Toxicology and Applied Pharmacology 206 (2005) 191 – 197

www.elsevier.com/locate/ytaap

Biomarkers of cadmium and arsenic interactions

G.F. Nordberga,T, T. Jina,b, F. Hongc, A. Zhangc, J.P. Buchetd, A. Bernardd
a
Environmental Medicine, Umeå University, S-901 87 Umeå, Sweden
b
Department of Occupational Health, School of Public Health, Fudan University, Shanghai, 200032 Shanghai, PR China
c
Department of Toxicology, School of Public Health, Guiyang Medical College, Guiyang 550004, PR China
d
Université Catholique de Louvain, Brussels 1200, Belgium

Received 17 March 2004; accepted 4 November 2004

Available online 8 April 2005

Abstract

Advances in proteomics have led to the identification of sensitive urinary biomarkers of renal dysfunction that are increasingly used in
toxicology and epidemiology. Recent animal data show that combined exposure to inorganic arsenic (As) and cadmium (Cd) gives rise to
more pronounced renal toxicity than exposure to each of the agents alone. In order to examine if similar interaction occurs in humans, renal
dysfunction was studied in population groups (619 persons in total) residing in two metal contaminated areas in China: mainly a Cd
contaminated area in Zhejiang province (Z-area) and mainly a As contaminated area in Guizhou province (G-area). Nearby control areas
without excessive metal exposure were also included. Measurements of urinary h2-microglobulin (UB2MG), N-acetyl-h-glucosaminidase
(UNAG), retinol binding protein (URBP) and albumin (UALB) were used as markers of renal dysfunction. Urinary Cd (UCd) and total As
(UTAs) were analyzed by graphite-furnace atomic absorption spectrometry. Urinary inorganic As and its mono- and di-methylated
metabolites (UIAs) were determined by Hydride generation.
Results. As expected, the highest UCd values occurred in Z-area (Geometric mean, GM 11.6 Ag/g crea) while the highest UTAs values
occurred in G-area (GM = 288 Ag/g crea). Statistically significant increases compared to the respective control area were present both for
UTAs, UCd and for UB2MG, UNAG and UALB in Z-area as well as in G-area. UIAs was determined only in Z area. In G-area, there was a
clear dose–response pattern both in relation to UTAs and UCd for each of the biomarkers of renal dysfunction. An interaction effect between
As and Cd was demonstrated at higher levels of a combined exposure to As and Cd enhancing the effect on the kidney. In Z-area an increased
prevalence of B2MG-uria, NAG-uria and ALB-uria was found in relation to UCd, but no relationship to UTAs was found. A statistically
significant relationship between UIAs and UB2MG was found among women in this area and an interaction between As and Cd was
indicated for B2MG.
Conclusion. The present studies, which employed sensitive biomarkers of renal dysfunction, give support to the idea that human co-
exposure to Cd and inorganic arsenic gives rise to more pronounced renal damage than exposure to each of the elements alone, but further
studies are needed to establish and clarify this interaction.
D 2005 Elsevier Inc. All rights reserved.

Keywords: Human health effects; Toxicity; Cadmium; Arsenic; Urinary proteins; Renal dysfunction

Introduction cadmium No 7 in the Priority list of Hazardous substances

The toxicology of arsenic and cadmium has been ex-
tensively studied both in experimental animals and humans
(ATSDR, 2000; Jarup et al., 1998). Arsenic is No 1 and
T Corresponding author. Fax: +46 90 7851705.
E-mail address: gunnar.nordberg@envmed.umu.se (G.F. Nordberg).
0041-008X/$ - see front matter D 2005 Elsevier Inc. All rights reserved.
doi:10.1016/j.taap.2004.11.028
in USA (ATSDR, 2001). These metals often occur together
as contaminants in soil and water (Fay and Mumtaz, 1996).
The critical effect in humans exposed to cadmium occupa-
tionally or environmentally is renal dysfunction (Jarup et al.,
1998). Only limited evidence of renal toxicity of arsenic
(kidney cancer excepted) is available from animal models
using relatively high doses. However, studies in mice have
reported that chronic exposure to cadmium produces more
192 G.F. Nordberg et al. / Toxicology and Applied Pharmacology 206 (2005) 191–197

