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Bone is one of the target organs for cadmium toxicity. However, few studies have shown the association between cumulative cadmium intake and prevalence of osteoporosis and bone fracture. In the present study, we evaluated the association between cumulative cadmium intake and osteoporosis and risk of fracture in a Chinese population. A total of 790 subjects (488 women and 302 men) living in a control area and two cadmium-polluted areas were included. The cumulative cadmium intake was estimated by a food survey. The bone mineral density was determined by using single-photon absorptiometry. The cumulative cadmium intakes were 0.48, 2.14, and 11.00 g for men, and 0.42, 2.11, and 11.12 g in women in control, and moderately and heavily polluted areas, respectively. In women, the odds ratios (ORs) of subjects with a cadmium intake between 2.21 and 10.63 g and10.63 g were 1.30 (95% CI: 0.58-2.94) and 2.36 (95% CI: 1.14-5.16), compared with those with a cadmium intake 0.58 g after adjusting to the confounders for osteoporosis. The ORs of subjects with a cadmium intake10.63 g were 2.34 (95% CI: 1.23-4.38) for all of the women and 2.62 (95% CI: 1.02-5.58) in women ≥ 60 years old, compared with those with a cadmium intake10.63 g after adjusting to the confounders for bone fractures. In men, similar trends were observed, but no statistical significance was found. In addition, those subjects with renal tubular dysfunction showed high risk of bone fracture. Our results indicate that a high level of cumulative cadmium intake is associated with an increased rate of osteoporosis and fractures among women.

Studies in vivo and in vitro have shown a protective effect of zinc against renal dysfunction caused by cadmium exposure. However, limited human data is available. In this study, we evaluated the association between renal tubular dysfunction and body zinc burden in a Chinese population exposed to cadmium. A total of 331 subjects (170 women and 161 men) living in control and cadmium-polluted area were included. Blood cadmium (BCd), urinary cadmium (UCd), serum zinc (SZn), zinc in hair (HZn), Zn/Cd ratio, and urinary β

The tolerable dietary intake of cadmium was recommended at provisional tolerable monthly intake of 25 μg kg

Background Trichloramine exposure in indoor swimming pools has been suggested to cause asthma in children. We aimed to investigate the risk of asthma onset among children in relation to individual trichloramine exposure. Methods A longitudinal nested case-control study of 337 children with asthma (cases) and 633 controls aged 16–17 years was performed within a population-based cohort from The Obstructive Lung Disease in Northern Sweden studies (OLIN). Year of asthma onset and exposure time at different ages were obtained in telephone interviews. Trichloramine concentrations in the pool buildings were measured. Skin prick test results for inhalant allergens were available from previous examinations of the cohort. The risk for asthma was analyzed in relation to the cumulative trichloramine exposure before onset of asthma. Results The participation rate was high in the original cohort (88 to 96%), and in the case-control study (80%). Trichloramine concentrations ranged from 0.020 to 0.55 mg/m3 (mean 0.15 mg/m3). Swimming pool exposure in early life was associated with a significantly higher risk of pre-school asthma onset. A dose-response relationship between swimming pool exposure and asthma was indicated in children with asthma onset at 1 year of age. Children who were both sensitized and exposed had a particularly high risk. Conclusions Early life exposure to chlorinated swimming pool environments was associated with pre-school asthma onset. Electronic supplementary material The online version of this article (10.1186/s12940-018-0383-0) contains supplementary material, which is available to authorized users.

