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Objective: Cadmium exposure is a common problem in the production of nickel-cadmium batteries. However, keeping the respective legislative occupational and safety policies is essential, but there are problems with compliance. We analysed the effect of strategies to increase compliance with precautions during 20132015 on 59 workers at a nickel-cadmium battery factory., Material and Methods: A health promotion program was implemented in two phases. The first phase included comprehensive education on the importance of appropriate behaviour and changes to the sanitation program. The second phase included renovation of sanitary facilities and modernization of the air exhaust ventilation., Results: The initial median cadmium urinary level in workers was 1.9 µg/g creatinine. After the first phase of interventions, levels dropped to 1.0 µg/g creatinine. After the second phase no significant further decrease was observed., Conclusion: Comprehensive education and changes in the sanitation program were able to halve cadmium levels and can be considered a useful and cost-effective preventive tool., (Copyright © 2019 by Academy of Sciences and Arts of Bosnia and Herzegovina.)

Background: In health examinations for local inhabitants in cadmium-polluted areas, only healthy people are investigated, suggesting that patients with severe cadmium nephropathy or itai-itai disease may be overlooked. Therefore, we performed hospital-based screening to detect patients with cadmium nephropathy in two core medical institutes in cadmium-polluted areas in Akita prefecture, Japan., Methods: Subjects for this screening were selected from patients aged 60 years or older with elevated serum creatinine levels and no definite renal diseases. We enrolled 35 subjects from a hospital in Odate city and 22 from a clinic in Kosaka town. Urinary ß 2 -microglobulin and blood and urinary cadmium levels were measured., Results: The criteria for renal tubular dysfunction and the over-accumulation of cadmium were set as a urinary ß 2 -microglobulin level higher than 10,000 μg/g cr. and a blood cadmium level higher than 6 μg/L or urinary cadmium level higher than 10 μg/g cr., respectively. Subjects who fulfilled both criteria were diagnosed with cadmium nephropathy. Six out of 57 patients (10.5% of all subjects) had cadmium nephropathy., Conclusions: This hospital-based screening is a very effective strategy for detecting patients with cadmium nephropathy in cadmium-polluted areas, playing a complementary role in health examinations for local inhabitants., Registration Number: No. 6, date of registration: 6 June, 2010 (Akita Rosai Hospital), and No. 1117, date of registration: 26 December, 2013 (Akita University).

Cadmium (Cd(2+)) is a major environmental pollutant that induces cytotoxicity by heavy-metal accumulation. Prolonged Cd(2+) exposure leads to cell damage by oxidative stress mainly in the kidneys, a critical organ for detoxification. To identify reliable on invasive protein biomarkers for Cd(2+)-induced nephrotoxicity, we performed 2-dimensional gel electrophoresis/matrix-assisted laser desorption/ionization time of flight mass spectra and stable isotope labeling by amino acids in cell culture/liquid chromatography-mass spectrometry analyses using conditioned media (CM) of HK-2 human kidney epithelial cells treated with CdCl2. Here, we identified heat shock cognate 71 kDa protein isoform1 (HSPA8) and α-enolase (ENO1) as potential biomarker candidates for the evaluation of Cd(2+)-induced nephrotoxicity. Treatment with CdCl2 increased the protein level of HSPA8 in CM and lysates of HK-2 cells. The mRNA level of HSPA8 was also increased by CdCl2 treatment, indicating transcriptional regulation. The level of ENO1 was increased in CM, but not in lysates of CdCl2-treated HK-2 cells. CdCl2 did not affect the mRNA level of ENO1. We provide evidence that the increases of HSPA8 and ENO1 in CM were due to Cd(2+)-induced cell death through oxidative stress. The increases of HSPA8 and ENO1 levels were also detected in CM of HK-2 cells treated with other nephrotoxic agents, such as HgCl2, NaAsO2, cisplatin, amphotericin B, and cyclosporine A. Urine and kidney tissues of CdCl2-treated rats showed increased levels of HSPA8. Taken together, this study identified HSPA8 and ENO1 as noninvasive biomarker candidates by 2 comparative proteomic analyses. These new biomarker candidates may have potential as alternatives to traditional biomarkers for the efficient and sensitive assessment of nephrotoxicity., (© The Author 2015. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Cadmium (Cd) is a common environmental pollutant, and urinary Cd (UCd) is generally used as a marker of exposure; however, our understanding on the related urinary metabolic changes caused by Cd exposure is still not clear. In this study, we applied a mass-spectrometry-based metabolomic approach to assess the urinary metabolic changes in human with long-term environmental Cd exposure, aimed to identify early biomarkers to assess Cd nephrotoxicity. Urine samples from 94 female never smokers aged 44-70 with UCd in the range of 0.20-68.67 μg/L were analyzed by liquid chromatography quadrupole time-of-flight mass spectrometry (LC-Q-ToF-MS) and gas chromatography-mass spectrometry (GC-MS). It was found that metabolites related to amino acid metabolism (L-glutamine, L-cystine, L-tyrosine, N-methyl-L-histidine, L-histidinol, taurine, phenylacetylglutamine, hippurate, and pyroglutamic acid), galactose metabolism (D-galactose and myo-inositol), purine metabolism (xanthine, urea, and deoxyadenosine monophosphate), creatine pathway (creatine and creatinine), and steroid hormone biosynthesis (17-α-hydroxyprogesterone, tetrahydrocortisone, estrone, and corticosterone) were significantly higher among those with a UCd level higher than 5 μg/L. Moreover, we noticed that the level of N-methyl-L-histidine had already started to elevate among individuals with a UCd concentration of ≥2 μg/L. The overall findings illustrate that metabolomics offer a useful approach for revealing metabolic changes as a result of Cd exposure.

First, the urinary metabolic profiling by gas chromatography-mass spectrometry (GC-MS), was performed to compare ten cadmium (Cd) toxicosis cases from a Cd-polluted area in Mae Sot (Thailand) with gender-matched healthy controls. Orthogonal partial list square-discrimination analysis was used to identify new biomarker candidates in highly Cd exposed toxicosis cases with remarkable renal tubular dysfunction. The results of the first step of this study showed that urinary citrate was a negative marker and myo-inositol was a positive marker for Cd toxicosis in Thailand. In the second step, we measured urinary citrate in the residents (168 Cd-exposed subjects and 100 controls) and found significantly lower levels of urinary citrate and higher ratios of calcium/citrate and magnesium/citrate, which are risk factors for nephrolithiasis, in highly Cd-exposed residents. Additionally, this inverse association of urinary citrate with urinary Cd was observed after adjustment for age, smoking and renal tubular dysfunction, suggesting a direct effect of Cd on citrate metabolism. These results indicate that urinary citrate is a useful biomarker for the adverse health effects of Cd exposure in a Thai population with a high prevalence of nephrolithiasis.