China. The present report is based on data from two

previous studies (Buchet et al., 2003; Hong et al., 2004) in
which sensitive biomarkers of renal dysfunction were
employed. These biomarkers had been developed based
on achievements in applied proteomics (Bernard, 2004;
Bernard et al., 1992, 1994; Jin et al., 1999) and included
urinary albumin as a biomarker for glomerular damage and
the urinary level of the following proteins as biomarkers of
renal tubular dysfunction: urinary retinol binding protein
(RBP), beta-2-microglobulin (B2M), and N-acetyl-h-d-
glucosaminidase (NAG).

Materials and methods

Study population. In China, a considerable number of

areas contaminated by As or Cd have been identified (Fig.
1). In some areas, there are combined contamination and
subsequent human exposure to As and Cd. The present
Fig. 1. Areas polluted by Arsenic and Cadmium in China. study was performed in a mainly As contaminated area
with some Cd exposure in Guizhou province, China (G-
area) and a mainly Cd polluted area with some As exposure
renal toxicity than arsenic and the combination of cadmium in Zhejiang province, China (Z-area). For each of the areas,
and arsenic produces even more renal injury than either of age- and sex-matched control groups in the same province,
the chemicals given alone (Liu et al., 2000). not contaminated by metals, were also studied in order to
In Guizhou province, China, the domestic use of arsenic allow comparison between exposed and non-exposed
containing coal gives rise to high arsenic concentrations in (i.e., control groups) and to provide low exposure ob-
ambient air and in some vegetables dried while exposed to servations for dose–response analyses. By a three-dimen-
the coal smoke, for example, 1000 mg/kg in capsicum. sional display of the data, possible interactions between
Arsenic in drinking water is low, less than 50 Ag/L (Zhang As and Cd exposures in inducing renal dysfunction were
et al., 2000). Consumption of fish and shrimp is very low in examined.
these areas, and therefore the dominate intake of arsenic is In G-area where burning coal contains As, concentrations
in the inorganic form from other kinds of food. of As is about 100–8300 mg/kg in coal, 16 mg/kg in soil.
Human health protection most frequently employs The average arsenic content of ambient air has been reported
exposure limits based on criteria for single agents as 0.22 mg/m3 and there is 1.8 mg/kg in rice, 11 mg/kg in
(WHO, 2002). Exposures, however, often are to mixtures corn and 1096 mg/kg in capsicum (Hong et al., 2004).
of organic and inorganic compounds and interactions Cadmium concentrations were 0.02, 0.06, 0.11, 0.17 and 2.1
among chemicals may be important. Nevertheless, infor- mg/kg in corn, capsicum, soil, rice and coal, respectively.
mation on the toxicity of the mixture is often lacking. And arsenic and cadmium levels in the tobacco were 0.39
Exposures to inorganic substances usually involve multiple mg/kg and 2.00 mg/kg, respectively. A nearby control area
compounds (Snow, 1992). For instance, arsenic (As) and without excessive metal exposure was also included (As in
cadmium (Cd) co-exposure frequently occurs in a variety
of settings (Diaz-Barriga et al., 1993; IARC, 1993). As and
Cd are also by-products obtained from processing other Table 1
metals, leading to common co-exposure in industrial Geometric means of urinary cadmium (UCd) and urinary arsenic (UAs) by
settings (IARC, 1993). Thus, there is a clear potential for gender for the exposed group and the control area in Guizhou province,
China (G-area)
simultaneous or sequential exposure to As and Cd in
UCd and As in residents living in G area
general populations and at workplaces. Interactions
between As and Cd have been reported that result in Sex N UAs UCd
(Ag/g Cr) (Ag/g Cr)
acute liver injury (Hochadel and Waalkes, 1997) and in
renal injury in mice (Liu et al., 2000), but little is known Control Males 68 60.67 0.79
Females 55 51.76 0.94
about their potential interaction in renal dysfunction in Total 123 56.23 0.86
human populations, especially from chronic exposure. The Exposed group Males 72 278.61T 2.22T
primary goal of the present studies was to characterize the Females 50 325.84T 2.06T
interaction of As and Cd in producing renal dysfunction in Total 122 288.40T 2.16T
humans exposed to combinations of these two agents in T P b 0.01.
 G.F. Nordberg et al. / Toxicology and Applied Pharmacology 206 (2005) 191–197 193