Background and objective: Long-term exposure to cadmium (Cd) causes renal dysfunction, but the change in renal function with exposure is unknown. We assessed the evolution of Cd-induced renal effects after a reduction in dietary exposure to Cd in rice. Methods: Four hundred twelve residents in previously Cd-polluted and nonpolluted areas were examined twice, in 1998 and in 2006. Changes in blood Cd, urinary Cd, and kidney function [N-acetyl-β-d-glucosaminidase (NAG), β2-microglobulin, and albumin in urine] were measured. Results: In the most polluted area, mean blood Cd was 8.9 μg/L and 3.3 μg/L in 1998 and in 2006, respectively, and urinary Cd was 11.6 and 9.0 μg/g creatinine. Urinary albumin in 1998 increased with urinary Cd, but no such exposure–response relation appeared for 2006 albumin versus urinary Cd 1998, indicating recovery. Other biomarkers of kidney function were also elevated in 1998. Partial recovery was observed for NAG among women and was suggested for β2-microglobulin among young individuals. The probability of having β2-microglobulin levels above the 95th percentile in 2006 was high in those with elevated β2-microglobulin in 1998 [odds ratio (OR) = 24.8; 95% confidence interval (CI): 11.2, 55.3] compared with albumin (OR = 3.0; 95% CI: 1.2, 7.5) and NAG (OR = 2.6; 95% CI: 1.6, 4.4). Conclusions: Results suggest that a Cd-mediated increase in urinary albumin excretion is reversible upon substantial reduction of exposure. For markers of tubular effects, we observed a tendency toward improvement but not complete recovery. Data from repeated observations suggest that β2-microglobulin may be more informative than NAG as an indicator for an individual’s future tubular function.

Epithelial cells from the kidney were freshly isolated from rats pretreated by daily subcutaneous doses of CdCl2 in vivo (0.5-2 mg Cd/kg X 5). Such cells were incubated in vitro in media with different concentrations of cadmium chloride (0-200 micrograms Cd/ml). There was no inhibition of cell growth in such cells. However, in cells isolated from non-treated rats, in vitro exposure to the same concentrations of CdCl2 caused a dose dependent decrease in viability. When cells, isolated from non-treated rats were pretreated in vitro with CdCl2 (10 micrograms/ml) and subsequently exposed to cadmium chloride (0-200 micrograms/ml), a protective effect was observed, which was similar to the one observed in cells isolated from animals pretreated with CdCl2. The concentration of metallothionein in the cells treated with cadmium was increased. A lower uptake of cadmium chloride, in vitro has been observed in kidney cells pretreated in vivo or in vitro compared to nonpretreated cells. Subcellular distribution studies indicate that Cd-distribution was similar in pretreated and non-pretreated cells, but concentrations were generally lower in the pretreated cells. The decreased uptake of Cd by pretreated kidney cells is a sign of Cd-interference with cellular function. These changes are suggested as a contributing mechanism to the prevention of acute toxic effects of cadmium on the kidney.

Chelating agents like NTA (nitrilotriacetic acid) STPP (sodiumtripolyphosphate, Na5P3O10) and EDTA (ethylenediaminetetraacetic acid) are used as components of detergents. An increased toxicity of some metal compounds when combined with NTA has led to decreased use of this chelating agent in relation to STPP. In the present studies short-term and long-term effects of these chelating agents on cadmium toxicity in mice were investigated. I: In the short-term study, mice subcutaneously exposed to CdCl2 (3.2 mg Cd/kg b. wt.) in combination with STPP (32 mg/kg b. wt.) demonstrated a markedly higher mortality compared to animals given CdCl2 alone. This increase in mortality was similar to the one encountered when CdCl2 (3.2 mg Cd/kg b. wt.) and NTA (32 mg/kg b. wt.) were combined. Animals exposed subcutaneously to CdCl2 + STPP or CdCl2 + NTA showed histological evidence of liver necrosis 24 hrs after exposure not seen in animals given the same dose of CdCl2 alone and also had markedly lower cadmium concentrations in the livers compared to only Cd-exposed animals. II: In the long-term study, mice were exposed orally to CdSO4 (50p.p.m Cd) alone or in combination with STPP (500 p.p.m.), NTA (500 p.p.m.) or EDTA (50 p.p.m.) by continuous administration via the drinking water for 18 months. A decreased total excretion of urine proteins was seen in all Cd-treated animals irrespectively of the combination with various chelating agents. The conclusion of the present work was the NTA and STPP given by subcutaneous injection to mice markedly increased the toxicity of cadmium but that neither NTA, STPP nor EDTA given orally altered the toxicity of cadmium during a period of long-term exposure of 18 months.

