiple regression analysis showed positive correlations between (1) urinary free deoxypyridinoline (FDPD-U) and Cd intake (p \ 0.05), (2) urinary cross-linked N-telopeptides of type I collagen (NTx-U) and Cd intake (p \ 0.05), and (3) FDPD-U or NTx-U and cadmium concentration in urine (p 0.01). No significant correlation between the parameters of ultrasonic bone evaluation and cadmium associated biomarkers was observed. Conclusions The results of the present study suggest the possibility of bone metabolic disorder induced by environmental low-grade cadmium exposure. With respect to osteoporosis, a long-term follow-up survey is required to assess the tolerable intake of cadmium in environmental exposure.
Environmental exposure to cadmium; Cadmium intake from rice; Ultrasonic bone evaluation; Non-polluted area; Bone metabolism
Cadmium is a toxic metal which adversely affects human
health. Several studies have investigated the adverse health
effects of cadmium via environmental exposure in
nonpolluted areas, while numerous studies have reported
occupational cadmium exposure and environmental
exposure in polluted areas including the Jinzu River basin in
Japan, where the infamous itai-itai (‘‘ouch-ouch’’) disease
had been prevalent [
]. The Food and Agriculture
Organization of the United Nations (FAO) and Joint Expert
Committee of Food Additives and Contaminants (JECFA)
of the World Health Organization (WHO) proposed a
provisional tolerable weekly intake (PTWI) of 7 lg/kg
body weight/week of cadmium in 1993 [
]. After various
investigations at subsequent meetings, the committee
established a provisional tolerable monthly intake (PTMI)
of 25 lg/kg body weight/month at the 73rd meeting of the
JECFA in 2010 [
]. This risk assessment was estimated
based on data from occupationally exposed workers. There
is some controversy over whether the present PTWI of
7 lg/kg body weight/week is applicable to populations
exposed to low-grade environmental cadmium via food,
beverages, air, dust, smoking, etc. For non-smokers, the
main source, almost 99% or more, of cadmium exposure in
Japan is the diet [
]. In the case of Japanese who eat large
amounts of rice, it is assumed that approximately 40% of
the cadmium exposure from food is ingested via rice [
To assess the environmental low-grade cadmium body
burden in Japan, it is worth investigating the
cadmiuminduced effect via rice. Cadmium content in polished rice
shows geographical differences in non-polluted areas.
International surveys have revealed that polished rice
harvested in Japan retained high concentrations of cadmium,
especially in the Hokuriku region, compared with other
countries in Asia and Europe, even though cadmium
content in Japanese rice has been reduced in recent years
mainly by field reclamation of agricultural land [
The biological half-time of cadmium taken into the body
is relatively long, ranging from several years to tens of years
]. Past studies have noted that intraorganic accumulation
of cadmium shows maximum values in the fifth decade of
]. Most of the patients suffering from itai-itai
disease were middle-aged and elderly women. Iron deficiency,
which is prevalent in women, creates a significant risk for
cadmium exposure [
]. It was considered reasonable to
investigate the data of middle-aged and elderly women
because the toxic effect of cadmium in each of the organs
was remarkable in female subjects in their fifties.
We investigated the relationship between osteoporosis
and environmental low-grade exposure to cadmium in
middle-aged and elderly women living in a non-polluted
area of the Hokuriku region, on the west coast of the Sea of
Japan, where cadmium intake via rice has been reported to
be relatively high [
Subjects, materials, and methods
From April to December 2003, middle-aged and elderly
women who had annual general health checkups conducted
by Joetsu City and adjacent cities, towns, or villages under
the Health and Medical Service Act for the Aged, or at their
workplace in the Joetsu region under the Industrial Safety
and Health Act for workers were selected. They were all
over the age of 39 years. Four hundred and twenty-nine of
521 subjects who had annual general health checkups
agreed to participate in this study. This investigation was
performed at the cities, towns, villages, and workplaces
where cooperation was obtained. No soil pollution by
cadmium has ever been reported in this area. The proportion
of participants in this study to the whole subject cohort was
2.5% in those who should have the annual general health
checkups under the Health and Medical Service Act for the
Aged in Joetsu city and adjacent cities, towns, or villages,
and 32.2% those who should have the annual general health
checkups under the Industrial Safety and Health Act.