Purpose: Research on the effect of co-exposure to Cd and Pb on the kidney is scarce. The objective of the present study was to assess the effect of co-exposure to these metals on biomarkers of early renal effect., Methods: Cd in blood (Cd-B), Cd in urine (Cd-U), Pb in blood (Pb-B) and urinary renal biomarkers, i.e., microalbumin (μ-Alb), beta-2-microglobulin (β₂-MG), retinol binding protein (RBP), N-acetyl-β-d-glucosaminidase (NAG), intestinal alkaline phosphatase (IAP) were measured in 122 metallurgic refinery workers examined in a cross-sectional survey., Results and Conclusions: The median Cd-B, Cd-U, Pb-B were: 0.8 μg/l (IQR = 0.5, 1.2), 0.5 μg/g creatinine (IQR = 0.3, 0.8) and 158.5 μg/l (IQR = 111.0, 219.3), respectively. The impact of Cd-B on the urinary excretion of NAG and IAP was only evident among workers with Pb-B concentrations ≥ 75th percentile. The association between Cd-U and the renal markers NAG and RBP was also evidenced when Pb-B ≥ 75th percentile. No statistically significant interaction terms were observed for the associations between Cd-B or Cd-U and the other renal markers under study (i.e., μ-Alb and β2-MG). Our findings indicate that Pb increases the impact of Cd exposure on early renal biomarkers., (Copyright © 2013 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.)

Objective: To analyze the clinical features of mild chronic cadmium poisoning induced by different causes., Methods: A total of 90 patients with mild chronic cadmium poisoning, who were hospitalized in our center from 2008 to 2011 and had complete clinical data, were divided into two groups according to the causes of poisoning: environmental pollution group (n = 45) and occupational poisoning group (n = 45). The clinical symptoms, signs, laboratory indices, and treatment outcomes of all patients were analyzed., Results: Compared with the environmental pollution group, the occupational poisoning group had more bone pain, less bone injury (based on imaging findings), and significantly increased abnormal rate of urinary retinol-binding protein (RBP) (P < 0.05); there were no significant differences in urinary β-2 microglobulin (MG) and urinary microalbumin between the two groups (P > 0.05). Urinary cadmium, urinary RBP, and urinary β-2 MG had no linear correlation between each other in the two groups. Both groups showed significant changes in urinary cadmium levels after treatment (P < 0.05)., Conclusion: The clinical features of mild chronic cadmium poisoning induced by various causes are different, and active nutritional support therapy plays a positive role in improving prognosis.

Heavy metal toxicity is often caused by occupational exposure. Chronic cadmium toxicity is a significant health concern among workers engaged in zinc smelting, battery production and silver jewellery industries, particularly in developing countries. We report the case of a 48-year-old man who presented with severe osteoporosis, impaired renal function and acquired Fanconi syndrome. He was finally diagnosed with chronic cadmium toxicity resulting from long-term occupational exposure. Cadmium has a long biological half-life and there is no effective treatment for people who are exposed to it. Therefore, an early diagnosis and prevention of further exposure are important.

Introduction: Toxic heavy metals have adverse effects on human health. However, the risk of hematuria caused by heavy metal exposure has not been evaluated., Methods: Data from 4701 Korean adults were obtained in the Korean National Health and Nutritional Examination Survey (2008-2010). Blood levels of the toxic heavy metals cadmium, lead, and mercury were measured. Hematuria was defined as a result of ≥+1 on a urine dipstick test. The odds ratios (ORs) for hematuria were measured according to the blood heavy metal levels after adjusting for multiple variables., Results: Individuals with blood cadmium levels in the 3rd and 4th quartiles had a greater OR for hematuria than those in the 1st quartile group: 3rd quartile, 1.35 (1.019-1.777; P=0.037); 4th quartile, 1.52 (1.140-2.017; P=0.004). When blood cadmium was considered as a log-transformed continuous variable, the correlation between blood cadmium and hematuria was significant: OR, 1.97 (1.224-3.160; Ptrend=0.005). In contrast, no significant correlations between hematuria and blood lead or mercury were found in the multivariate analyses., Discussion: The present study shows that high cadmium exposure is associated with a risk of hematuria., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objectives: Cadmium (Cd) toxicity of the kidney varies between individuals despite similar exposure levels. In humans Cd is mainly bound to metallothioneins (MT), which scavenge its toxic effects. Here we analyzed whether polymorphisms in MT genes MT1A and MT2A influence Cd-related kidney damage., Methods: In a cross-sectional study N=512 volunteers were selected from three areas in South-Eastern China, which to varying degree were Cd-polluted from a smelter (control area [median Cd in urine U-Cd=2.67 μg/L], moderately [U-Cd=4.23 μg/L] and highly [U-Cd=9.13 μg/L] polluted areas). U-Cd and blood Cd (B-Cd) concentrations were measured by graphite-furnace atomic absorption spectrometry. MT1A rs11076161 (G/A), MT2A rs10636 (G/C) and MT2A rs28366003 (A/G) were determined by Taqman assays; urinary N-Acetyl-beta-(D)-Glucosaminidase (UNAG) by spectrometry, and urinary β2-microglobulin (UB2M) by ELISA., Results: Higher B-Cd (natural log-transformed) with increasing number of MT1A rs11076161 A-alleles was found in the highly polluted group (p-value trend=0.033; all p-values adjusted for age, sex, and smoking). In a linear model a significant interaction between rs11076161 genotype and B-Cd was found for UNAG (p=0.001) and UB2M concentrations (p=0.001). Carriers of the rs11076161 AA genotype showed steeper slopes for the associations between Cd in blood and natural log-transformed UB2M (β=1.2, 95% CI 0.72-1.6) compared to GG carriers (β=0.30, 95% CI 0.15-0.45). Also for UNAG (natural log-transformed) carriers of the AA genotype had steeper slopes (β=0.55, 95% CI 0.27-0.84) compared to GG carriers (β=0.018, 95% CI -0.79-0.11)., Conclusions: MT1A rs11076161 was associated with B-Cd concentrations and Cd-induced kidney toxicity at high exposure levels., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background and Objectives: We applied an updated hybrid approach to estimate the benchmark doses (BMD) and their 95% lower confidence limits (BMDL) for cadmium-induced renal effects as the threshold of urinary cadmium in humans. Using this method, the BMD and BMDL were estimated based on continuous exposure and continuous effect marker, thereby avoiding categorization of subjects, an inevitable outcome of previously used approaches., Methods: The target subjects were 547 men and 723 women, aged 50 years or older, who lived in a cadmium non-polluted area of Japan. We measured urinary cadmium (U-Cd) as a marker of long-term exposure, and urinary protein, β2-microglobulin (β2-MG) and N-acetyl-β-D-glucosaminidase (NAG) as renal effect markers. BMD and BMDL corresponding to an additional risk (BMR) of 5%, were calculated with the background risk at zero exposure set at 5%., Results and Conclusions: The BMDL of U-Cd for renal effect markers were 2.1 (urinary protein), 2.6 (β2-MG) and 4.1 (NAG) μg/g creatinine in men and 1.5 (urinary protein), 1.4 (β2-MG) and 3.1 (NAG) μg/g creatinine in women. The BMDLs in the present study may contribute to further discussion on health risk assessment of cadmium exposure, when compared to BMDLs obtained by previously reported methods., (Copyright © 2010 Elsevier GmbH. All rights reserved.)