Table 2 persons with data on both Cd and As in urine were included

Geometric means of Urinary proteins by gender from the Control area in the present study.
(Control) and the polluted area (Exposed group) in Guizhou province (G-
area) China Subjects were asked to answer a detailed questionnaire
by trained and supervised interviewers. No statistically
Renal function in G area
significant differences were observed between exposed vs.
Sex N Uh2-MG UNAG UALB
controls in the respective study areas in the social and
(Ag/gCr) (U/gCr) (mg/gCr)
economic status. Subjects were asked to answer a detailed
Control M 68 125.03 4.30 4.89
F 55 106.66 3.17 4.05
questionnaire by trained and supervised interviewers.
T 123 114.81 3.68 4.49 The study was carried out with permission of the local
Exposed M 72 220.80T 12.37T 13.49T authority and the ethics committee of Shanghai Medical
group F 50 196.79T 10.45T 12.71T University or Fudan University, Shanghai, China (Hong et
T 122 213.80T 11.88T 13.12T al., 2004). For the study in Z-area approval was also
Note. Uh2-MG: urinary beta-2-microglobulin; UNAG: urinary N-acetyl-h- obtained from the ethics committee of the medical faculty of
d-glucosaminidase; UALB: urinary albumin. Umea University, Sweden (Buchet et al., 2003; Jin et al.,
T P b 0.01.
2002; Nordberg et al., 2002). Informed consent was
obtained from each participating individual.
capsicum 0.5 mg/kg and in rice 0.4 mg/kg, Cd in capsicum
0.03 and in rice 0.04 mg/kg). Participants were randomly Urine collection and analytical method. Urine samples
selected from people living since birth in the contaminated were collected from all participants and were kept frozen at
and control areas matched for age and sex. The total number 20 8C until analysis. Each urine sample was divided into
of participants in G area was 245, made up of 122 in the three parts immediately after collection. Of these, a part,
polluted area (72 men and 50 women) and 123 in the control which was used for arsenic and cadmium measurement,
area (68 men and 55 women) cf. Table 1. was acidified with concentrated nitric acid. A part was
Z-area is a mainly Cd contaminated area with some As treated with 0.1 M NaOH and was used for the measure-
exposure. It is located in Zhejiang province. A nearby ment of h2MG. The third part was assayed for ALB, NAG
control area was also studied. Cd levels in rice were 2.4 mg/ and creatinine without pre-treatment. UAs and UCd
kg in the contaminated area and 0.05 mg/kg in the control concentrations were measured by graphite-furnace atomic
area (Jin et al., 2002; Nordberg et al., 2002). Levels of As in absorption spectrometry (AAS, David et al., 1991; Jin et al.,
rice were 0.14 mg/kg in the contaminated area and 0.09 mg/ 2002). For analytical quality assurance, both calibration
kg in the control area. Persons who had resided in the standards and one run of reference materials (Seronorm
respective areas since birth were selected as described Trace Elements Urine, Oslo. Norway) were used for every
previously (Jin et al., 2002). The present study included 195 set of analyses performed. Urinary Cd was determined
persons (91 men and 104 women) from the heavily Cd using the standard addition method with proven accuracy
polluted area and 179 persons (79 men and 100 women) (Jin et al., 2002). Urinary Inorganic Arsenic (UIAs) and its
from the control area. The numbers are slightly fewer than metabolites were determined by hydride generation and
in the original study (Jin et al., 2002; Nordberg et al., 2002) atomic fluorescence spectrometry and URBP by latex
because of the lack of urine samples for As analysis. Only immunoassay (Buchet et al., 2003). Uh2MG and UALB