Two types of self-administered questionnaires, and
pedometers, were distributed to the participants in advance
of the health checkups. They responded to the
questionnaires and recorded the number of steps walked daily before
measurements of height and weight were taken. It takes
about 40 min to complete the questionnaires. One of the
questionnaires asked about the general health condition of
participants, with items such as birth date, lifestyle, history
of place of residence (village/town/city), and present
medical history. The other questionnaire, on diet history, has
been described as well-validated [
] (Table 1). We
used this questionnaire to determine the average amount of
rice intake in the months prior to the investigation. At the
time of the health checkups, we collected the questionnaires
and samples of rice which the participants usually ate and
brought from home. Three hundred and thirty-seven
homegrown rice samples and 92 commercially available
rice samples were collected. We measured the participants’
height and weight, and collected blood and urine samples
from them. Quantitative ultrasound (QUS) bone
measurements were also performed at this time.
It is difficult to evaluate the adverse effects of cadmium
among smokers because smokers are exposed to various
kinds of chemicals including cadmium in tobacco smoke.
Therefore, 29 smokers in the homegrown rice group and
five smokers in the commercially available rice group were
excluded from this analysis. Six subjects who had histories
of chronic renal diseases were also excluded. Subjects
whose current history included anemia (15 females) and
diabetes mellitus (7 females who had not been diagnosed
with diabetic nephropathy) were included in order to
analyze the health effects of cadmium exposure among these
groups. We investigated the data of 389 subjects and
collected 302 homegrown rice samples and 87 commercially
available rice samples. None of the 389 subjects had ever
been exposed to cadmium occupationally. No subject had a
history of residence in a reported cadmium polluted area
].The average [arithmetic mean ± arithmetic standard
deviation (AM ± SD)] age was 54.6 ± 9.1 years
(minimum age 39 years and maximum 77).
Bone measurements by QUS were performed at the right
calcaneus in each subject, using an ultrasound bone
evaluation device (AOS-100: ALOKA, Tokyo, Japan). Three
QUS parameters were measured: (1) speed of sound (SOS;
m/s), which reflects the bone density of the calcaneus, (2)
the transmission index (TI; ls), which reflects cancellous
bone volume, and (3) the osteo sono-assessment index
(OSI; m2/s), which reflects bone elasticity [
OSI value was calculated by the following equation:
(TI) 9 (SOS)2, where SOS is ultrasound velocity when
ultrasound is transmitted through the calcaneus and TI is
the full width at half maximum of the first ultrasonic wave
detected through the calcaneus. Bone measurement by
QUS was applied to the clinical diagnosis of osteoporosis
in the early 1990s in Japan. Ultrasonic evaluation has
several advantages over bone mass measurement
techniques. Measurement of ultrasonic evaluation requires no
radiation, and the equipment is more portable and less
costly than bone densitometry equipment such as that
required for dual-energy X-ray absorptiometry (DXA) and
quantitative computed tomography [
]. It takes only about
5–8 min, to measure bone properties using ultrasonic
]. Some studies have reported that this
technique was useful for assessment of the risk of
osteoporotic fracture in epidemiologic investigations [
However, bone measurements by QUS are influenced by
the temperature of the atmosphere and the subject’s skin,
dirt on the skin of the subject’s heel, the location of the
subject’s heel on the equipment, and the volume of
subcutaneous fat tissue . The measurement of DXA is the
standard method for evaluating individual bone mineral
density of the lumbar spine. We used QUS to evaluate bone
mass properties in this study for the reasons described
above, especially since individual examination time is
limited in the annual general health checkups.