Cadmium is a well-known nephrotoxic agent with extremely long biological half-time of 10-30 years in human. To investigate the evolution of cadmium-induced renal effects in the population, a number of 148 residents who lived in cadmium-polluted area were followed-up for 3 years after the reduction of cadmium exposure in rice. Urinary cadmium (UCd), beta(2)-microglobulin (B2M) and albumin (ALB) were analyzed in 1995 and 1998, respectively. The results demonstrated that the changes of renal effects of residents depended on the levels of UCd before inflow of cadmium to human body declined. In cases where UCd were less than 10 microg/g creatinine in 1995, evidence was found indicating significant decreases in proteinuria (i.e., B2M and ALB) 3 years later, whereas, in cases where the excretion of UCd exceeded 10 microg/g creatinine in 1995, progression was observed. The study of dose-response relationships between UCd and B2M or ALB also showed that the cadmium-induced renal dysfunction might be reversible if UCd concentration was low-level before exposure decreasing, otherwise it might be irreversible or aggravated.

Background: By-products of water disinfectants have been suggested to cause asthma, especially in atopic children. However, studies on indoor swimming pool attendance and asthma in children have presented conflicting results. The present study examined the relationship between indoor swimming pool attendance and asthma among sensitized and non-sensitized children aged 11-12 years. Methods: An extended ISAAC questionnaire was sent to the families of all children attending fifth or sixth grade, aged 11-12 years, in two municipalities in Northern Sweden in 2010. A total of 1866 participated (96% of those invited) in the questionnaire study and 1652 (89%) also participated in skin prick testing for 10 standard airborne allergens. Asthma was defined as physician-diagnosed asthma in combination with wheeze or use of asthma medication in the last 12 months. Current swimming pool attendance was reported as >= 1/week or = 1/week. Children currently attending swimming pools >= 1/week had an increased risk of current asthma. Stratified analyses for allergic sensitization adjusted for sex, parental smoking, parental asthma, and damp housing, showed a statistically significant association for current asthma only among sensitized subjects (OR 95% CI 1.90 1.09-3.32). No association was found between current pool attendance and wheeze, sensitization, rhinitis or eczema. Conclusions: The present study supports the proposed link between indoor swimming pool attendance and asthma in sensitized children.

OBJECTIVE—It has been reported that diabetes may increase the risk of cadmium-induced kidney damage. The presence of metallothionein antibody (MT-Ab) increased the susceptibility for tubular damage among cadmium workers. This study focused on the relationships between levels of MT-Ab, urinary cadmium, and kidney function in a Chinese type 2 diabetic population. RESEARCH DESIGN AND METHODS—A cross-sectional study was performed on 229 type 2 diabetic patients (92 men and 137 women) who were recruited from two community centers in one district of Shanghai City in China. Information was obtained from interviews, health records, and blood and urine samples. RESULTS—Levels of the tubular biomarker β2-microglobulin increased significantly when the levels of MT-Ab and urinary cadmium were elevated in male and female subjects; in contrast, the levels of urinary albumin, a glomerular biomarker, did not display such a pattern. After adjusting for potential confounding covariates, logistic regression showed that the odds ratios (ORs) of tubular dysfunction increased upon 1) increasing the MT-Ab concentration from a low to high level (OR 5.56 [95% CI 2.25–13.73]) and 2) increasing the level of urinary cadmium from CONCLUSIONS—This study proves that the presence of MT-Ab can potentiate tubular dysfunction among diabetic subjects and that patients with high MT-Ab levels are more prone to development of tubular damage.