Fig. 2. Prevalence (%) of elevated urinary excretion (above cut off level) of biomarker proteins by Urinary Cadmium (UCd) and by Urinary Arsenic in G-area.
Footnote: Uh2MG: Urinary beta-2-microglobulin, UNAG: Urinary N-acetylglucosaminidase, UALB: Urinary albumin.
194 G.F. Nordberg et al. / Toxicology and Applied Pharmacology 206 (2005) 191–197

Fig. 3. Prevalence (%) of elevated excretion for three biomarker proteins in G-area in relation to combined exposure to Cd and As as indicated by urinary As
and Cd excretion. Footnote: UB2MG: Urinary beta-2-microglobulin, UNAG: Urinary n-acetylglucosaminidase, UALB: Urinary albumin.

and UMT (urinary metallothionein) were measured by polluted area were significantly higher than those in the
ELISA (Neuman and Cohen, 1989) and UNAG was control area. There were no significant differences in UAs,
measured as described by Price (1992). h2MG, ALB and UCd and urinary parameters of renal dysfunction between
NAG kits were purchased from the Debo Bioengineering males and females within the exposed or within the control
Ltd., China. Creatinine was measured by the Jaffe reaction area.
method (Hare, 1950). All urinary parameters were adjusted In Fig. 2, the prevalence of B2M-uria, NAG-uria and
for creatinine in urine. ALB-uria is shown in various UAs strata (0, 50, 100, 200,
400 Ag/g creatinine) and UCd strata (0, 1.0, 2.00, 5.00 Ag/g
Cut-off points for renal dysfunction biomarkers creatinine) in G area. A clear dose–response pattern is
(proteinuria). B2M-uria, RBP-uria, NAG-uria and ALB- evident both in relation to UAs and UCd for each of the
uria were defined as urinary excretion of the respective biomarkers of renal dysfunction. In Fig. 3, the combined
proteins above the cut-off point. The cut-off point was effect of Cd and As is illustrated. There were no subjects
defined based on the upper 5% limit value in the non- exposed to low UAs. An interaction effect between As and
polluted area. The cut-off values of Uh2MG, URBP, Cd is illustrated, at higher levels (200 Ag/g creatinine) of a
UNAG and UALB were 0.30 mg/g creatinine, 0.3 mg/g combined exposure to As and Cd demonstrating an
creatinine, 23.00 U/g creatinine and 15.00 mg/g creatinine, enhancing effect of Cd on As-induced renal dysfunction.
respectively. UCd and UAs levels in the Z area are shown in Table 3.
Higher values of As as well as for Cd are found in the
Statistical analysis. Procedures of the SPSS version 11.0 exposed group compared to the control group. Results of
software were used for frequency means, correlation, determinations of urinary protein biomarkers in participants
variance, regression analyses. The cut-off points (abnormal from G-area are given in Table 4. For each of UB2M,
values) for the criterion variables were defined as the 95%
upper limit values, which were calculated from the control
group. For comparisons between more than two groups, a Table 3
Urinary levels of Cadmium (UCd) and Arsenic (As) in residents living in
one-way analysis of variance (ANOVA) was used. Distri-
the Control area in Zhejiang province (Z-area) and in residents in the
butions of the biological measurements were normalized by heavily polluted area (Exposed group)
logarithmic transformation. Data were expressed in terms of
UCd and As in residents living in Z area
geometric means.
Sex N UCd UAs
(Ag/gCr) (Ag/gCr)
Control M 79 2.17 61.96
Results F 100 1.86 53.16
T 179 1.99 56.87
The concentrations of arsenic and cadmium in urine by Exposed group M 91 10.08T 132.07T
gender in G area are shown in Table 1. UAs and UCd F 104 13.11T, TT 176.20T, TT
concentrations in the polluted areas were significantly T 195 11.61T 154.03T
higher than those in the control areas. In the polluted area, M = male participants, F = female participants T = total number of
participants. Open squares indicate statistical significance in relation to
the geometric mean of UAs and UCd were 288 Ag/g
control group. Filled triangle indicates statistical significance between
creatinine and 2.16 Ag/g creatinine, respectively. The males and females.
h2MG, ALB and NAG levels in urine are shown in Table T P b 0.01.
2. The levels of Uh2MG, UALB and UNAG in the TT P b 0.05.
 G.F. Nordberg et al. / Toxicology and Applied Pharmacology 206 (2005) 191–197 195