The number of steps walked by the subjects was
measured with a pedometer (HJ-005: OMRON
HEALTHCARE, Tokyo, Japan) for three consecutive days. The
mean number of steps walked by each subject per day was
calculated to evaluate the correlation between steps walked
and other parameters.
The questionnaires and samples were checked twice by
nurses and nutritionists. A portion, 2 g (fresh weight), of
raw rice was wet-ashed by heating in the presence of
mineral acids, as described previously [
] until a clear
residue (approx. 0.3 ml) was obtained. The residue was
then diluted to a volume of 10 ml by the addition of
deionized water, and the diluted wet ash was subjected to
analysis for cadmium by inductively coupled plasma mass
spectrometry (ICP–MS). The ICP–MS apparatus
(connected to an autosampler) was a product of Seiko
Instruments (Tokyo, Japan). Isotopes were selected for cadmium
determination, and indium (In) and thallium (Tl) were used
as the internal standards in the preparation of calibration
curves. The recovery was approximately 95% for
cadmium, and the accuracy, when examined with bovine liver,
typical diet, and rice flour as reference materials, was
96–118% (104% average). The detection limit was 0.1 ng/g
(when a signal/noise ratio of 2 was taken), which was
considered sufficient. In practice, the autosampler could
accommodate 50 samples in a series. The determination of
cadmium in one series (including the input of operation
conditions to the system) took 2.5–3 h, making it possible
to measure 100–150 samples per day.
Peripheral blood samples, with one drop of 7.5% nitric
acid added to stabilize the cadmium content, were
centrifuged. Then the serum samples were stored at -80 C until
analysis. Urine samples, with one drop of 0.75% nitric acid
added to stabilize the cadmium content, were stored at -80 C
until analysis. The cadmium concentrations were measured
by flameless atomic absorption spectrometry, using the
Z-8100 (Hitachi, Hitachi City, Ibaraki, Japan) apparatus.
Cadmium measurements were checked using the cadmium
standard (Kanto Chemical, Tokyo, Japan). All items in
contact with the samples, including plastic bottles, tubes, and
syringes, had no detectable cadmium contamination.
b2-Microglobulin in urine (b2-MG-U) and
N-acetyl-b-Dglucosaminidase in urine (NAG-U) were measured as
indicators of renal dysfunction. Blood and urine samples
were obtained in the morning from 9:00 a.m. to noon.
Second morning urine samples were collected at the health
checkup location. After collection of the urine sample, the
pH was checked by a pH indicator method (Eiken
Chemical, Nogi Town, Tochigi, Japan) and kept neutral (pH 4–8)
without any regulation process, then preserved at -80 C
until analysis. The concentrations of b2-MG-U were
measured by a latex agglutination method (Eiken Chemical).
The concentration of NAG-U was measured by a rate
method (Shionogi, Settsu City, Osaka, Japan). Creatinine
in urine was measured by an enzyme method (Kanto
Chemical). Free deoxypyridinoline in urine (FDPD-U) and
cross-linked N-telopeptides of type I collagen in urine
(NTx-U) were measured by enzyme immunoassay. Serum
bone-specific alkaline phosphatase (BAP-S) was measured
by polyacrylamide gel electrophoresis.
Stock solutions for certified references (1000 ppm) and
mineral acids of trace element analysis grade were
purchased from Wako Pure Chemicals (Osaka, Japan).
Standard reference materials of bovine liver (NBS 1577b), and
rice flour (NBS 1588) were obtained from the National
Institute of Standards and Technology (Gaithersburg, MD,
USA) and that of rice flour (NIES 10a, 10b, and 10c) was
obtained from the National Institute for Environmental
Sciences (Tsukuba City, Ibaraki, Japan). Deionized water
was prepared by filtration of city water through a
Millipore-O system (Millipore, Molsheim, France).
