Cadmium - Toxicology of Metals - page 455

have been reported in Cd/Ni battery workers (Friberg,
1950). An increased occurrence of osteoporosis in these
workers has been reported by Alfven et al . (2000).
In Japan, the highest prevalence of osteomalacia is
found in the Cd-polluted Jintsu River basin in Toyama
Prefecture, with hitherto 188 cases confi rmed and rec-
ognized as Itai-Itai disease (see Section 7.2.9). Char-
acteristics of the Itai-Itai disease are osteomalacia,
osteoporosis, renal tubular dysfunction, malabsorption,
and anemia (WHO/IPCS, 1992). In addition, two cases
of Cd-induced osteomalacia have been reported in the
Kakehashi River basin in Ishikawa Prefecture, fi ve in
the Ichi River basin in Hyogo Prefecture (Nogawa et al .,
1975) and nine in Tsushima in the Nagasaki Prefecture
(Takebayashi et al ., 2000). All of these cases manifested
tubular dysfunction, with most also exhibiting glomer-
ular dysfunction. In the Cd-polluted Jinzu River basin
in the Toyama Prefecture and the Kakehashi River
basin in the Ishikawa Prefecture, renal dysfunction
and decreased bone density were found to be closely
related (Aoshima et al ., 1988b; Kido et al ., 1990b), clari-
fying that, in Japanese Cd-polluted areas, numerous
residents sustained the bone effects of Cd.
In a group of 508 inhabitants of mildly to moder-
ately Cd-polluted districts in Belgium, the relationships
between forearm bone density, bone fracture incidence,
and 24-hour urinary Cd excretion were investigated.
In postmenopausal women, proximal and distal bone
densities decreased by nearly 0.01 g/cm 2 with a dou-
bling of the 24-hour urinary Cd excretion at baseline
(median, 6.6 years earlier). A doubling of the Cd excre-
tion at baseline was associated with a 73% increase in
the risk of fractures in women (Staessen et al ., 1999).
In a survey of 43 Swedish Cd workers, the mineral
densities in the bones of the forearm, lumbar spine,
and hip, even when adjusted for confounding factors,
correlated inversely with the levels of blood Cd and
urinary Cd (Jarup et al ., 1998a). In a survey of 520 men
and 544 women exposed to Cd, a dose-response rela-
tionship was found between urinary Cd and decreased
bone mineral density; it was further clarifi ed that Cd
exposure increased the incidence of bone fracture
(Alfvén et al ., 2000; 2004). The mean urinary Cd con-
centration in this population at the time bone density
was determined was 0.74

urinary Cd concentration, even after adjusting for fac-
tors such as age, body weight, and menstrual status
(Honda et al ., 2003). Although a recent survey of 1380
women in a mildly Cd-polluted region of Japan found
no association between bone density and urinary
and blood Cd concentrations (Horiguchi et al ., 2005),
numerous other studies have demonstrated that mild
Cd exposure is associated with decreased bone density.
The following mechanisms have been proposed
for the infl uence of Cd on bone matter: (1) impair-
ment of vitamin D activity in the kidney, (2) the action
of Cd within the digestive tract interfering with the
absorption of calcium, and (3) the direct action of Cd
on the bone with derangement of collagen metabo-
lism. Figure 7 depicts the different possible points of
action of Cd on calcium and vitamin D metabolism;
Kjellstrom (1992) has reviewed the animal and in vitro
evidence concerning these possible points of action.
The 1

25(OH) 2 D levels measured in fi ve Itai-Itai dis-
ease patients and 36 inhabitants of a Cd-polluted area
manifesting renal injury were signifi cantly lower than
those of a group of 17 inhabitants of a non-Cd-polluted
area. Moreover, the level of 1

α

,25(OH) 2 D correlated
negatively with the levels of serum

α

β 2 -mg and PTH and
positively with the %TRP (Nogawa et al ., 1987). These
associations exhibited a gender difference; it was pro-
nounced in women, but not evident in men (Tsuritani
et al ., 1992). The levels of 1

,25(OH) 2 D measured in 21
men and 13 women residing in the Cd-polluted Jintsu
River basin of the Toyama Prefecture correlated signif-
icantly with creatinine clearance (for both sexes), the
fractional excretion of

α

β 2 microglobulin (for women),
the serum creatinine (for men), and the %TRP (for men),
with the level of 1

,25(OH) 2 D reported to decrease in
parallel with decreasing renal function (Aoshima et al .,
1993). Although no comparison was performed with
a control group, it was emphasized, however, that the
magnitude of this decrease remained within the nor-
mal range. Chalkley et al . (1998) measured the levels of
vitamin D metabolites in workers exposed to lead and
Cd (blood-Cd: 6-145 nmol/L; urine-Cd: 3-161 nmol/L).
Plasma 24R,25(OH)2D levels were depressed below
the normal range when the levels of blood and urinary
Cd increased. High Cd levels were associated with
decreased levels of 1

α

g/g CR.
Results from China (Nordberg et al ., 2002; Wang
et al ., 2003) have indicated bone effects—measured as
decreased mineral density in the bone of the forearm
and increased prevalence of fractures—at cumula-
tive doses somewhat lower than those giving rise to
the classical Itai-Itai cases in Japan among residents in
a Cd-polluted region. In a survey of 908 women in a
non-Cd-polluted region of Japan, calcaneal bone mass
displayed a signifi cant negative correlation with the

µ ,25(OH) 2 D when lead concentra-

tions were also elevated. Accordingly, there is evidence
supporting a Cd-related decrease in 1

α

,25(OH) 2 D in
humans when there is combined exposure to lead and
when there is pronounced Cd-induced renal injury.
The signifi cance of these fi ndings for the development
of bone injury has not, however, been clarifi ed suffi -
ciently. As for the second and third pathways, no evi-
dence is available to support their existence in man.
Most animal studies have indicated that Cd may exert

α