Table 4 masks a possible effect of inorganic As. In order to examine

Results from Z-area: urinary excretion of proteins used as biomarkers of the specific effect of Inorganic arsenic for Z area, UIAs was
renal dysfunction in persons residing in the polluted area (Exposed Group)
and in the nearby control area (control) determined by hydride generation on the same urine
samples. Urinary excretion of the renal biomarkers RBP,
Kidney function in residents living in Z area
B2M and NAG were examined in relation to UIAs by
Sex N Uh2-MG UNAG UALB
multiple regression analyses (Buchet et al., 2003). A
(Ag/gCr) (U/gCr) (mg/gCr)
statistically significant relationship was found between all
Control M 79 209.48 2.96 3.28
F 100 180.59 2.72 3.61
three urinary biomarkers and UCd among men and women
T 179 193.16 2.82 3.46 (data not shown here). A statistically significant relationship
Exposed M 91 718.70T 7.25T 5.70TT between UIAs and URBP or UB2M was found among
group F 104 651.58T 10.77T, TTT 9.21T, TTT women (but not among men) and there was also evidence
T 195 682.67T 8.97T 7.39T for an interaction between IAs and Cd among women (Table
Open squares indicate statistical significance in relation to controls. Filled 5, Buchet et al., 2003).
triangles indicate statistical significance in relation to males.
Uh2-MG: Urinary beta-2-microglobulin; UNAG: Urinary N-acetyl-h-d-
glucosaminidase; UALB: Urinary albumin.
T P b 0.01. Discussion
TT P b 0.05.
TTT P b 0.01. The present study in two metal (and metalloid) contami-
nated areas in China provides evidence that renal dysfunc-
UNAG and UALB, there were statistically significant tion was induced in humans in a dose-related pattern by the
higher values in the exposed group compared to controls exposures occurring in these areas. The main contribution of
(Table 4). Women had higher levels than men of UNAG and the present studies is in relation to a mutually enhancing
UALB in the exposed area (Table 4). The prevalence of interaction between As and Cd exposures in inducing renal
elevated excretion of the respective proteins (above the cut dysfunction in humans. Although there was a lack of
off point) were plotted in relation to UCd and As and shown persons with low As exposure and high Cd exposure in G-
in (Fig. 4) in Z area. In general, a dose–response pattern is area, a clear enhancing effect of simultaneous Cd exposure
seen. The dose–response pattern is somewhat more con- was demonstrated in subgroups with high UAs. There was a
sistent for UCd. When plotting the prevalence of each lack of persons with low arsenic exposure but at higher As
biomarker in relation to combined exposure to UAs and exposures a clear enhancing effect of simultaneous Cd
UCd (Fig. 5), a dose–response relationship in relation to exposure was demonstrated. Also in Z-area, an interaction
UCd remains, but there is no relationship with (total) UAs between Cd and inorganic As was indicated. The reason that
(Fig. 5). Since Z area is a coastal area and consumption of interaction was statistically significant only among women
fish and seafood is prevalent, it is likely that UAs to a large is probably related to the fact that renal tubular toxicity
extent represents excretion of organic arsenic compounds occurred with higher prevalence among women than men,
occurring in fish and other seafood. Such arsenic com- the number of men studied was not sufficiently large to
pounds are virtually non-toxic and their occurrence in urine achieve statistical significance. The data for both areas thus