In order to evaluate the efficiency and renal protective effects of glutathione during Ca(++)-EDTA chelation therapy for chronic cadmium intoxication, we measured the renal excretion of cadmium, β(2)-microglobulin, proteinuria, and hematuria during intravenous administration of glutathione with Ca(++)-EDTA in a 54-year-old patient with chronic cadmium intoxication. We administered 500 mg of Ca(++)-EDTA and 50 mg/kg of glutathione alone or in 1 L of normal saline over the next 24 hours and repeated this over 12 consecutive days. During the first 3 days, the basal levels (only saline administration) were determined; during the second 3 days, Ca(++)-EDTA only was administered, for the third sequence of 3 days, Ca(++)-EDTA with glutathione was provided, and for the last 3 days, glutathione alone was given. One month later, the same protocol was repeated. There were six blood and urine samples to analyze in each group. The blood cadmium level was higher when the EDTA was infused together with glutathione (7.44 ± 0.73 µg/L, p < 0.01) compared to the basal level of 4.6 ± 0.44 µg/L. Also, the renal cadmium excretion was significantly higher in the EDTA with glutathione group than in the basal group (23.4 ± 15.81 µg/g creatinine vs 89.23 ± 58.52 µg/g creatinine, p < 0.01). There was no difference in the protein/creatinine and β(2)-microglobulin/creatinine ratio in the urine (p > 0.05) among the groups. Furthermore, microhematuria and proteinuria did not develop over the observation period of 6 months. These results suggest that glutathione administration with EDTA might be an effective treatment modality for patients with cadmium intoxication.

Background: An association between cadmium exposure and bone mineral density (BMD) has been demonstrated in elderly women, but has not been well studied in youths and men. Some studies report either no or a weak association between cadmium exposure and bone damage., Objectives: This study was designed to investigate the relationship between the urinary cadmium (U-Cd) levels and BMD of females and males of all ages., Methods: A total of 804 residents near an industrial complex were surveyed in 2007. U-Cd and BMD on the heel (non-dominant calcaneus) were analyzed with AAS-GTA and Dual-Energy X-ray absorptiometry, respectively. Demographic characteristics were collected by structured questionnaires. Osteoporosis and osteopenia were defined by BMD cut-off values and T-scores set by the WHO; T score>-1, normal; -2.5

Purpose: The cadmium-polluted Jinzu River Basin in Toyama, Japan, where nephropathy and itai-itai disease were endemic among resident farmers decades ago, has been almost completely restored. The aim of this study is to investigate whether inhabitants there would still exhibit cadmium accumulation and its effects on kidneys, bones, and erythropoiesis., Methods: We performed a cross-sectional study of 150 subjects from the polluted area and 144 controls from the same prefecture. Participants included female inhabitants from 34 to 74 years of age who underwent examinations to gather anthropometrical and medical information, obtain rice, blood and urine samples, and measure bone mineral density., Results: Cadmium concentration in rice from the polluted area was lower than the level in the control area. Blood and urinary cadmium and urinary β(2)-microglobulin levels were higher in subjects from the polluted area than controls, and the urinary β(2)-microglobulin was independently affected by urinary cadmium. Bone mineral density did not differ between the two areas, but it was affected by renal tubular function in subjects from the polluted area. Serum bone alkaline phosphatase was lower in subjects from the polluted area compared to controls. We detected three cases of cadmium nephropathy among the subjects. One of them suffered from a renal anemia type of itai-itai disease., Conclusion: Inhabitants in the formerly polluted area still had high cadmium accumulations and showed a characteristic natural history of chronic cadmium toxicity, indicating that the risk remains for developing nephropathy or itai-itai disease in the future.

Background: It is unclear whether environmental cadmium exposure is associated with cardiovascular disease, although recent data suggest associations with myocardial infarction and peripheral arterial disease., Objective: The objective of this study was to evaluate the association of measured cadmium exposure with stroke and heart failure (HF) in the general population., Methods: We analyzed data from 12,049 participants, aged 30 years and older, in the 1999-2006 National Health and Nutrition Examination Survey (NHANES) for whom information was available on body mass index, smoking status, alcohol consumption, and socio-demographic characteristics., Results: At their interviews, 492 persons reported a history of stroke, and 471 a history of HF. After adjusting for demographic and cardiovascular risk factors, a 50% increase in blood cadmium corresponded to a 35% increased odds of prevalent stroke [OR: 1.35; 95% confidence interval (CI): 1.12-1.65] and a 50% increase in urinary cadmium corresponded to a 9% increase in prevalent stroke [OR: 1.09; 95% CI: 1.00-1.19]. This association was higher among women [OR: 1.38; 95% CI: 1.11-1.72] than men [OR: 1.30; 95% CI: 0.93-1.79] (p-value for interaction=0.05). A 50% increase in blood cadmium corresponded to a 48% increased odds of prevalent HF [OR: 1.48; 95% CI: 1.17-1.87] and a 50% increase in urinary cadmium corresponded to a 12% increase in prevalent HF [OR: 1.12; 95% CI: 1.03-1.20], with no difference in sex-specific associations., Conclusions: Environmental exposure to cadmium was associated with significantly increased stroke and heart failure prevalence. Cadmium exposure may increase these important manifestations of cardiovascular disease., ((c) 2009 Elsevier Inc. All rights reserved.)

Aim: To study the specific features of porphyrin metabolic disturbances in cadmium poisoning., Material and Methods: The paper describes a patient who has developed clinical and biochemical syndromes of acute porphyrinopathy after exposure to cadmium-containing paint the vapors. The levels of delta-aminolevulinic acid, porphobilinogen, coproporphyrin, and uroporphyrin in urine and those of coproporphyrin and protoporphyrin in feces were measured. The concentrations of lead, cadmium, and copper were determined in whole blood and urine; selective screening of amino acids for hereditary metabolic diseases was made., Results: The clinical signs of acute porphyrinopathy developed in the patient mimicked those of acute porphyries known by the current classification. The biochemical syndrome more corresponded to lead poisoning. However, the blood and urinary lead levels were not greater than the normal values, but the blood showed a 4-fold increase in cadmium, which seemed to induce porphyrin dysmetabolism.

Objectives: Indigenous people of the Torres Strait (Australia) have greater potential for cadmium exposure and renal damage than other Australians due to high cadmium in some traditional seafood and a high prevalence of Type 2 diabetes, hypertension, smoking, and obesity. This study explored associations between albuminuria and an index of cadmium exposure (urinary cadmium excretion) in the presence and absence of Type 2 diabetes., Research Design and Methods: Two population-based, cross-sectional studies were undertaken in the Torres Strait to obtain data on body mass index (BMI), blood pressure, chronic disease, smoking, urinary cadmium, and albumin creatinine ratio (ACR)., Results: Age- and BMI-adjusted urinary cadmium levels were significantly higher (p<0.01) among people with diabetes and albuminuria (n=22, geometric mean (GM) 1.91 microg Cd/g creatinine) compared to those with diabetes and normal ACR (n=21, GM 0.74 microg Cd/g creatinine). Urinary cadmium was also strongly associated (p<0.001) with ACR among people with diabetes in regression models and remained significant after controlling for age, sex, BMI, smoking status, and hypertension (or continuous systolic and diastolic measurements)., Conclusions: While the study has methodological limitations and the nature of the association is unclear, the striking dose-dependent links between markers of cadmium exposure and of Type 2 diabetic nephropathy highlight the need for further definitive research on the health effects of cadmium in the presence of diabetes.

