Cadmium - Toxicology of Metals - page 462

administration, renal injury generally develops in
half of the Cd-exposed animals when values exceed
100-150 mg/kg wet weight (review by Kjellstrom,
1986a; Stowe et al ., 1972; Tohyama et al ., 1981; 1987).
On the basis of a comprehensive evaluation of Cd con-
centrations obtained through biopsy or autopsy from
persons exposed occupationally to Cd, the presence or
absence of proteinuria, and renal pathological fi ndings,
as well as data derived from animal experiments, Frib-
erg et al . (1974) concluded that, for humans, the criti-
cal Cd concentration in persons highly susceptible to
renal injury is approximately 200 mg/kg. From meas-
urements of renal Cd concentrations in Cd workers, on
the basis of the in vivo NAA method (Ellis et al ., 1984;
Roels et al ., 1981), the mean PCC (PCC-50) in the renal
cortex was found to be approximately 250-300 mg/
kg, with the level at which 10% of workers exceeded
their critical concentrations (PCC-10) estimated to be
approximately 170-200 mg/kg (Kjellström, 1986a). In
the IPCS document, the critical Cd concentration in the
renal cortex for inducing renal tubular dysfunction in
10% of Cd-exposed populations was estimated to be
200 mg/kg wet weight (WHO/IPCS, 1992). In calcu-
lations from a metabolic/toxicokinetic model based
on data from human and animal studies (Kjellström
and Nordberg, 1978; 1985) and the statistical distribu-
tion of renal cortex Cd concentrations, a 10% response
rate (prevalence of effects above background) was
estimated to occur at a daily intake of approximately
200

workers are women, some of child-bearing age, lower
permissible occupational exposure limits than 50 g/

m 3 should be recommended; indeed, they have been
recommended in several countries (see Section 4.2).
For environmental exposure, Diamond et al . (2003)
estimated a lower confi dence limit for PCC-10 (in their
terminology, “RC10L”) of 84

µ

g/g kidney cortex. Using
the toxicokinetic model described by Choudhury et al .
(2001)—cf. Section 5.5 in this chapter and Chapter 3
in this Handbook—these authors estimated that such
a kidney cortex level would be attained at a constant
chronic intake of 1

µ

g/
kg/day in males. The RC10L was 1.6-3.0 times higher
than the 95 th percentile of renal cortical levels in the
US population (50

µ g/kg/day in females and 2.2 µ

g/g in males),
and the authors stated that, for most of the US popula-
tion, diet-derived risks are likely to be negligible in the
absence of exposure from other sources.

µ g/g in females; 27 µ

8.2 Direct Observations of Dose-Response
and Risk Characterization
A number of studies of workers who have experi-
enced prolonged Cd exposure have been published
(Kjellstrom et al ., 1977a; reviews by Thun et al . [1991]
and Jarup et al ., [1998c]). The conclusions from the
evaluations and calculations by Thun et al . (1991) are
mentioned in Section 8.1. The further studies reviewed
by Jarup et al . (1998c) pointed out the greater sensi-
tivity to development of renal effects among older
workers.
Numerous reports from Japan have focused on
the dose-response relationships of the inhabitants of
Cd-polluted areas. In Japan, because 50-70% of the
amount of Cd ingested orally derives from rice (Tsuch-
iya and Iwao, 1978), the Cd concentration in rice and
the lifetime Cd intake are used as indices of Cd expo-
sure. These dose-response relationships have been
most thoroughly investigated for the inhabitants of
the Jinzu River basin, Toyama Prefecture, where Itai-
Itai disease occurred, and for those in the Cd-polluted
Kakehashi River basin of the Ishikawa Prefecture. In
the former area, signifi cant associations have been
identifi ed between the urinary fi nding positive rates
(protein, glucose) in 13,183 persons in 1967-1968 and
the Cd concentrations in 2446 rice samples investigated
from 1971-1976 (Figure 9) and between the lifetime Cd
intake (calculated from Cd concentrations in the rice
samples) and the period of residence (Chiyoda et al .,
2003; Osawa et al ., 2001;Watanabe et al ., 2002; 2004).
Permissible values determined by the authors from
regression lines of dose-response relationships using
proteinuria plus glucosuria as an index were estimated
to be 0.11 mg/kg (ppm) for the rice Cd concentration

g from food after 45 years of exposure; it was sur-
mised that, in Cd workers, a 10% response rate would
be found after 10 years' exposure at a Cd concentra-
tion of approximately 50

µ

g/m 3 (Kjellström and Nor-
dberg, 1985). Thun et al . (1991) reviewed studies up
to 1991 using the metabolic model and critical organ
concept for calculating the risk of renal damage after
occupational exposure to Cd. They found that cumula-
tive exposure, corresponding to 45 years of exposure,
to between 5 and 10

µ

g of Cd in industrial air would be
expected to lead to a distinct increase in tubular dys-
function in a small proportion of exposed workers. In
view of the recent estimates of lower levels of Cd as
the PCC-10 in the general population (cf. Section 8.2),
estimates of response rates based on calculations using
a metabolic/toxicokinetic model will be correspond-
ingly lower compared with the calculations presented
previously, which were based on the higher values for
PCC-10 cited in the foregoing text. At present, however,
there are no published articles presenting such values
for occupational exposure. The estimated values for
PCC-10 cited previously for a male working popula-
tion may still be valid, but in view of the fact that occu-
pational exposure frequently lasts for more than 10
years and that nowadays an increasing proportion of

µ