ToxSci Advance Access originally published online on February 14, 2007
Toxicological Sciences 2007 97(1):189-195; doi:10.1093/toxsci/kfm016
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Estimation of Benchmark Dose for Pancreatic Damage in Cadmium-Exposed Smelters
,1
* Department of Occupational Health, School of Public Health, Fudan University, Shanghai 200032, China
Environmental Medicine; Department of Public Health and Clinical Medicine, Umeå University, SE-90187 Umeå, Sweden
Institute of Environmental Medicine, Karolinska Institutet, SE-171 77, Stockholm, Sweden
1 To whom Correspondence should be addressed. Fax: +86-21-64178160. E-mail: tyjin{at}shmu.edu.cn.
Received November 20, 2006; accepted December 13, 2006
 |
ABSTRACT |
|---|
 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
|---|
The aim of this study was to estimate the benchmark dose (BMD) for pancreas dysfunction caused by cadmium (Cd) exposure in smelters. Smelter workers who had been exposed to Cd for more than 1 year and matching nonoccupationally exposed subjects were asked to participate in this study. Urinary cadmium (UCd) was used as a biomarker for exposure, serum insulin and amylase were used as biomarkers for pancreatic effects. In this study, serum insulin and amylase were lower in the smelter workers than in the nonoccupationally exposed subjects. A significant dose-response relationship with UCd was displayed. BMDs in terms of urinary Cd corrected for creatinine were calculated by use of BMDS (version 1.3.2). The benchmark dose lower limit of a one-sided 95% confidence interval (BMDL) for 10% excess risk was also determined. It was found that the BMDL10 for serum insulin and serum amylase was 3.7 and 5.3 µg/g Cr, respectively. Compared to the BMDL for renal damage caused by Cd exposure, identified by the effect biomarkers urinary ß2-microglobulin, urinary N-acetyl-ß-glucosaminidase, and urinary albumin (UALB), it was shown that BMDL10 for serum insulin is the lowest among all values and UALB gave the highest value (5.8 µg/g Cr). This study indicates that Cd exposure can result in pancreatic dysfunction and the effect appears at lower urinary Cd level than renal dysfunction. The endocrine function of the pancreas was affected at lower urinary levels of Cd, compared to the exocrine function, which was seen at higher urinary levels of Cd than those giving rise to renal tubular dysfunction.
Key Words: cadmium exposure; benchmark dose; pancreas; biomarker; renal; endocrine.
|
INTRODUCTION |
|---|
|
TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
|---|
Cadmium (Cd) (CAS Reg. no. 7440-43-9) is a naturally occurring component of the earth's crust. Its physicochemical characteristics e.g., low melting point and malleability explain its wide use in industry and extensive environmental dispersed (Verougstraete et al., 2002
). Cd is a toxic metal of continuing occupational and environmental concern which causes a variety of adverse health effects. Cd has an extremely long biological half-life i.e., 20–30 years in humans, that essentially make it a cumulative toxicant (WHO, 1992). Still the only effective treatments for chronic Cd intoxication (Waalkes, 2000) is either to decrease or to stop exposure to Cd. In mammals, Cd preferentially accumulates in the liver, kidney, and reproductive systems which are the major target organs of Cd toxicity (Swiergoz-Kowalewska, 2001; WHO, 1992). Biological monitoring of renal dysfunction caused by Cd has been performed in China both in the general and in the occupational population (Cai et al., 1995, 1998; Jin et al., 1999b, 2002; Nordberg et al., 1997). Long-term exposure to Cd induces excretion of protein and glucose in the urine. It was considered that the increase of urinary glucose was related to a change in renal concentration of Cd as an outcome of exposure to Cd. Jin et al. (1999a) demonstrated that diabetic rats are more susceptible to Cd nephrotoxicity than normal rats. However, pancreatic dysfunction, such as decrease in insulin production, can also result in increased urinary glucose levels. Impaired insulin action or lack of insulin secretion is a well-known cause of the metabolic derangement characteristics of diabetes mellitus (Hardikar, 2004; Schwitzgebel, 2001). In spite of the fact that Cd accumulates in the pancreas (Jerome, 1981) and that a decrease in pancreatic function is one of the characteristics of Itai-Itai disease, there have been few investigations of the effects of Cd on pancreas (Ghafghazi and Mennear, 1973). The pancreas is a unique organ because the endocrine pancreas, composed of the hormone-producing cells, is located within