The objective of this study was to study the impact of work-related exposure to mainly arsenic and lead versus smoking in primary smelter workers developing lung cancer.In a cohort of 3979 primary smelter workers, 46 subjects had contracted respiratory malignancies. They were compared with 141 age-matched male referents by conditional logistic regression analysis.Cases showed a significantly higher smoking rate as compared with referents: odds ratio (OR) = 4.0; 95% confidence interval (CI) = 1.6-10.1; P = 0.003. When restricted to smokers (33 cases, 63 referents), the cumulative air arsenic exposure index, but not the lead exposure indices, was significantly higher among the cases: OR = 1.07; 95% CI = 1.02-1.11; P = 0.005.Cumulative arsenic exposure and smoking were identified as risk factors for the development of lung cancer; lead exposure, however, was not.

Advances in proteomics have led to the identification of sensitive urinary biomarkers of renal dysfunction that are increasingly used in toxicology and epidemiology. Recent animal data show that combined exposure to inorganic arsenic (As) and cadmium (Cd) gives rise to more pronounced renal toxicity than exposure to each of the agents alone. In order to examine if similar interaction occurs in humans, renal dysfunction was studied in population groups (619 persons in total) residing in two metal contaminated areas in China: mainly a Cd contaminated area in Zhejiang province (Z-area) and mainly a As contaminated area in Guizhou province (G-area). Nearby control areas without excessive metal exposure were also included. Measurements of urinary beta(2)-microglobulin (UB2MG), N-acetyl-beta-glucosaminidase (UNAG), retinol binding protein (URBP) and albumin (UALB) were used as markers of renal dysfunction. Urinary Cd (UCd) and total As (UTAs) were analyzed by graphite-furnace atomic absorption spectrometry. Urinary inorganic As and its mono- and di-methylated metabolites (UIAs) were determined by Hydride generation. Results. As expected, the highest UCd values occurred in Z-area (Geometric mean, GM 11.6 microg/g crea) while the highest UTAs values occurred in G-area (GM = 288 microg/g crea). Statistically significant increases compared to the respective control area were present both for UTAs, UCd and for UB2MG, UNAG and UALB in Z-area as well as in G-area. UIAs was determined only in Z area. In G-area, there was a clear dose-response pattern both in relation to UTAs and UCd for each of the biomarkers of renal dysfunction. An interaction effect between As and Cd was demonstrated at higher levels of a combined exposure to As and Cd enhancing the effect on the kidney. In Z-area an increased prevalence of B2MG-uria, NAG-uria and ALB-uria was found in relation to UCd, but no relationship to UTAs was found. A statistically significant relationship between UIAs and UB2MG was found among women in this area and an interaction between As and Cd was indicated for B2MG. Conclusion. The present studies, which employed sensitive biomarkers of renal dysfunction, give support to the idea that human co-exposure to Cd and inorganic arsenic gives rise to more pronounced renal damage than exposure to each of the elements alone, but further studies are needed to establish and clarify this interaction.

To explore possible effects of environmental cadmium exposure on prostate in humans, and the possible relationship of serum sex hormones to occurrence of clinic signs of tissue changes in the prostate, a case-control study was undertaken in the southeast part of China in 1998. A total of 297 male volunteers from a control area and two cadmium-polluted areas were included as subjects in this study. All the subjects were required to answer a questionnaire and to undergo a complete physical examination including digital-rectal examination (DRE). Blood and urine samples were collected. Serum total prostate specific antigen (PSA), total serum testosterone (T), follicle stimulating hormone (FSH) and luteinizing hormone (LH) were measured by radioimmunoassay and enzymeimmunoassay method, respectively. The data of urinary cadmium (U-Cd) and blood cadmium (B-Cd) were obtained by atomic absorption spectrometry (AAS) as an indicator of cadmium body burden. Statistical analysis was applied to investigate a possible relation between cadmium exposure and prostate pathological changes. The results show that there is a clear dose-response relationship between cadmium exposure and the prevalence of cases with abnormal PSA. The blood cadmium content in cases with positive DRE was significantly higher than that of subjects with negative DRE (P