The relationship between oxidative stress and carcinogenic metals including nickel and cadmium is a matter of interest. To assess the oxidative stress status of workers exposed to nickel and cadmium simultaneously, we determined urinary excretion of 8-hydroxyguanine (8-OH-Gua), a urinary oxidative stress marker. Our subjects were 66 (64 males and 2 females) nickel-cadmium battery workers. Spot urine and blood samples were collected. The levels of cadmium in blood (Cd-B) and nickel in urine (Ni-U) were determined by graphite furnace atomic absorption spectrophotometry. 8-OH-Gua in urine was analyzed using a high performance liquid chromatography-electrochemical detector (HPLC-ECD) system. Data on age, sex, duration of present work and smoking status were also obtained from each subject. Creatinine-adjusted 8-OH-Gua was significantly correlated with age, Ni-U and Cd-B in univariate analysis, while multivariate analysis revealed that Ni-U and Cd-B were significant independent variables and that these two biological exposure indices were positively correlated with 8-OH-Gua. The data were also analyzed in the context of mixture toxicity. The subjects were divided into groups based on median level of Ni-U and Cd-B (2.86 mug/g creatinine and 0.23 mug/dl, respectively). Workers with high Ni-U/high Cd-B (Group IV) had the highest levels of 8-OH-Gua levels (GM (GSD), 21.7(2.0)), followed by those with high Ni-U/low Cd-B (11.5(1.6) Group III), those with low Ni-U/high Cd-B (8.9(1.9) Group II), and those with low Ni-U/low Cd-B (8.5(1.5) Group I). The p values of Students' t-tests between Group I and Group II, III and IV were 0.847, 0.050 and <0.001, respectively. The combined effect of Cd and Ni on the urinary excretion of 8-OH-Gua departed from additivity.

This study explored urinary cadmium levels among Torres Strait Islanders in response to concerns about potential health impact of high levels of cadmium in some traditional seafood (dugong and turtle liver and kidney). Cadmium levels were measured by inductively coupled mass spectrometry in de-identified urine samples collected during general screening programs in 1996 in two communities with varying dugong and turtle catch statistics. Statistical analysis was performed to identify links between cadmium levels and demographic and background health information. Geometric mean cadmium level among the sample group was 0.83 mug/g creatinine with 12% containing over 2 microg/g creatinine. Cadmium level was most strongly associated with age (46% of variation), followed by sex (females >males, 7%) and current smoking status (smokers >non-smokers, 4.7%). Adjusting model conditions suggested further positive associations between cadmium level and diabetes (p=0.05) and residence in the predicted higher exposure community (p=0.07). Positive correlations between cadmium and body fat in bivariate analysis were eliminated by control for age and sex. This study found only suggestive differences in cadmium levels between two communities with predicted variation in exposure from traditional foods. However, the data indicate that factors linked with higher cadmium accumulation overlap with those of renal disease risk (i.e. older, females, smokers, diabetes) and suggest that levels may be sufficient to contribute to renal pathology. More direct assessment of exposure and health risks of cadmium to Torres Strait Islanders is needed given the disproportionate level of diet-related disease and the cultural importance of dugong and turtle. This study highlights the need to consider social and cultural variation in exposure and to define "safe" cadmium levels during diabetes given its rising global prevalence.

Objective: This study was initiated to investigate if and to what extent the elevations in urinary alpha(1)- and beta(2)-microglobulins (alpha(1)-MG and beta(2)-MG, respectively) are specific to Cd nephro-toxicity., Methods: Stored urine samples, collected from 1,000 adult women in 11 prefectures all over Japan, were analysed for eight elements (Ca, Cd, Co, Cu, Mg, Mn, Ni and Zn), alpha(1)-MG, beta(2)-MG, creatinine (CR) and specific gravity (SG); the data were cited from previous publications. The levels of eight elements and two MGs were expressed as observed and after correction for CR or SG (1.016). Age, CR and SG distributed normally, whereas two MGs and eight elements distributed log-normally. The 1,000 cases were classified into quartiles (i.e., 250 cases/group) of the lowest to the highest values (Groups A to D) for each element., Results: alpha(1)-MG and beta(2)-MG increased as a function of Ca, Cd and Cu when corrected for CR, and the two MGs increased in parallel only with Cd and Cu after SG correction. Prevalence of alpha(1)-MG-uria (cut-off values; 5.3 and 6.5 mg/g cr or l) and beta(2)-MG-uria (cut-off values; 300 and 400 microg/g cr or l) was elevated with increasing Ca, Cd and Cu when corrected for CR, but only with Cd and Cu when corrected for SG. Multiple regression analysis of 353 cases of 50-59 year-old women with the eight element levels as independent variables and one of the two MGs as a dependent variable showed that Cu was the most influential element, and both Cd and Zn were less influential., Conclusions: Urinary levels of alpha(1)-MG and beta(2)-MG among women with no environmental Cd exposure correlated more closely with Cu levels than Cd levels in urine. The observation suggests that sub-clinical elevation in alpha(1)-MG and beta(2)-MG is not always attributable to nephro-toxicity of Cd, and that consideration on possible effects of other elements such as Cu is necessary.

The objective of this study was to assess changes in concentrations of cadmium in the blood (Cd-B), cadmium in the urine (Cd-U), beta2-microglobulin in the serum (beta2-mG-S) and beta2-microglobulin in the urine (beta2-mG-U) of workers at a cadmium (Cd) pigment factory in Japan in which exposure conditions improved. We evaluated reversibility of these markers in continuously employed workers in relation to changes in exposure levels resulting from improvements in the workplace and the reduced production of Cd. Our study involved both environmental and biological monitoring. Data were collected for four years. We measured the Cd concentration in the air of each work area, using the time-weighted average (TWA). Cd-B and Cd-U were measured in workers as direct indices of Cd exposure. beta2-mG-S and beta2-mG-U were measured as markers of renal tubular function. Exposure levels were high in all work areas, according to the criteria set by the American Conference of Governmental Industrial Hygienists (ACGIH). Workers' Cd-B and Cd-U concentrations reflected high levels of exposure. Correlation was found between these direct indices and beta2-mG-S concentrations. Since the second year, ambient Cd concentrations decreased and reacted markers have been improved. Our results suggest that Cd-B, Cd-U, beta2-mG-S and beta2-mG-U are appropriate markers for monitoring both the level of Cd exposure and the tubular function of workers. Reversibility of urinary low molecular weight protein was observed in the workers over the four years.