the exocrine part of the tissue (Hardikar, 2004). The endocrine part consists of four different cell types which are organized as islets of Langerhans with a core of beta cells surrounded by alpha, delta, and PP cells. Insulin is the key regulator of the glucose homeostasis. The exocrine part secretes digestive enzymes which play key role in metabolism of glucose. Animal studies have shown that Cd can decrease both the endocrine and the exocrine pancreatic function (Ghafghazi and Mennear, 1973; Linari et al., 2001). In rats and mice, Cd damages pancreatic ß cells, reduces glucose tolerance, and is diabetogenic (Ghafghazi and Mennear, 1975; Ithakissios et al., 1975). The decrease of serum insulin was found in rats given drinking water containing 100 and 200 mg/l for 30 days, with no change of the levels of blood glucose (Lei et al., 2005). A significant glucose intolerance was found in rats administrated Cd sc with 1.0 and 2.0 mg/kg bw for 7 days, corresponding with the decrease of serum insulin in 2.0 mg/kg bw (Lei et al., in press). But little is known about the effect of Cd on human pancreas and no study on biomarkers of pancreatic damage has not been reported relative to Cd exposure has been reported.
In the present study, we used the benchmark dose (BMD) approach to characterize the relationship between urinary Cd and pancreatic damage, as well as renal dysfunction. For this purpose, serum insulin (EI Beitune et al., 2005) and serum amylase (Moridani and Bromberg, 2003) were measured as indicators of pancreatic function. Urinary cadmium (UCd) was determined in all the subjects. Renal biomarkers such as urinary N-acetyl-ß-glucosaminidase (UNAG), urinary ß2-microglobulin (UB2M), and urinary albumin (UALB) were also determined.
|
METHODS |
|---|
|
TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
|---|
Study population.
One hundred and three workers (85 males and 18 females; aged 23–55 years) in a smelter located in east Hunan Province, Central China, were selected to be the exposed population and constituted the Cd-exposed group. Thirty-six healthy persons (29 males and 7 females) working in a hospital and with no exposure to Cd were selected as nonoccupationally exposed (reference) subjects and constituted the control group (nonoccupationally exposed). Twenty-five females, 18 of occupationally exposed and 7 of nonoccupationally exposed, were in the present study. The selection criteria of exposure were comparable with regard to socioeconomic status, employment at the present place of work for at least 1 year with no disease or nonoccupational exposure related to Cd. The number of smokers in the exposed group and nonoccupationally exposed group was 61 and 14, respectively. There were no significant differences in the smoking habits between the two groups by statistical analysis. A detailed questionnaire including data on age, marital status, smoking habits, alcohol consumption, and professional and medical history from each subject was evaluated by well-trained interviewers.
Ethical permission was given by the Ethics Committee of Fudan University and the study was performed with permission for the local authority. Informed consent was attained for each participant.
Collection and treatment of biological samples.
Venous blood was drawn into anticoagulant and metal-free tube after 10–12 h of fasting to determine blood cadmium (BCd) and glucose, serum insulin, and serum amylase activity. Glucose oxidase method (Roche Glucotrend 2) was used to measure glucose. BCd concentrations were measured by graphite-furnace atomic absorption spectrometry using standard addition as described by Jin et al. (2002). Serum insulin levels were determined by radioimmunoassay. The intra- and interassay coefficients of variation were of 8.1 and 6.8%, respectively. Serum amylase activity was determined by an assay method measuring the starch digestive power using the starch iodine reaction (Demeester et al., 1997).
Urine samples were collected from all participants and tested for glucose, which is not normally present and divided into three aliquots. The first was acidified with concentrated nitric acid and was used for assay Cd; the second was used to measure B2M after being made alkaline; and the third was used to determine NAG and creatinine. UCd concentrations were measured by graphite-furnace atomic absorption spectrometry described by Jin et al. (2002). UNAG was measured as described by Tucker et al. (1980). UB2M and UALB were analyzed by ELISA. Creatinine was measured by the Jaffe reaction method. All urinary parameters were adjusted for creatinine in urine (Jin et al., 2002).
BMD method.