The first health effect of cadmium (Cd) was lung damage, reported in workers already in the 1930's, while bone effects and proteinuria were reported in the 1940's. After World War II, a bone disease with fractures and severe pain, the itai-itai disease, a form of Cd-induced renal osteomalacia, was identified in Japan. Subsequently, the toxicokinetics and toxicodynamics of Cd were described including its binding to the protein metallothionein. International warnings of health risks from cadmium pollution were issued in the 1970's. WHO, 1992, identified renal dysfunction as the critical effect and a crude quantitative evaluation was presented. In the 1990's population groups in China exposed to Cd via rice were studied and new information on skeletal, renal and reproductive toxicity of Cd was obtained in the ChinaCad project. There was a decrease in Bone Mineral Density (BMD), an increased prevalence of fractures and an increased urinary content of marker proteins of renal dysfunction among persons with long term exposure to Cd. The development of such biomarkers can be seen as a result of applied 'proteomics' research. Variation in metallothionein gene expression was related to development of renal dysfunction, supporting the usefulness of this 'genomic' approach. The ongoing rapid development of 'genomics' and 'proteomics' technologies will improve possibilities for molecular epidemiology studies in the future, providing an even better basis for preventive action. In many countries, Cd exposures are now under better control than in the past. The target for the 21st century is to achieve a totally acceptable exposure situation without adverse health effects from Cd.

We have performed a study aimed at investigating the critical concentration of urinary cadmium (UCd) required for the development of renal dysfunction. We studied population groups (totally 790 persons) living in two cadmium exposed areas and one control area in China. UCd, was determined as an indicator of cadmium exposure and accumulation, while the concentrations of N-acetyl-beta-D-glucosaminidase (NAG), its iso-form B (NAG-B), beta2-microglobulin (B2M), retinol binding protein (RBP), and albumin (ALB) in urine were measured as indicators of the renal effects caused by cadmium. There was a significantly increased prevalence of hyperNAGuria, hyperNAG-Buria, hyperB2Muria, hyperRBPuria and hyperALBuria with increasing levels of Cd excretion in urine. We used the benchmark dose (BMD) procedure to estimate the critical concentration of urinary cadmium in this general population. The lower confidence limit of the BMD (LBMD-05) of urinary cadmium for a 5% level of risk above the background level was estimated for each of the renal effect indicators. The BMD-05/LBMD-05 were estimated to be 4.46/3.99, 6.70/5.87, 8.36/7.31, 7.98/6.98 and 15.06/12.18 microg/g creatinine for urinary NAG-B, NAG, B2M, RBP and ALB, respectively. Our findings suggest, based on the present study, that the Lower Confidence Limit of the Population Critical Concentration of UCd (LPCCUCd-05) of tubular dysfunction for 5% excess risk level above the background may be ca. 3-4 microg/g creatinine, and that cadmium concentration in urine should be kept below this level to prevent renal tubular damage. This report is the first to use the BMD method in this field and to define the concept of critical concentration in urine.