Few studies have estimated the prevalence and mean urinary cadmium levels in U.S. workers and the factors associated with high cadmium exposure. In this study, urinary cadmium measurements were obtained on 11228 U.S. workers aged 18 to 64 years who participated in the Third National Health and Nutrition Examination Survey (NHANES III, 1988-1994). Urinary cadmium levels ranged from 0.01 to 15.57 microg/L, with a geometric mean of 0.30 microg/L (0.28 microg/g creatinine) for all U.S. workers. The prevalence of urinary cadmium levels >or=5 microg/L was 0.42% (551000) for U.S. workers aged 18 to 64 years. Among U.S. workers in the metal industry (two-digit Standard Industrial Classification or SIC codes 33 and 34), the geometric mean urinary cadmium level was 0.48 microg/L (0.39 microg/g creatinine), and 0.45% of these workers had urinary cadmium levels >or=10 microg/L. The prevalence of urinary cadmium levels >or=15 microg/L was 0.0028% (3907). The agriculture industry (two-digit SIC codes 01, 02, and 07-09) was associated with low urinary cadmium levels, compared with repair services industries (two-digit SIC codes 75 and 76). Results from ordinary least squares regression analyses indicated that smokers had significantly higher urinary cadmium levels than nonsmokers (p

Relationships between cadmium (Cd) body burden, kidney function and coumarin metabolism were investigated using two groups of 197 and 200 healthy Thais with men and women in nearly equal numbers. A mean age of one group was 30.5 years and it was 39.3 years for the other group. Of 397, 20 subjects (5%) excreted urine Cd between 1.4 microg/g and 3.8 microg/g creatinine and these subjects faced 10-15% increase in the probability of having abnormal urinary excretion of N-acetyl-beta-D-glucosaminidase (NAG-uria). The prevalence of NAG-uria varied with Cd body burden in a dose-dependent manner (chi2 = 22, P < 0.008). Also NAG-nuria was one of the three kidney effect markers tested that showed the greatest strength of correlation with urine Cd in both men and women (r = 0.48, P < 0.001). In addition, urine Cd excretion of men and women showed a positive correlation (r = 0.46 to 0.54, P < 0.001) with urine 7-hydroxycoumarin (7-OHC) excretion which was used as a marker of liver cytochrome P450 2A6 (CYP2A6) enzyme activity. Urinary Cd excretion accounted for 25% of the total variation in urine 7-OHC excretion (P < 0.001). These data suggest that Cd may increase the expression of CYP2A6 in liver, resulting in enhanced coumarin metabolism in subjects with high Cd body burden.

We investigated a dose-response relationship between renal dysfunction and lifetime cadmium intake in individual subjects using logistic regression analysis and calculated the allowable level of lifetime cadmium intake among the inhabitants of the Jinzu River basin. From the participants of 1967 and 1968 health examinations, target subjects in whose hamlet the cadmium concentration in rice was known and whose history of residence was also known were selected. Cadmium concentrations in rice from data analyzed by the Toyama Prefecture from 1971 to 1976 were used. The urinary examination was done by semiquantitative determination of protein and glucose. All odds ratios for lifetime cadmium intake obtained from logistic regression analysis were more than 1 in both males and females who had resided in their current hamlet since birth with and without subjects who moved from nonpolluted areas and with or without the control group. The allowable levels of lifetime cadmium intake were calculated by substituting the abnormality rates of urinary findings of the controls 40, 50, 60, and 70 yr old into the logistic regression formula. The allowable levels of lifetime cadmium intake were less than 1.58 g for both sexes and each age group using proteinuria with glucosuria measurements.

Comparative evaluation was made on alpha(1)-microglobulin (alpha(1)-MG), beta(2)-microglobulin (beta(2)-MG), retinol binding protein (RBP) and N-acetyl-beta-D-glucosaminidase (NAG), as a marker of renal tubular dysfunction after environmental exposure to cadmium (Cd), with special references to the effects of aging and correction for creatinine concentration. For this purpose, a previously established database of 817 never-smoking Japanese women (at the ages of 20 to 74 years) on hematological [hemoglobin, serum ferritin (FE), etc.] and urinary parameters [alpha(1)-MG, beta(2)-MG, creatinine (cr), and a specific gravity] was revisited. For the present analysis, the database was supplemented by the data on RBP and NAG in urine. The exposure of the women to Cd was such that the geometric mean Cd in urine was 1.3 microg/g cr. Among the four tubular dysfunction markers, NAG showed the closest correlation with Cd, followed by alpha(1)-MG and then beta(2)-MG, and RBP was least so although the correlations were all statistically significant. The observed values of the markers gave the best results, whereas correction for a urine specific gravity gave poorer correlation, and it was the worst when correction for creatinine concentration was applied. Age was the most influential confounding factor. The effect of age appeared to be attributable at least in part to the fact that both creatinine and, to a lesser extent, the specific gravity decreased as a function of age. Iron deficiency anemia of sub-clinical degree as observed among the women did not affect any of the four tubular dysfunction markers. In conclusion, NAG and alpha(1)-MG, rather beta(2)-MG or RBP, are more sensitive to detect Cd-induced tubular dysfunction in mass screening. The use of uncorrected observed values of the markers rather than traditional creatinine-corrected values is recommended when comparison covers people of a wide range of ages.

Objective: To examine if there is a threshold in urinary cadmium concentration that induces elevation in urinary microglobulins., Methods: The database developed in a previous field survey (Ezaki et al. 2002) was employed. In the survey conducted in 2000 and 2001, more than 10,000 middle-aged women (with no occupational exposure to Cd) in ten prefectures all over Japan gave morning spot urine samples, which were analyzed for cadmium (Cd-U), calcium (Ca-U), magnesium (Mg-U), zinc (Zn-U), alpha(1)- and beta(2)-microglobulins (alpha(1)- and beta(2)-MG-U), and creatinine (cr). The urinary analyte concentrations were corrected for cr concentration (to be expressed as, e.g., Cd-Ucr), and the data thus obtained were subjected to statistical evaluation. The largest geometric mean (GM) for Cd-Ucr among the ten prefecture was 3.2 microg Cd/g cr, and the maximum Cd-Ucr observed among the women studied was 20.9 microg Cd/g cr., Results: Both alpha(1)-MG-Ucr and beta(2)-MG-Ucr increased as a function of the increase in Cd-Ucr among all the women and also in sub-populations of narrow age ranges (i.e., 41-50 and 51-60 years), with no apparent threshold Cd-Ucr. Comparison of the cases exceeding cut-off alpha(1)-MG-Ucr and beta(2)-MG-Ucr levels also indicated a Cd dose-dependent increase in the prevalence, similarly without a threshold Cd-Ucr. In addition, such findings were essentially reproducible when elevation in alpha(1)-MG-Ucr and beta(2)-MG-Ucr levels was examined with the three essential elements, especially with Ca-Ucr and Mg-Ucr, although less clearly with Zn-Ucr. The observations as a whole suggest a possibility that the dose-dependent increases in alpha(1)-MG-Ucr and beta(2)-MG-Ucr with no apparent threshold for element concentration is not specific to Cd-Ucr but common to other elements., Conclusions: No threshold Cd-Ucr was detected in relation to the increases in alpha(1)-MG-Ucr and beta(2)-MG-Ucr. The element dose-dependent increases in the two MGs with no threshold in the element concentration might be not limited to Cd, but common to other elements. Further studies are apparently necessary.