Fig. 4. Prevalence of elevated urinary excretion of biomarker proteins in Z-area. Footnote: UB2-MG: Urinary beta-2-microglobulin; UNAG: Urinary N-acetyl-
h-d-glucosaminidase; UALB: Urinary albumin.
196 G.F. Nordberg et al. / Toxicology and Applied Pharmacology 206 (2005) 191–197
Fig. 5. Prevalence of elevated urinary excretion of biomarker proteins in Z area. Footnote: UB2-MG: Urinary beta-2-microglobulin; UNAG: Urinary N-acetyl-
h-d-glucosaminidase; UALB: Urinary albumin.
indicate that combined exposure to inorganic As and Cd
gives rise to a higher prevalence of renal dysfunction than
either of the exposures alone. The potentiation by arsenic of
cadmium nephrotoxicity previously observed in mice
included a statistically significant additivity and/or syner-
gism between the two elements (Liu et al., 2000) and a
similar situation is observed in humans in our study.
The interactions illustrated by the evidence presented in
the present paper are further supported by data recently
reported by Hong et al. (2004) for G-area and by Jin et al.
(2004) for Z-area. The benchmark dose of Cd required for
renal dysfunction to occur was much lower in the heavily As
contaminated G-area (Hong et al., 2004) than in the mainly
Cd contaminated Z-area (Jin et al., 2004).
In addition to the observations concerning interactions, it
is interesting that in area G, where arsenic exposure was
most prominent, effects on albumin excretion, a biomarker
of glomerular dysfunction was most prevalent. It has not
previously been clearly demonstrated in humans that
environmental exposures to arsenic give rise to renal
glomerular dysfunction. It is most probable that As-
exposures in G-area are predominantly inorganic As.
However, the determinations of UAs were only for total
Table 5
Relationship between UCd, UIAs and RBP, B2M among women in Z-area
(Data from Buchet et al., 2003)
UCd, UIAs and RBP and B2M in women living in Z area
N RBP
(mg/gCr)
UCd b 4.8 Ag/gCr As b 36a 124 0.059
As N 36a 87 0.083
UCd N 4.8 Ag/gCr As b 36a 75 0.077
As N 36a 130 0.163
a
UIAs (Ag/gCr).
As. Since G-area is an inland area where consumption of
fish and shellfish is very low, and exposure to inorganic As
is high, it is still reasonable to assume that UAs values
reflect mainly inorganic As.
Renal tubular toxicity has been well documented
previously in humans exposed for a long time to environ-
mental Cd (Jarup et al., 1998; Jin et al., 2004; Nordberg,
2004; Nordberg et al., 2002). In the present study, renal
tubular dysfunction, indicated by a high prevalence of
elevated excretion of NAG and B2M, occurred in both G-
and Z-areas among persons with high exposure to Cd and
low exposure to As. It is interesting to note that also among
persons with predominant As-exposure (and low exposure
to Cd), there was increased prevalence of renal tubular
dysfunction biomarkers (increased UB2M and UNAG).
Such a relationship between As exposure and renal tubular
dysfunction in humans has not been well documented
previously.
There is a need to confirm the presently reported findings
by additional epidemiological studies employing improved
methods for determination of As in urine and possibly
improved biomarkers of biological damage and dysfunction
on a larger sample of the exposed populations.
Conclusions
! The present studies, which employed sensitive bio-
markers of renal dysfunction, give support to the idea
B2M
(mg/gCr) that human co-exposure to Cd and inorganic As gives
0.140
rise to more pronounced renal damage than exposure to
0.189 each element alone.
0.202 ! Further studies, possibly including additional new bio-
0.344 markers and improved exposure assessment technology,
are needed to firmly establish this interaction.
 G.F. Nordberg et al. / Toxicology and Applied Pharmacology 206 (2005) 191–197
Acknowledgments
This study was funded by the European Commission
INCO-DC programme (No.ERB3514PL971430) and by
the National Natural Science Foundation of China
(No.30060077/C030108).
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