Airway irritants such as ozone are known to impair lung function and induce airway inflammation. Clara cell protein (CC16) is a small anti-inflammatory protein secreted by the nonciliated bronchiolar Clara cells. CC16 in serum has been proposed as a noninvasive and sensitive marker of lung epithelial injury. In this study, we used lung function and serum CC16 concentration to examine the pulmonary responses to ambient O3 exposure and swimming pool attendance. The measurements were made on 57 children 10-11 years of age before and after outdoor exercise for 2 hr. Individual O3 exposure was estimated as the total exposure dose between 0700 hr until the second blood sample was obtained (mean O3 concentration/m3 times symbol hours). The maximal 1-hr value was 118 microg/m3 (59 ppb), and the individual exposure dose ranged between 352 and 914 microg/m3hr. These O3 levels did not cause any significant changes in mean serum CC16 concentrations before or after outdoor exercise, nor was any decrease in lung function detected. However, children who regularly visited chlorinated indoor swimming pools had significantly lower CC16 levels in serum than did nonswimming children both before and after exercise (respectively, 57 +/- 2.4 and 53 +/- 1.7 microg/L vs. 8.2 +/- 2.8 and 8.0 +/- 2.6 microg/L; p0.002). These results indicate that repeated exposure to chlorination by-products in the air of indoor swimming pools has adverse effects on the Clara cell function in children. A possible relation between such damage to Clara cells and pulmonary morbidity (e.g., asthma) should be further investigated.

Cadmium may have both direct and indirect effects on bone turnover. It is nephrotoxic and can interfere with vitamin D metabolism. Such perturbation may result in osteoporosis and osteomalacia. In this study, a total of 790 persons (302 males and 488 females) participated; they were all over 35 years old and resided in an area near a cadmium smelter in southeast China. All participants completed a questionnaire, and bone mineral density was measured by SPA-4 single-photon absorptiometry at the radius and ulna. Cadmium content of urine was determined by graphite-furnace atomic absorption spectrophotometry as a measure of dose. The decline in bone mineral density with age in a heavily polluted area was greater than that in a control area for subjects over 60 years of age of both sexes (p < 0.05). In single regression, forearm bone densities were negatively correlated with urinary cadmium excretion in both males and females (p < 0.001), whereas stepwise regression showed that forearm bone density decreased linearly with age (p < 0.001) and urinary cadmium (p < 0.01) in both sexes, suggesting a dose-effect relationship between cadmium dose and bone mineral density. Based on the World Health Organization criteria, (bone mineral density < -2.5 SDs below the normal young adult), the prevalence of osteoporosis in women increased from 34.0% in the control area to 51.9% in the heavily polluted area (p < 0.01) among subjects over 50 years old, and the odds ratio value was 2.09 (95% CI: 1.08-4.03) for the highly polluted area compared with the control area. A striking observation in the study was the marked increase of the prevalence of fracture in the cadmium-polluted area in both sexes. It was concluded that environmental exposure to cadmium is associated with an increased loss of bone mineral density in both males and females, leading to osteoporosis and increased risk of fractures, especially in the elderly and in females.

Cadmium (Cd) is a widespread environmental pollutant, characterized by its ability to affect various organs. Adverse effect of Cd on the testis including decreased testosterone production are well-known phenomena, but the cellular events explaining these effects have not yet been established. In the present study the initial steps of gonadotropin mediated testosterone biosynthesis were examined in vivo in rats, in relation to Cd dose and time after injection. In the dose-response experiment Male Sprague-Dawley rats received a single subcutaneous (s.c.) injection of CdCl(2) (1, 5 or 10 micromol/kg body weight) and were sacrificed 48 h after injection. A statistically significant decrease in luteinizing hormone (LH) receptor mRNA level in the testicular tissue was demonstrated at the highest dose (10 micromol/kg). In the temporal-response experiment rats were given 10 micromol/kg of CdCl(2) s.c. and sacrificed 0.48, 4.8, 48 or 144 h after injection. LH receptor mRNA levels as well as cyclic adenosine monophosphate (cAMP) levels were found to be significantly lowered at 48 and 144 h. These observations of the mechanisms whereby Cd exerts its effect on the initial steps of testosterone biosynthesis are the first from in vivo experiments.