The BMD was defined by Crump (1984) as a lower confidence limit corresponding to a moderate increase in risk (1–10%) above the background risk. Crump suggested that the BMD could be used to replace the no observed adverse effect level (NOAEL) or the lowest observed adverse effect level (LOAEL) for noncarcinogenic effects in the regulatory process for setting acceptable daily intakes for human exposure to potentially toxic substances (Gaylor et al., 1998). The main advantage with the BMD methodology is that it uses all dose-response data from a study (Falk et al., 2003). Gaylor et al. (1998) redefined the BMD as the point estimate of the dose corresponding to a specified low level of risk and suggested that the concept of BMDL (lower confidence limit of benchmark dose) could be used as a replacement for the NOAEL or LOAEL (Gaylor et al., 1998). The BMDL resulting from this approach is more accurate than a NOAEL or LOAEL. The BMDL is typically calculated using the lower 95% confidence limit on the dose-response curve to a 1–10% level if risk above the background. A 10% benchmark response level (BMR) is conventionally used for dichotomous end points because it is at the low end of the observable range for many common study designs.
In the present study, UCd concentration was used as the dose parameter. During long-term low-level exposure, there is good agreement between average kidney Cd burden or body Cd burden and the average daily urinary Cd excretion (Friberg et al., 1985a; WHO, 1992). We used the BMDL to estimate the lower confidence limit of the population critical concentration of UCd.
The BMD is the dose of UCd that results in an increased probability of abnormal test performance by a BMR in the study. The BMR considered in the study was 10% extra risk. The median UCd concentrations of different UCd groups (1.43, 3.04, 6.72, 15.18 µg/g Cr, respectively) were used to estimate the values of the BMD10 and BMDL10 for different indicators of renal and pancreatic dysfunction. The BMDL was specified as the lower 95% confidence limit on the dose corresponding to the BMR. The goodness of fit was determined through application of several dose-response models. The BMD analysis for serum insulin was used as an example to explain the models selected. p values 
0.05 can be found in all models (Table 1), providing an initial indicator of goodness of fit. The BMDL from the log-logistic and log-dose probit models were lower than those of logistic and probit models (Table 1). However, according to these results, the BMDL of insulin was 0.19 and 0.23 µg/g Cr, respectively (showed in Fig. 1). In fact, these values were too low to be accepted as a critical exposure levels. We have used logistic models to estimate BMDL value for Cd-induced renal dysfunction (Chen et al., 2006; Jin et al., 2002). In order to compare with the pervious results, we chose the logistic model for application in the present study. The probit model has been used to calculate BMDL in this study, which gives similar results to logistic models (data not shown). Thus, the unconstrained logistic linear regression model was used as a model in this present study. The BMDL was specified as the lower 95% confidence limit on the dose corresponding to the BMR in the study and the smooth option of the model was applied.
|
|
The equation of this model is
 |
The BMDs from this work are not directly useful for environmental regulation since they are given as biomarker levels, and not as ambient exposure concentrations.
Statistical analysis.
The data were expressed in terms of geometric means (GM) and 95% confidence interval for GM and entered into a database using SPSS (version 11.0) statistical analysis software. For comparisons between more than two groups, one-way ANOVA was used. The criterion for significance was set at p < 0.05. The dichotomous dose-response models in the United States Environmental Protection Agency BMD software (version 1.3.2) were used in this work.
|
RESULTS |
|---|
|
TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
|---|
Body Burden of Cd
Data in Table 2 show the Cd body burden, which was estimated by UCd, and BCd, in the nonoccupationally exposed group and the smelters. The BCd and UCd in smelters were significantly higher than in the nonoccupationally exposed group.
|
Subjects were further divided according to smoking habits. The results (Table 3) show that the average BCd and UCd concentrations of smokers were significantly higher than those of nonsmokers in the respective Cd exposure groups.
|
Comparison of the Serum Insulin, Amylase and Urinary NAG, B2M, and ALB at Different UCd Levels
One of the biomarkers for exposure to Cd is UCd corrected for creatinine. The degree of exposure was ranked as follows: <2, 2-, 5-, 10-µg/g Cr (Jin et al., 2002
). The levels of serum insulin and amylase were inversely correlated with UCd (Table 4). No significant change in blood glucose was found in the different UCd groups. The frequency of urinary glucose in the 2-µg/g Cr UCd was statistically higher than that in <2-µg/g Cr UCd group (Table 4). Table 5 shows that with the increase of UCd, all urinary biomarkers including UNAG, UB2M, and UALB increase dramatically.