A follow-up study on 5442 inhabitants (2699 men, 2743 women) was conducted to determine the association between urinary Ca excretion level and mortality of the general population of three different areas of the Jinzu River basin area, namely, non-Jinzu River, mixed, and the Jinzu River water systems, over a period of 6127 d. More than 98% of the subjects were followed completely in each area. In comparison with the low- and high-Ca-excretion groups (cutoff values; 25.1 mg/dL in men, 20.4 mg/dL in women), the mortality rates per 1000 person-years and standardized mortality ratios (SMRs) tended to be greater in the low-Ca-excretion groups than in the high-Ca-excretion groups in both sexes for each of the three areas. Moreover, Cox's hazard ratios in men and women of the three areas exhibited negative values, 0.99 except for men of the mixed water system. These values were statistically significant in both sexes for the Jinzu River water system and in women for the non-Jinzu River water system. We conclude that the life-span becomes shorter as urinary Ca excretion levels become lower.

We investigated the association between the Cd concentration in rice and renal dysfunction in individuals living in the Cd-polluted Jinzu River basin, using a logistic regression analysis. In the cases of logistic regression analysis for people (1) who had either resided in the present hamlet since birth or who had moved there from a non-polluted area and for those (2) who had resided in the present hamlet since birth, except for glucosuria in males, all partial correlation coefficients between the Cd concentration in rice and occurrence of abnormal urinary findings were statistically significant in both sexes. The allowable level of Cd concentration in rice was calculated by substituting the abnormality rates of urinary findings of the controls in the 40-49, 50-59 and 60-69 year age groups into the logistic regression formula for people (3). The value for subjects aged 50 years was 0.13 and 0.17 ppm for males and females, respectively, with regard to proteinuria and 0.15 and 0.10 ppm for males and females, respectively, with regard to proteinuria+glucosuria.

This report covers part of the assessment of a site in northern France polluted by industrial metal emissions. Our objectives were to assess the cadmium burden in children aged 8 to 11 years and look for factors that affected it. A cross-sectional population-based study took place in 1996-1997 and included 400 children (200 in the metal-polluted area). The geometric mean of the blood cadmium (CdB) levels of children living on the polluted site was 0.51 microg/L (95% CI=[0.49-0.53]); that of the nonexposed children was 0.47 microg/L (95% CI=[0.45-0.49]) (P<0.01). The geometric mean of the urinary cadmium (CdU) levels of children living on the polluted site was 1.16 microg/g creatinine (95% CI=[1.01-1.34]); that of the nonexposed children was 0.99 microg/g creatinine (95% CI=[0.86-1.14]) (P=0.10). Mean CdB was higher among children within 4 km of a zinc smelter and consuming > or =500 ml of tap water daily (x1.34; 95% CI=[1.14-1.51]) compared with children living more than 4 km away and consuming <500 ml of tap water daily. Independently of this association, consumption of fish and shellfish (> or =once a week vs. or =once daily vs.

Long-term exposure to cadmium (Cd) causes renal damage in the general population. The maximum allowable urinary Cd concentration, which was calculated from our previous study performed in a Cd-polluted area, was almost the same as the mean urinary Cd concentration of people living in nonpolluted areas. We assessed whether environmental Cd exposure is related to renal dysfunction of people in nonpolluted areas in Japan. Blood and urine samples were collected from 2753 subjects (1105 men and 1648 women) ages over 50 years old in three nonpolluted areas. Blood was analyzed for Cd and urine was analyzed for Cd, total protein, beta(2)-microglobulin (beta(2)-mg), and N-acetyl-beta-D-glucosaminidase (NAG). Cd in blood or urine was employed as indicators of internal dose; and urinary total protein, beta(2)-mg, and NAG were used as an indicator of renal dysfunction. Multiple regression analysis and logistic regression analysis were performed to clarify the dose-effect and dose-response relationship between blood or urinary Cd concentration and indicators of renal dysfunction. Multiple regression analysis demonstrated a significant dose-effect relationship between Cd in blood and urine and indicators of renal dysfunction. Logistic regression analysis also showed that the probability that individual subjects would have abnormal values of the renal variables was significantly related to Cd in blood and urine., (Copyright 2000 Academic Press.)

The urinary excretion of N-acetyl-beta-D-glucosaminidase (U-NAG) and urinary Cadmium (U-Cd) concentration, a measure of the metal load in the body, were evaluated in 28 workers exposed to Cd, to determine the relation between the two parameters. In urine from 22 exposed workers with U-Cd<2 microg/g creatinine (Cr) there was no significant difference in U-NAG value (0.98+/-0.59 U/gCr) compared to non-exposed (0.73+/-0.48 U/gCr). In the six workers with 2 microg/gCr < or =U-Cd<10 microg/gCr the U-NAG (2.32+/-0.61 U/gCr) was statistically (P<0.05) higher than in other workers. In both the U-Cd intervals examined there were no altered values of beta2-microglobulin from urine of exposed workers compared to non-exposed (<0.30 mg/l). The U-NAG isoenzymes were separated by DEAE-cellulose chromatography from urine of non-exposed subjects and exposed workers. The U-NAG isoenzyme profile in urine of non-exposed subjects showed a high percentage (about 95%) of the A (acid) form, a much lower percentage (about 4.5%) of B (basic) form and a negligible percentage (about 0.5%) of I (intermediate) form. In the urine of 22 exposed workers with U-Cd<2 microg/gCr, the percentages of U-NAG isoenzymes were not different from non-exposed. In the urine of six workers with 2 microg/gCr< or =U-Cd<10 microg/gCr the percentage (8.34+/-0.91) of isoenzyme B (U-NAG-B), a marker of lesional enzymuria, was statistically increased (P<0.05) compared to non-exposed (4.42+/-0.56). These results suggest that adopting a biological limit for U-Cd equal to 10 microg/gCr might not be sufficiently protective. The increase in U-NAG-B content at 2 microg/gCr

Objective: The present study was initiated to investigate the validity of cadmium (Cd) and lead (Pb) in urine in comparison with the metals in blood as a biological marker of nonoccupational exposure of general populations to these metals as environmental pollutants., Design: Peripheral blood samples, morning spot-urine samples, and 24-h total food duplicate samples were collected from 107 nonsmoking women (aged 30-59 years) in four urban and rural survey sites in Korea., Methods: Portions of the samples were digested by heating in the presence of mineral acids, and the digests were analyzed for Cd and Pb by graphite furnace atomic absorption spectrophotometry. The metal concentrations in urine were adjusted for creatinine concentration and a specific gravity of 1.016. The analyte levels were evaluated on an individual basis (n = 107) and also on a group basis, i.e., in terms of geometric means for the survey sites (n = 4)., Results: Cd in urine correlated with Cd in blood on an individual as well as survey-site basis and tended to correlate with Cd in food duplicates on a group basis. The correlation of Pb in urine with Pb in blood was weaker than that of Cd in urine with Cd in blood when evaluated on an individual and survey-site basis. Pb in urine correlated with Pb in food duplicates either weakly or even negatively when examined on a survey-site basis., Conclusions: Cd in urine proved to be valid as a biological marker of environmental exposure of general populations, whereas less support was obtained for Pb in urine as an exposure marker.