This paper presents the main findings of a study on health effects of environmental cadmium pollution in China, performed in 1998, i.e. approximately 25 years after the first warnings of such effects were published in Ambio. Forearm bone mineral density (BMD) and renal dysfunction were assessed in population groups exposed to cadmium via rice. Decreased BMD was found in postmenopausal women with elevated urinary cadmium (CdU) or cadmium in blood (CdB) and among men with elevated CdB. Also, clear and statistically significant dose-effect and dose-response relationships were found between CdB or CdU and renal dysfunction (increased excretion of retinol-binding protein). This is the first report of bone effects among Cd-exposed population groups in Asia outside Japan. The report is also of interest since it demonstrates that bone effects, a comparatively severe adverse health effect of Cd, in combination with renal dysfunction, still occurs in environmentally exposed population groups in Asia. Recent reports on bone effects in Cd-exposed population groups in Europe are discussed.

Workers at a copper and lead smelter in northern Sweden have a multifactorial exposure to a number of heavy metals. The concentrations of cadmium, copper and zinc in liver, lung, kidney and brain tissues have been determined by atomic absorption spectrometry in 32 deceased long-term exposed male lead smelter workers, and compared with those of 10 male controls. Furthermore, copper and zinc levels in hair and nails were determined by energy-dispersive X-ray fluorescence. The highest cadmium concentrations among both workers and controls were observed in kidney, followed in order by liver, lung and brain. The levels in kidney, liver and lung were all significantly higher in the workers than in the controls (p < 0.03). Among the workers relatively strong positive correlations (p < 0.03) were observed between cadmium concentrations in liver and lung, liver and kidney, liver and brain, and lung and brain. In the exposed workers a positive correlation was observed between cadmium and zinc concentrations in the kidney (rs = 0.38; p = 0.034). This is probably mainly due to the protein metallothionein, which is stored in the kidney, binding equimolar amounts of these two metals. The highest concentrations of copper were found in hair and nails among both workers and controls, followed in order by liver, brain, kidney and lung. The tissue concentrations of copper in brain, lung and kidney were all significantly higher among the smelter workers than in the controls (p < 0.036). Copper levels in lung and age at time of death were positively correlated among the exposed workers (rs = 0.39; p = 0.029). In the same group, positive correlations between copper and zinc concentrations in kidney (rs = 0.45; p = 0.009) and nails (rs = 0.68; p < 0.001) were also observed, reflecting possible biological interactions between these two metals. Among both workers and controls, the highest zinc concentrations were found in hair, followed in order by nails, liver, kidney, brain and lung. Significantly higher tissue concentrations among the workers as compared with the reference group were noted in kidney, liver and brain (p < 0.033). Neither copper nor zinc concentrations in hair and nails seemed to provide a useful measure of the trace element status of the smelter workers.

Urinary beta 2-microglobulin and N-acetyl-beta-D-glucosaminidase have been recommended as sensitive indicators of renal dysfunction induced by cadmium. However, an increase in urinary calcium in early renal damage induced by cadmium has been reported both in humans and in animal experiments. To investigate the feasibility of using urinary calcium as a biomarker of renal dysfunction induced by cadmium, two areas were selected in this study, namely, a polluted area with a 3.71 mg/kg cadmium concentration in rice and a control area with a 0.07 mg/kg cadmium concentration. The total number of participants was 499, made up of 252 in the control group and 247 from the cadmium-polluted area. Urinary cadmium, urinary calcium, and zinc concentrations were measured by atomic absorption spectrometry, and beta 2-microglobulin and N-acetyl-beta-D-glucosaminidase in urine were analyzed. The levels of urinary cadmium and urinary calcium in persons from the exposed area were significantly higher (P0.05) than those in the control area for both men and women, but there was no significant difference regarding urinary zinc between the two areas. A significant dose-response relationship between the prevalence of hypercalciuria and the excretion of urinary cadmium was observed, and a significantly increased prevalence of calciuria was found when excretion of urinary cadmium exceeded 2 micrograms/g creatinine. The findings were similar to those for excess urinary secretion of beta 2-microglobulin and N-acetyl-beta-D-glucosaminidase. Because cadmium can affect Ca2+ uptake by tubular cells, with decreased renal Ca2+ reabsorption, calciuria may reflect tubular cell damage caused by cadmium. It was concluded that cadmium exposure can result in increased excretion of urinary calcium in a general population and that there is a significant dose-response relationship. Urinary calcium can therefore be used as a biomarker of renal dysfunction induced by cadmium.