|
|
Because age might affect Cd accumulation and effects, Pearson correlation was used to explore the relationship between age and renal dysfunction. The coefficient between UB2M, UNAG, UALB, and age was 0.087, 0.127, and 0.091 (p > 0.05) in all subjects, respectively. The relationship between age, serum insulin, and amylase was examined as well. The coefficient between serum insulin, serum amylase, and age was 0.076 and 0.041 (p > 0.05) in all subjects.
Prevalence of Low Insulin, Low Amylase, HyperNAGuria, HyperB2Muria, and HyperALBuria at Different Cd Concentrations in Urine
We defined the normal cutoff point based on the 10th percentile value for serum insulin (6.74 µIU/ml) and serum amylase (77.98 U) in the nonoccupationally exposed group. Values below the defined cutoff points were defined as abnormal (positive) of the pancreatic function. The cutoff point of serum insulin in this study is close to lower limit of normal reference value of our country (7 µIU/ml). In the nonoccupationally exposed group, a 90th percentile value was the normal cutoff point for UNAG, UB2M, and UALB. Values higher than the normal cutoff point were defined as the renal abnormal function (Chen et al., 2006). The cutoff points of UNAG, UB2M, and UALB were 10.72 U/gCr, 162.55 µg/g Cr, and 16.79 mg/g Cr, respectively. The prevalence of low insulin, low amylase, hyperNAGuria, hyperB2Muria, and hyperALBuria at different concentrations of Cd in urine were calculated in all subjects (Table 6). This finding demonstrates that there is a significantly increased prevalence of low insulin, low amylase, hyperNAGuria, hyperB2Muria, and hyperALBuria with the increase of urinary Cd.
|
The Values of BMD and BMDL of UCd for Different Indicators
The estimated parameters and corresponding values of BMDL10 are presented in Table 7. The chi-square values and p values provide a goodness-of-fit measure of the models. We find that when serum insulin is used as an indicator of pancreatic dysfunction, the BMDL10 is 3.7 µg/g Cr, which is lower than the estimated values for UB2M and UNAG (3.8 and 4.1 µg/g Cr, respectively), common biomarkers of Cd-induced renal tubular dysfunction.
|
|
DISCUSSION |
|---|
|
TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
|---|
Cd is a nonessential metal that accumulates in the human pancreas. There are several studies documenting nonnegligible concentrations of Cd in the pancreas (Ghafghazi and Mennear, 1973
; Jerome, 1981). The concentrations of Cd in pancreas are usually below 2 mg/kg wet weight in samples obtained from humans living in the United States and Europe (Elinder et al., 1976; Tipton and Cook, 1963) and 2–3 mg/kg in Japanese (Friberg et al., 1985b).
It is well recognized that the renal damage is the mainly adverse effect related to Cd exposed (WHO, 1992), and the concentration of Cd in kidney gives rise to the first irreversible damage thus rendering the kidney as the critical organ in Cd exposure. The effects of Cd on the kidney have been of interest for the toxicologists for many years. The increase of urinary glucose related to Cd exposure and the accumulation of Cd in the pancreas has so far only been of limited interest. Few reports about the effects and/or damage of pancreas caused by xenobiotics can be found. Intact function of the pancreas is essential for the production of a number of hormones and digestive enzymes, and for maintaining an even blood sugar level. It is thus important to not underestimate the value of intact pancreatic function.
Until now, the major concern from Cd exposure has been the concentration of Cd in urine and its relationship to renal dysfunction (Bernard et al., 1979; Buchet et al., 1990; Jin et al., 1999a; Nordberg et al., 1997; WHO, 1992). UNAG and UB2M have been suggested as sensitive biomarkers of renal tubular dysfunction. UALB is biomarker for glomerular damage. It suggested that Cd levels in the kidneys and in urine should be kept below 2.5 µg/g Cr in order to avoid clinical disease (Jarup et al., 1998).