We calculated total dietary cadmium intake from rice by
multiplying the consumption amount and cadmium
concentration in rice (Cd-R), then we calculated the total daily
cadmium intake from food based on the average Japanese
cadmium intake levels cited in the total diet study
conducted by the National Institute of Health Science in 2002
]. This calculation is based on the following equations.
½Total dietary cadmium intake from rice per day
¼ ½Consumption amount of rice per day
½Total daily cadmium intake from food
¼ ½Total dietary cadmium intake from rice per day
½Average Japanese total cadmium
intake from food per day in 2002
½Average Japanese cadmium intake from
rice per day in 2002
According to this survey, the average Japanese total
cadmium intake from food in 2002 was 26.0 lg/day, and
from rice it was 10.8 lg/day, so we applied 41.5% as the
proportion of total dietary cadmium intake from rice per
day to total daily cadmium intake from food. Then we
calculated the weekly cadmium intake per body weight
from the total daily cadmium intake to compare the
calculated amount with the present PTWI level [
Concentrations are expressed on a fresh weight basis. A
preliminary analysis of the distribution of the
concentrations showed that arithmetic standard deviations (ASD)
were often greater than one-third of the corresponding
means [arithmetic mean (AM)], as observed previously [
]. Thus, a natural logarithmic distribution was
6, 29, 30
] so that geometric means (GMs) and
standard deviations (GSDs) were taken as representative
parameters of distribution. In calculating the GM and GSD,
the value below the detection limit was assumed to be half
the detection limit. Further, multiple regression models
were used to analyze the relationship between the indicator
of cadmium burden and renal function or bone metabolism,
adjusting the effect of age with SAS statistical analysis
software version 8.2 (SAS Institute, Cary, NC, USA).
All participants in this study were informed about the
content and objectives of this study and gave their
informed consent to participate. Local ethics committees of
Toho University School of Medicine gave permission to
perform this study (Admission number: 14-046).
The mean (AM ± SD) Cd-R was 70.8 ± 44.7 lg/kg
(minimum 0.2 lg/kg, maximum 256.4 lg/kg). The mean
cadmium intake (Cd intake) from rice (AM ± SD) was
1.61 ± 1.17 lg/kg body weight/week (minimum 0.006 lg/
kg weight/week, maximum 7.761 lg/kg body weight/week).
The mean daily Cd intake from rice (GM) was 9.12 lg/day
(GSD 2.33; minimum 0.04 lg/day, maximum 51.27 lg/
day). The mean serum cadmium concentration (Cd-B: GM)
was 1.57 lg/l (GSD 2.11; minimum 0.50 lg/l, maximum
10.00 lg/l). The mean cadmium concentration in urine
(Cd-U: GM) was 1.93 lg/g creatinine (cr.) (GSD 2.05;
minimum 0.29 lg/g cr., maximum 11.83 lg/g cr.) (Table 2).
In the first evaluation, we assessed partial correlation
coefficients between parameters. As age had a statistically
significant relation to all parameters but number of steps
walked, we investigated relationships between parameters
adjusting for age. Table 3 shows the age-adjusted
correlation coefficients between parameters. We mainly
investigated the relationships between cadmium-associated
biomarkers and bone metabolic markers, as well as
ultrasonic bone evaluation parameters, because previous studies
reported that bone absorption was accelerated by cadmium
intake. The other parameters will be investigated in a
further study [
]. Correlation between two substances in
urine was calculated from the original measured values,
adjusted by age and logarithmic transformed creatinine,
while correlations between substances in urine and other
parameters were calculated from values in urine corrected
by urinary creatinine adjusted by age . As shown in
Table 3, log Cd-U was positively associated with log Cd
intake and log Cd-B, with correlation coefficients of 0.134
0.384, respectively. In regard to skeletal biomarkers, log
FDPD-U was positively associated with log Cd intake and
log Cd-U, with correlation coefficients of 0.106 and 0.152,
respectively, and log NTx-U showed the same trend as log
FDPD-U, with correlation coefficients of 0.125 and 0.163,
respectively, while OSI was not associated with log Cd-U,
log Cd-B, or log Cd intake.