Glomerular filtration rate (GFR) is known to decline in patients with cadmium (Cd)-induced nephropathy. However renal hemodynamics in Cd-induced nephropathy remain unknown. We investigated renal hemodynamics in experimental Cd-induced nephropathy. Male Sprague-Dawley rats were given 0.18 mg/rat of cadmium chloride i.p. three times a week for 3 and 16 months. Age-matched control rats were given physiological saline. Mean arterial pressures after 3 and 16 months were identical among the groups. In comparison with age-matched control rats, significant decreases in GFR associated with a significantly lower filtration fraction (FF) were demonstrated in both groups of Cd-treated rats, but the changes were more prominent in the 16-month Cd-treated rats. Renal plasma flow was significantly decreased in the 3-month Cd-treated rats whereas it was preserved in the 16-month Cd-treated rats because of anemia. Urinary sodium excretions in both groups of Cd-treated rats were significantly greater than those in the respective control rats. On light microscopic examination, only mild degeneration of tubular cells and interstitial edema in limited areas of the proximal tubules were observed in the 3-month Cd-treated rats. In the 16-month Cd-treated rats multifocal tubular atrophy and interstitial fibrosis in the outer cortex were noted. Electron microscopic examinations revealed conspicuous degenerative changes in the proximal tubular epithelial cells, diffuse thickening of glomerular basement membranes, and foot process fusions in 16-month Cd-treated rats. These data suggested that the decline in GFR in the Cd-treated rats resulted mainly from the decline in FF, which might be functional rather than structural in origin and might be associated with proximal tubular dysfunctions.

Objectives: (1) To examine the relation between concentrations of cadmium (Cd) in rice and urinary concentrations of indicators of renal dysfunction and the prevalence of abnormalities in urine in areas polluted by Cd. (2) To establish the maximum allowable concentration of Cd in rice from these findings., Methods: The target population consisted of 1703 inhabitants (832 men and 871 women) aged over 50 years who consumed home grown rice and had lived in the same hamlet in areas polluted by Cd in the Kakehashi River basin in Ishikawa Prefecture, Japan for at least 30 years. The correlation coefficients between concentrations of Cd in rice and several urinary substances, the prevalence of abnormalities in urine and sex in hamlets polluted by Cd were calculated. Finally, regression analysis was performed for significant indicators to calculate the maximum allowable concentration of Cd in rice based on values in a control group., Conclusions: Significant correlations between concentration of Cd in rice and concentrations of urinary beta 2-microglobulin, metallothionein, glucose, and aminonitrogen were established. Similarly, there were significant correlations between concentration of Cd in rice and the prevalence of beta 2-microglobulinuria, metallothioneinuria, glucosuria, proteinuria, proteinuria with glucosuria, and aminonitrogenuria. The highest maximum allowable concentration of Cd in rice calculated for these indicators was 0.34 ppm/l and 0.29 ppm/g creatinine. Both values are lower than 0.4 ppm, the tentative limit prescribed by the Japanese government.

Background: Acute serious inhalation of cadmium fumes often causes chemical pneumonitis or metal fume fever. Because symptoms of both diseases begin several hours after exposure and closely mimic each other, one often mistakes chemical pneumonitis for metal fume fever in the early stages. It is, however, essential to differentiate between the two since chemical pneumonitis can progress to serious consequences., Case: A 43-year-old man was admitted to the hospital 2 d after exposure to cadmium fumes. The initial diagnosis was metal fume fever on the basis of his history, and he was treated accordingly. His symptoms worsened however, and transient renal impairment was identified as consistent with cadmium-induced renal toxicity. Although the possibility of drug-induced renal damage could not be excluded, abnormal urinalysis findings on admission suggested that the renal tubular damage was caused by inhaled cadmium before admission., Conclusions: Measuring the urinary cadmium concentration is an effective method for confirming acute cadmium poisoning.

An acute oral protein load causes a transient hyperfiltration that might reveal a loss of glomerular permselectivity properties. The effect of an oral protein load on the urinary excretion rate of albumin (UAE), beta-2-microglobulin (UB2MGE), and retinol-binding protein (URBPE) was thus examined in cadmium- and lead-exposed workers. The results show a transient increase in UB2MGE and URBPE without relevant changes in UAE. These changes were also observed in control groups and are due to competitive inhibition of tubular protein reabsorption by absorbed cationic amino acids. These results do not support the hypothesis that the acute protein load test is of great utility in revealing a silent glomerular filtration disturbance in lead- or cadmium-exposed workers. However, it might disclose imminent renal tubular dysfunction in cadmium workers not yet showing increased microproteinuria under baseline conditions.

Urinary human intestinal alkaline phosphatase (IAP), beta 2-microglobulin (beta 2-MG) and N-acetyl-beta-D-glucosaminidase (NAG) were analyzed in 40 Japanese environmental-cadmium (Cd)-exposed and 40 non-exposed subjects to evaluate early biological markers for Cd-induced renal damage. All urinary indicators were significantly higher in the Cd-exposed subjects than non-exposed subjects. A fourth-order function was fitted for the relationship between beta 2-MG and IAP or NAG. The beta 2-MG concentration corresponding to the inflexion point for IAP was smaller than that for NAG. This result may support the contention that the cells containing IAP are damaged earlier than those containing NAG, and that IAP is a useful marker for detecting renal tubular dysfunction in people moderately exposed to Cd. However, in the stage of severe renal damage, the combination of IAP and beta 2-MG is considered to be more useful.

The renal effects of cadmium (Cd) have been studied in industrial workers exposed to Cd and inhabitants of Cd-polluted districts, as the kidney is a critical organ in exposure to Cd. Several biological indicators of Cd have been proposed including N-acetyl-beta-D-glucosaminidase (NAG) and beta 2-microglobulin (BMG) in urine for the detection of early renal effects. The average concentrations of Cd in urine samples were over 10 micrograms/g.creatinine in classic researches. Even in the industrial field, this exposure level is now hardly observed in Japan and western countries. The situation is the same with inhabitants in general living in a Cd-polluted district. From the viewpoint of consistency of the association, the relationship between Cd and NAG has become fairly definite. Stability in the pH change, simplicity, low cost and the reliability of measurements were also satisfactory. NAG is one of the recommended tools for detecting minimum renal effects under 10 micrograms/g.creatinine of Cd.

Six foundrymen occupationally exposed to cadmium fumes excreted in random urine samples 4.8 +/- 2.9 micrograms cadmium/g creatinine (+/- S.D.). Six controls excreted 0.15 +/- 0.09 microgram/g creatinine (+/- S.D.). The excretion of glycosaminoglycans by exposed men (2.3 +/- 1.1 mg/mmol creatinine, +/- S.D.) did not differ from that of controls (2.3 +/- 1.6 mg/mmol, +/- S.D.). However, electrophoretic analysis of the isolated urinary proteoglycan fraction revealed a dose-dependent progressive increase in the intensity of two bands with a molecular weight between 45,000 and 50,000. In control urines and in samples with urinary cadmium less than 3 micrograms/g creatinine, only one major band with a molecular weight of 100,000 was detected. The changes may serve as early indicators of the harmful effects of cadmium on the proteoglycan-containing barriers of the nephron.