Insulin is normally secreted by the beta cells of the pancreas in response to an increase in blood glucose for regulation of glucose levels. In normal conditions, the stimulus for insulin secretion is an increase of blood glucose. In this study, the blood glucose levels did not differ significantly with different levels of UCd, while serum insulin did. It is indicated that the serum insulin might be a sensitive index of pancreatic damage caused by Cd. The release of insulin is a calcium-dependent phenomenon. A rapid influx of calcium ions can initiate insulin secretion. But Cd has been shown in laboratory animals to inhibit stimulation of amylase secretion by the activity of blocking calcium channel (Linari et al., 2001). This may lead to speculation that Cd can influence the biosynthesis and release of insulin.
Although amylase is present in saliva of some mammals, including humans, the major source of amylase in all species is pancreatic secretions. There was an excellent correlation between pancreatic and total amylase in obese Zucker rats (Majid and Irvin, 2003). At a lower concentration, it is a strong inhibitor of stimulated pancreatic secretion of amylase acting directly, and possibly indirectly, on the acinar cell (Linari et al., 2001). Insulin may play a major role in the control of pancreatic amylase biosynthesis. Severe insulin resistance was associated with impairment of amylase gene expression (Trimble et al., 1986). Thus, it seems that insulin alterations may influence pancreatic function through several machanisms.
This study documents the dose-response relationship between UCd and both serum insulin and amylase, as well as between UCd and indicators of renal dysfunction. The BMD procedure was used to calculate the critical concentration of UCd from population data. The BMDL value for UB2M is 3.8 µg/g Cr. The results are in agreement with several previous studies from Japan (Nogawa et al., 1992). Abe et al. (2001) used path analysis and mathematically proved that the excretion of B2M was the most sensitive urinary indicators of the early stage of chronic Cd-induced renal dysfunction. Surprisingly in the study it was found that if serum insulin is taken as an indicator of pancreatic dysfunction, the BMDL (3.7 µg/g Cr) is lower than the BMDL value for UB2M. These results suggest that Cd-induced pancreatic dysfunction may appear earlier or at the same time as renal damage. It suggests that the serum insulin could be regarded as a sensitive biomarker of Cd impact. The decrease of serum amylase also appeared in smelters after long-term and low-dose Cd exposure. The BMDL for serum amylase is higher than that for serum insulin. It can be concluded that the exocrine dysfunction is later than the endocrine, partly because insulin can influence the biosynthesis of amylase.
Recently, the critical concentration of Cd in urine has been suggested to have been overestimated (Jarup et al., 1998; Jin et al., 2004). The obtained BMDL value is lower than that in previously reported studies. The value of BMDL lies in the range of 3.7–5.8 µg/g Cr in the present study. This range implied that there is an increased 10% prevalence of pancreatic dysfunction in this occupational population.
In conclusion, this study showed that more than 1-year exposure to Cd can decrease the serum levels of insulin and amylase. It was also shown that BMDL of UCd related to a decrease of the serum insulin is lower than comparable BMDL for renal dysfunction. The endocrine dysfunction develops earlier than the exocrine dysfunction. In this study, insulin and amylase were used as biomarkers of endocrine and exocrine effects. Further researches into the precise role of the sensitive biomarkers and the approaches of BMD or BMDL are warranted to increase our understanding of the effects of cadmium toxicology.
|
ACKNOWLEDGMENTS |
|---|
This study was supported by the National Key Research and Development Program of China (No. 2002 CB 512905). The authors certify that all research involving human subjects was done under full compliance with all government policies and the Helsinki Declaration.