AM arithmetic mean with arithmetic standard deviation, GM geometric mean with geometric standard deviation, SD standard deviation, OSI
osteo sono-assessment index (m2/s), Cd-B Cd concentration in blood (lg/l), Cd-U Cd concentration in urine (lg/g creatinine [cr.]), Cd-R
cadmium concentration in rice, b2-MG-U b2-microglobulin in urine (lg/g cr.), NAG-U N-acetyl-b-D-glucosaminidase in urine (U/g cr.), FDPD-U
free deoxypyridinoline in urine (nmol/mmol cr.), BAP-S bone-alkaline phosphatase in serum (U/l), NTx-U cross-linked N-telopeptides of type I
collagen in urine (nmol BCE/mmol cr.), BCE Bone Collagen Equivalents, TI transmission index (the full width at half maximum of the first
ultrasonic wave detected through the calcaneus), SOS speed of sound
We assessed the relationship between bone metabolic
indices and cadmium-associated parameters using multiple
regression analysis (Table 4). Partial regression
coefficients between log FDPD-U and cadmium-associated
parameters were all lower than 0.25. Partial regression
coefficients between log NTx-U and cadmium-associated
parameters were also lower than 0.25 [
]. These results
suggest that environmental cadmium exposure does not
strongly influence bone metabolism.
Although we investigated the subjects’ history of
osteoporotic fracture by questionnaire, we could not
discriminate individual fractures from non-osteoporotic fractures.
FDPD-U free deoxypyridinoline concentration in urine (nmol/l), NTx-U cross-linked N-telopeptide of type I collagen concentration in urine
(nmol BCE/l), BMI body mass index, Steps walked steps/day, Cd-intake Cd intake from rice/day (lg/day), Cd-U Cd concentration in urine (lg/l),
b2-MG-U b2-microglobulin concentration in urine (lg/l), NAG-U N-acetyl-b-D-glucosaminidase concentration in urine (U/l), Crea-U creatinine
concentration in urine (g/l), R2 coefficient of determination
* p \ 0.05; ** p \ 0.01
Neither the exact location of a fracture nor a detailed
description of the mechanism of the forces producing the
fracture was given in most of these questionnaires, and a
detailed follow-up survey for all participants who had
histories of fractures was impossible. Therefore, we did not
assess the relationship between cadmium exposure and
bone metabolic biomarkers from the viewpoint of each
participant’s history of osteoporotic fractures.
The influence of menopause on environmental cadmium
burden on the human body was assessed. The NTx-U value
was positively associated with b2-MG-U (p \ 0.01) and
BAP-S was positively associated with NAG-U (p \ 0.01)
in premenopausal women, while there was no significant
correlation between NTx-U and b2-MG-U or between
BAP-S and NAG-U in postmenopausal women. In
evaluating correlation coefficients in premenopausal and
postmenopausal women, the correlation coefficient between
NTx-U and b2-MG-U was significantly greater among
premenopausal women than postmenopausal women
(p \ 0.05). The correlation coefficient between BAP-S and
NAG-U was significantly greater among premenopausal
women than postmenopausal women (p \ 0.01).
Frequency of pregnancy and breast-feeding did not
significantly influence the correlation between bone
metabolic biomarkers and cadmium-associated indices.
With regard to the effects of environmental low-grade
cadmium exposure on human health, the FAO and JECFA
of WHO proposed a PTWI of 7 lg/kg body weight/week of
cadmium based on the data of an occupationally exposed
group in 1993 [
]. However, Hayashi noted that the report
overestimated the influence of cadmium in environmental
low-grade cadmium exposure [
]. Renal dysfunction is a
well-known adverse effect of cadmium on human health.