Concentration-dilution of spot urine samples is a shortcoming of the biological monitoring of industrial xenobiotics. To ascertain whether the adjustment of urinary cadmium measured in spot samples is appropriate, urine samples were taken three times, once a week for 3 successive weeks, from 25 welders employed in the manufacture of jewelry (total 75 samples). Cadmium, creatinine, specific gravity, total urinary solutes, urinary volume and urinary flow rate were measured in 12-h collections and in spot samples taken immediately afterwards. Creatinine and total urinary solutes showed high inverse correlation with urinary flow rate (r = -0.858 and r = -0.768 respectively). Urinary cadmium displayed a similar trend but the correlation was not significant (r = -0.145). Creatinine adjustment of urinary cadmium values in spot samples increased the correlation with the same index in timed samples adjusted for urinary volume (r = -0.808) or urinary flow rate (r = 0.821) compared with non-adjustment (r = 0.732 and r = 0.738, respectively). Creatinine adjustment of spot sample values is also suitable for a wide range of urinary concentrations; discarding excessively diluted or concentrated urines, correlation of urine samples improved for non-adjusted or specific gravity-adjusted values, whereas no changes were observed for creatinine-adjusted values.

The excretion of urinary glycosaminoglycans by five occupationally exposed men with urinary cadmium levels of 1 to 6.5 micrograms/g creatinine did not differ significantly from that of six age-matched non-exposed controls (2.8 +/- 1.8 mg/mmol creatinine vs. 2.3 +/- 1.6 mg/mmol creatinine, +/- S.D.) as analyzed in random urine samples. However, there was a cadmium concentration-dependent increase in the excretion of 50 kD proteoglycan as analyzed by polyacrylamide electrophoresis of the isolated proteoglycan fraction in the same urine samples. This may represent the early dose-dependent effect of cadmium on renal tubules which leads to decrease in the renal cell sialic acid content and protein excretion at higher exposure levels.

A 9-y follow-up study of 3,178 persons who lived in a cadmium-polluted area was conducted to assess the influence of environmental cadmium exposure on long-term outcome. The standardized mortality ratios of the urinary beta 2-microglobulin-positive subjects (> 1,000 micrograms/g creatinine) of both sexes were higher than those of the general Japanese population, whereas the cumulative survival curves were lower than those of the urinary beta 2-microglobulin-negative group. A significant association was also found between urinary beta 2-microglobulin and mortality, using a Cox's proportional hazards model. Moreover, mortality rates increased in proportion to increases in the amount of urinary beta 2-microglobulin excreted. These results suggest that the prognosis for cadmium-exposed subjects with proximal tubular dysfunction is unfavorable. The mortality rate tended to become higher as the severity of renal dysfunction progressed.

The dose-response relationship for environmental cadmium exposure was assessed using logistic regression analysis. The prevalence of metallothioneinuria was employed as a response variable, while age and total cadmium intake, calculated from the average cadmium concentration in rice and duration of residence in the cadmium-polluted area, were used as explanatory variables. The target population comprised of 1843 cadmium-exposed and 240 non-exposed inhabitants of Ishikawa, Japan. The individuals were divided into 96 subgroups by sex, age (4 categories), cadmium concentrations in rice (3 categories) and length of residence in the polluted area (4 categories). Only total cadmium intake had a significant association with the prevalence of metallothioneinuria. In the non-exposed subjects total cadmium intakes corresponding to 2.5% prevalence of metallothioneinuria were calculated. Based on metallothionein levels expressed as either microgram/l urine or microgram/g creatinine, the total intakes were: 2.221 or 2.207 g in men and 2.365 or 0.319 g in women, respectively. Most of these values were similar to those reported by us previously, employing simple regression analysis. It is concluded, therefore, that a maximum allowable intake of about 2 g cadmium is a reasonable estimate for preventing the cadmium-induced renal dysfunction.

We tested the diagnostic sensitivity of various urinary analytes for detecting cadmium-induced nephropathy at an early stage. We investigated 73 healthy persons (control group 1) and individuals exposed to cadmium, either environmentally (n = 36, risk group 2) or occupationally (n = 62, exposed group 3). All data were related to limits of the central 95% reference intervals of the control group. The serum creatinine and ribonuclease values, indicators of the glomerular filtration rate, were not different in the three groups. In the exposed persons (group 3), proximal tubular indicators (low-M(r) proteins lysozyme, ribonuclease, retinol-binding protein, and alpha 1-microglobulin) were more often increased than the glomerular indices (higher-M(r) proteins transferrin, IgG, and albumin). Both the low-M(r) proteins and tubular enzymes were differently altered in their excretion rates. Alanine aminopeptidase, alkaline phosphatase, and N-acetyl-beta-D-glucosaminidase increased even in the risk group 2. alpha 1-Microglobulin was increased in the exposed persons whose cadmium excretion was < 5 mumol/mol creatinine. The combined determination of alpha 1-microglobulin and N-acetyl-beta-D-glucosaminidase exceeded the corresponding upper reference limits in 30% of group 2 and 39% of group 3. We recommend screening for these two analytes to detect cadmium-induced renal dysfunction at an early stage.

Cadmium (Cd) was the third heavy metal investigated in the European collaborative research project on the development and validation of new markers of nephrotoxicity. Fifty workers exposed to Cd and 50 control workers were examined. After application of selection criteria 37 workers (mean age 43) exposed to Cd for an average of 11.3 years; and 43 age matched referents were retained for final analysis. The average concentrations of Cd in blood (Cd-B) and urine (Cd-U) of exposed workers were 5.5 micrograms Cd/l and 5.4 micrograms Cd/g creatinine respectively. By contrast with lead and mercury, Cd had a broad spectrum of effects on the kidney, producing significant alterations in amounts of almost all potential indicators of nephrotoxicity that were measured in urine--namely, low and high molecular weight proteins, kidney derived antigens or enzymes, prostanoids, and various other biochemical indices such as glycosaminoglycans and sialic acid. An increase in beta 2-microglobulin and a decrease of sialic acid concentration were found in serum. Dose-effect/response relations could be established between most of these markers and Cd-U or Cd-B. The thresholds of Cd-U associated with a significantly higher probability of change in these indicators were estimated by logistic regression analysis. Three main groups of thresholds could be identified: one around 2 micrograms Cd/g creatinine mainly associated with biochemical alterations, a second around 4 micrograms Cd/g creatinine for high molecular weight proteins and some tubular antigens or enzymes, and a third one around 10 micrograms Cd/g creatinine for low molecular weight proteins and other indicators. The recent recommendation by the American Conference of Governmental Industrial Hygienists (ACGIH) of 5 micrograms Cd/g creatinine in urine as the biological exposure limit for occupational exposure to Cd appears thus justified, although for most of the effects occurring around this threshold the link with the subsequent development of overt Cd nephropathy is not established. In that respect, the very early interference with production of some prostanoids (threshold 2 micrograms Cd/g creatinine) deserves further investigation; although this effect might contribute to protect the filtration capacity of the kidneys, it might also play a part in the toxicity of Cd on bone.