|
REFERENCES |
|---|
|
TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
|---|
Abe T, Kobayashi E, Okubo Y, Suwazono Y, Kido T, Shaikh ZA, Nogawa K. Application of path analysis to urinary findings of cadmium-induced renal dysfunction. J. Environ. Sci. Health A Tox. Hazard. Subst. Environ. Eng. (2001) 36:75–87.[CrossRef][Web of Science][Medline]
Bernard A, Buchet JP, Roels H, Masson P, Lauwerys R. Renal excretion of protein and enzymes in workers exposed to cadmium. Eur. J. Clin. Invest. (1979) 9:11–22.[Web of Science][Medline]
Buchet JP, Lauwerys R, Roels H, Bernard A, Bruaux P, Claeys F, Ducoffre G, de Plaen P, Staessen J, Amery A, et al. Renal effects of cadmium body burden of the general population. Lancet (1990) 336:699–702.[CrossRef][Web of Science][Medline]
Cai S, Yue L, Jin T, Nordberg G. Renal dysfunction from cadmium contamination of irrigation water: Dose-response analysis in a Chinese population. Bull. World Health Organ. (1998) 76:153–159.[Web of Science][Medline]
Cai S, Yue L, Shang Q, Nordberg G. Cadmium exposure among residents in an area contaminated by irrigation water in China. Bull. World Health Organ. (1995) 73:359–367.[Web of Science][Medline]
Chen L, Jin T, Huang B, Nordberg G, Nordberg M. Critical exposure level of cadmium for elevated urinary metallothionein—an occupational population study in China. Toxicol. Appl. Pharmacol. (2006) 215:93–99.[CrossRef][Web of Science][Medline]
Crump KS. A new method for determining allowable daily intakes. Fundam. Appl. Toxicol. (1984) 4:854–871.[CrossRef][Web of Science][Medline]
Demeester J, Dekeyser PM, Samyn S, Verhamme I, Sierens W, Lauwers A. Assays. In: Pharmaceutical Enzymes.—Lauwers A, Scharpé S, eds. (1997) New York: Marcel Dekker. 401.
El Beitune P, Duarte G, Foss MC, Montenegro RM Jr, Quintana SM, Figueiro-Filho EA, Nogueira AA. Effect of maternal use of antiretroviral agents on serum insulin levels of the newborn infant. Diabetes Care (2005) 28:856–859.
Elinder G-G, Kjellstrom T, Friberg L, Lind B, Linnman L. Cadmium in kidney cortex, liver, and pancreas from Swedish autopsies. Arch. Environ. Health (1976) 31:292–302.[Web of Science][Medline]
Filipsson AF, Victorin K. Comparison of available benchmark dose softwares and models using trichloroethylene as a model substance. Regul. Toxicol. Pharmacol. (2003) 37:343–355.[CrossRef][Web of Science][Medline]
Friberg L, Elinder CG, Kjellstrom T, Nordberg GF. Cadmium and Health: A Toxicological and Epidemiological Appraisal. Vol. I Exposure, Dose, and Metabolism (1985) Inc Boca Raton, FL: CRC Press. 161.
Friberg L, Elinder CG, Kjellstrom T, Nordberg GF. Cadmium and Health: A Toxicological and Epidemiological Appraisal. Volume I. Exposure, Dose, and Metabolism (1985) Inc Boca Raton, FL: CRC Press. 96–97.
Gaylor D, Ryan L, Krewski D, Zhu YL. Procedures for calculating benchmark doses for health risk assessment. Regul. Toxicol. Pharmacol. (1998) 28:150–164.[CrossRef][Web of Science][Medline]
Ghafghazi T, Mennear JH. Effects of acute and subacute cadmium administration on carbohydrate metabolism in mice. Toxicol. Appl. Pharmacol. (1973) 26:231–240.[CrossRef][Web of Science][Medline]
Ghafghazi T, Mennear JH. The inhibitory effect of cadmium on the secretory activity of the isolated perfused rat pancreas. Toxicol. Appl. Pharmacol. (1975) 31:134–142.[CrossRef][Web of Science][Medline]
Hardikar AA. Generating new pancreas from old. Trends. Endocrinol. Metab. (2004) 15:198–203.[CrossRef][Web of Science][Medline]
Ithakissios DS, Ghafghazi T, Mennear JH, Kessler WV. Effect of multiple doses of cadmium on glucose metabolism and insulin secretion in the rat. In: Toxicol. Appl. Pharmacol. (1975) 31:143–149. (Abstract).[CrossRef][Web of Science][Medline]