Disorders of bone metabolism such as that found in itai-itai
disease are also considerable adverse effects of cadmium.
Based on an investigation of patients suffering from itai-itai
disease, cadmium-associated osteoporosis has been
considered to be induced by the following mechanism [
impaired activation of vitamin D via proximal renal tubular
dysfunction induced by cadmium results in decreased
calcium absorption through the intestine, and decreased renal
tubular reabsorption of calcium and phosphate, followed by
increased calcium and phosphate excretion in urine. This is
the same mechanism as that found in acquired Fanconi
syndrome. Studies of experimental animals and cultured
tissue have demonstrated the stimulation of osteoclast-like
cell formation and the activation of osteoclast-like cells
resulting in the acceleration of bone resorption ,
decrease in the compression strength of bone [
], and the
stimulation of calcium release from bone and the inhibition
of mineralization and collagen synthesis [
] due to a
cadmium burden. A decrease in bone mineral density and
inhibition of bone formation before the manifestation of
renal dysfunction was reported in experimental animals
]. Furthermore, Coonse and colleagues [
] reported that
cadmium induced apoptosis in the cultured osteoblast-like
cell line Saos-2. Thus, the possibility of a direct effect of
cadmium on bone has been suggested [
However, the physiological response to cadmium varies
greatly among animal species. The results obtained from
experimental animals or cultured tissue cannot always be
extrapolated to the human body. Further investigation is
required to clarify the role of cadmium in the etiology of
cadmium-induced bone damage.
Several population-based studies showed an association
between osteoporosis and environmental cadmium
exposure. Zhu and colleagues [
] investigated a population
living in an area near a lead, zinc, and cadmium smelter
and a population in a control area in southeast China.
Forearm bone mineral densities of the participants were
measured by SPA-4 single-photon absorptiometry. They
reported that osteoporosis was significantly prevalent in the
heavily polluted area compared with the control area in
females over 50 years old, and spontaneous fracture was
significantly prevalent in the highly polluted area in
subjects over 40 years old. The Swedish OSCAR study
investigated workers occupationally exposed to cadmium,
subjects environmentally exposed to cadmium living in an
area near battery plants, and people residing in an area
further away from battery plants. This study showed a
negative dose–effect relationship between cadmium dose
and bone mineral density measured by DXA for people at
the age of 60 or older, and an increasing hazard ratio for
forearm fractures with increased urinary cadmium levels
for people beyond the age of 50 years [
]. A Japanese
study in a non-cadmium-polluted area (Kanazawa City)
revealed that the urinary cadmium in subjects with a mean
concentration of 2.87 lg/g creatinine showed a significant
correlation with NAG but not with b2-MG-U [
study carried out QUS bone measurements of the calcaneus
and demonstrated that the stiffness index, which is used as
an index of bone mass, was significantly inversely
correlated with urinary cadmium. They emphasized the need for
reassessment of the significance of cadmium exposure in
the general Japanese population. Horiguchi and colleagues
] conducted health examinations in 1380 female farmers
whose age ranged from 41 to 75 years from five districts in
Japan who consumed rice contaminated by
low-to-moderate levels of cadmium. They concluded that environmental
exposure to cadmium at levels insufficient to induce renal
dysfunction does not increase the risk of osteoporosis,
strongly supporting the established explanation for bone
injury induced by cadmium as a secondary effect, not a
direct effect, because the increase in urinary calcium
excretion by cadmium exposure occurring at levels much
less than the threshold of irreversible renal tubular
dysfunction was considered to be due to decreased renal
Akesson and colleagues [
cadmiumrelated effects on bone in 820 women (53–64 years of age).
They reported that urinary cadmium was negatively
associated with bone mineral density and parathyroid hormone
in blood, and positively associated with urinary
deoxypyridinoline and bone alkaline phosphatase in serum. They
also stated that the negative effects of low-level cadmium
exposure on bone seemed to intensify after menopause.