Jarup L, Berglund M, Elinder CG, Nordberg G, Vahter M. Health effects of cadmium exposure—a review of the literature and a risk estimate. Scand. J. Work Environ. Health (1998) 24(Suppl. 1):1–50.[Web of Science][Medline]
Jin T, Nordberg M, Frech W, Dumont X, Bernard A, Ye TT, Kong Q, Wang Z, Li P, Lundstrom NG, et al. Cadmium biomonitoring and renal dysfunction among a population environmentally exposed to cadmium from smelter in China (ChinaCad). Biometals (2002) 15:397–410.[CrossRef][Web of Science][Medline]
Jin T, Nordberg G, Sehlin JO, Wallin H, Sandberg S. The susceptibility to nephrotoxicity of streptozotocin-induced diabetic rats subchronically exposed to cadmium chloride in drinking water. Toxicology (1999a) 142:69–75.[CrossRef][Web of Science][Medline]
Jin T, Nordberg G, Wu X, Ye T, Kong Q, Wang Z, Zhuang F, Cai S. Urinary NAG isoenzymes as biomarker of renal dysfunction caused by cadmium in a general population. Environ. Res. (1999b) 81:167–173.[Medline]
Jin T, Wu X, Tang Y, Nordberg M, Bernard A, Ye T, Kong Q, Lundstrom NG, Nordberg GF. Environment epidemiological study and estimation of benchmark dose for renal dysfunction in a cadmium-polluted area in China. Biometals (2004) 17:525–530.[CrossRef][Web of Science][Medline]
Lei LJ, Jin TY, Zhou YF. Effects of cadmium on levels of insulin in rats. In: Wei Sheng Yan Jiu. (2005) 34:394–396. (In Chinese).[Medline]
Lei LJ, Jin TY, Zhou YF. Insulin expression in rats exposed to cadmium. In: Biomed. Environ. Sci. (2007) (in press).
Linari G, Nencini P, Nucerito V. Cadmium inhibits stimulated amylase secretion from isolated pancreatic lobules of the guinea-pig. Pharmacol. Res. (2001) 43:219–223.[CrossRef][Web of Science][Medline]
Majid YM, Irvin LB. Lipase and pancreatic amylase versus total amylase as biomarkers of pancreatitis: An analytical investigation. Clin. Biochem. (2003) 36:31–33.[CrossRef][Web of Science][Medline]
Moridani MY, Bromberg IL. Lipase and pancreatic amylase versus total amylase as biomarkers of pancreatitis: An analytical investigation. Clin. Biochem. (2003) 36:31–33.[CrossRef][Web of Science][Medline]
Nogawa K, Kido T, Shaikh ZA. Dose–response relationship for renal dysfunction in a population environmentally exposed to cadmium. IARC Sci. Publ. (1992) 118:311–318.[Medline]
Nordberg GF, Jin T, Kong Q, Ye T, Cai S, Wang Z, Zhuang F, Wu X. Biological monitoring of cadmium exposure and renal effects in a population group residing in a polluted area in China. Sci. Total Environ. (1997) 199:111–114.[CrossRef][Medline]
Nriagu JO. Cadmium in the Environment. (1981) Ontario, Canada: Canada Centre for Inland Waters Burlington. 624.
Schwitzgebel VM. Programming of the pancreas. Mol. Cell. Endocrinol. (2001) 20:99–108.[CrossRef]
Swiergoz-Kowalewska R. Cadmium distribution and toxicity in tissues of small rodents. Microsc. Res. Techniq. (2001) 55:208–222.[CrossRef][Web of Science][Medline]
Tipton IH, Cook MJ. Trace elements in human tissues. II. Adults subjects from the United States. Health Phys. (1963) 9:103–145.[Medline]
Trimble ER, Bruzzone R, Belin D. Insulin resistance is accompanied by impairment of amylase-gene expression in the exocrine pancreas of the obese Zucker rat. Biochem. J. (1986) 237:807–812.[Web of Science][Medline]
Tucker SM, Boyd PJR, Thompson AE. Automated assay of N-acetyl-ß-glucosaminidase in normal and pathological human urine. Clin. Chim. Acta (1980) 62:333–339.[CrossRef]
Verougstraete V, Lison D, Hotz P. A systematic review of cytogenetic studies conducted in human populations exposed to cadmium compounds. Mutat. Res. (2002) 511:15–43.[CrossRef][Web of Science][Medline]
Waalkes MP. Cadmium carcinogenesis in review. J. Inorg. Biochem. (2000) 79:241–244.[CrossRef][Web of Science][Medline]
WHO/IPCS. Environmental Health Criteria Document 134 Cadmium. (1992) Geneva: WHO.
CiteULike 
Connotea 
Del.icio.us What's this?
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||