The present study showed a weak positive correlation
(0.124) between cadmium intake and FDPD-U in
postmenopausal women, suggesting that the influence of
menopause on the effects of cadmium on bone is not
denied, while the correlation between cadmium intake and
FDPD-U in premenopausal women was 0.055.
According to the Website of the Japanese Ministry of
Agriculture, Forestry and Fisheries [
], the supply of
brown rice with cadmium concentrations ranging from 0.4
to 1 mg/kg has been stopped since 1970. Sales of brown
rice containing cadmium concentrations over 1 mg/kg have
been prohibited and the remaining brown rice was disposed
of by incineration, in line with the Food Sanitation Act
since 1970. Moreover, the Japanese Ministry of
Agriculture, Forestry and Fisheries has designated rice fields where
brown rice with cadmium concentrations of over 1 mg/kg
has been harvested as soil-polluted agricultural land
requiring countermeasures, and provided guidance to
farmers in improving their soil. Cadmium intake in the
Japanese people has been decreasing year by year due to
such management of rice distribution, as well as a general
decrease in rice intake among the Japanese.
The present study revealed a weak positive correlation
between bone resorption markers and cadmium intake,
Cd-U, b2-MG-U, or NAG-U. This suggests the possibility
that bone metabolism may be affected by low-grade
exposure to cadmium. Because subjects who had a history
of renal disease were excluded from this study, it is
uncertain whether cadmium affects bone directly without
signs of cadmium-induced kidney damage, as Honda and
] reported, or whether cadmium affects
bone indirectly by causing renal dysfunction. In the
present study, ultrasonic bone evaluation did not
demonstrate that low-grade exposure to cadmium increased the
risk of fracture. In general, women, who often tend to be
in an iron-deficient state, are more sensitive to cadmium
than men because iron deficiency accelerates the
absorption of cadmium from the intestinal tract. Therefore,
environmental low-grade exposure to cadmium is
considered to influence women more strongly than men.
According to a total diet study carried out by the Japanese
Ministry of Health, Labour and Welfare, the average daily
cadmium intake from food for a Japanese person from
2003 to 2007 was 21.9 lg/day. The average daily
cadmium intake from rice for a Japanese person was 9.8 lg/
day. The ratio of the daily cadmium intake from rice to
that in all daily meals was 44.8% [
]. When we applied
this ratio to our investigation, the cadmium intake from
food for one subject was 3.60 lg/kg body weight/week,
as cadmium intake from rice was 1.61 lg/kg body
weight/week. This value is much smaller than the PTWI
of 7 lg/kg body weight/week, which the FAO and JECFA
of WHO proposed in 1993, and is equal to 51.4% of the
PTWI. The present study could not determine a cadmium
burden to the human body which would not affect bone
metabolism. From the viewpoint of bone metabolism, the
influence of environmental cadmium exposure on human
health must not be disregarded, especially among women
in Japan, where environmental cadmium exposure is
relatively high even in non-polluted areas, compared with
other countries. However, the cadmium intake of Japanese
people from food has been decreasing year by year. It is
necessary to assess the cadmium burden on the human body
in long-term follow-up surveys. Furthermore, because
multiple factors besides cadmium affect bone metabolism,
assessment of bone metabolism disorder based only on
cadmium is inappropriate. Further investigation is required
to determine the tolerable cadmium intake in circumstances
of environmental low-grade cadmium exposure and to
elucidate the mechanism of the effect of cadmium on bone
Acknowledgments This work was supported in part by research
grants-in-aid from the Environment Agency of the Government of
Japan to Minoru Sugita from 1993 to 2005. We express special
gratitude for the cooperation of the Joetsu Medical Association and
Dr. Shin-ichirou Shimbo of Kyoto Women’s University. Thanks are
also due to Mrs. Chika Onozawa for her skillful work in statistical
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