Cadmium-metallothionein (CdMT) induced calciuria may result from disturbed calcium (Ca) transport through the renal tubular epithelium. The present study aimed at defining time of onset and the degree of disturbed calcium transport. Kidneys were obtained from rats at 4, 12 and 24 h after a single injection of CdMT (dose 0.4 mg Cd/kg b.w.), and compared to saline injected controls. Rapid-filtration 45Ca-assays were performed on basolateral and luminal membrane vesicles, isolated from kidney cortex using a sequential ultracentrifugation procedure. Luminal 45Ca uptake was increased at 4 h and then declined to about 80% of controls, suggesting an early phase perturbation of Ca absorption. Basolateral 45Ca uptake was reduced to less than 50% of controls, starting already at 4 h while 45Ca binding was reduced at 8 h. This may reflect an inhibited basolateral Ca pump mechanism after the binding step. Since the Ca pump normally expels Ca from the cell, an accumulation of intracellular calcium was indicated. Metal analysis verified a four-fold increase of Ca in kidney cortex at 24 h. This suggests that Cd impact on tubular cells involves disturbances on cellular absorption as well as expulsion of Ca.

Apoptosis and a change in the expression of p53, c-jun and MT-I genes occurred in rats exposed to cadmium in a way known to cause carcinogenesis in testes and ventral prostate. In situ end labelling (ISEL), DNA electrophoresis, and RT-PCR methods were used in present study. Adult male Wistar rats were given a single (s.c.) injection of 0, 5, 10, or 20 micromol/kg CdCl2. Then 12, 48 or 96 h after administration of cadmium, animals were sacrificed. It was observed that cadmium markedly induced apoptosis in the testes at the dose of 5 micromol/kg while 10 and 20 micromol/kg cadmium caused more necrosis than apoptosis. Apoptosis in the ventral prostate was markedly induced by all the doses of cadmium and there was an obvious time- and dose-dependent relationship between apoptotic index (AI) and cadmium treatment. Far fewer apoptotic cells appeared in liver, compared to the testes and ventral prostate. p53 mRNA expression was clearly enhanced in the ventral prostate but clearly suppressed in the testes by cadmium exposure, and the time- and dose-effect was very clear. The expression level of p53 in the liver was not affected by cadmium treatment. Cadmium-induced overexpression of c-jun gene appeared at 12 h in the liver, but not until 96 h in the testes and ventral prostate. Although the MT-I gene was found to be expressed in all tissues, marked induction by cadmium of the expression of MT-I gene was only observed in the liver. These results indicate: (1) that apoptosis is an early mechanism of acute tissue damage by cadmium in the testes and ventral prostate; (2) that p53 and c-jun genes may be involved in cadmium-induced cytotoxicity (apoptosis) and related carcinogenicity in male reproductive tissues; and (3) that the enhanced expression of MT-I in the liver could protect this organ from cadmium-induced cytotoxicity (apoptosis) and carcinogenicity.

N-Acetyl-beta-D-glucosaminidase (NAG) and its isoenzymes in urine have been studied in a population group residing in a polluted area in China. The area studied was contaminated by industrial wastewater from a nearby smelter that discharged cadmium-polluted wastewater into a river used for the irrigation of rice fields. Cadmium concentrations in rice were 3.70, 0.51, and 0.07 mg/kg for the highly and moderately polluted areas and the control area, respectively. Cadmium concentrations in urine exceeded 5 microgram/liter in the majority of subjects in the most highly polluted area. There was a marked dose-dependent increase in NAG and NAG B content of urine related both to urinary cadmium and to the calculated cadmium uptake. It is concluded that urinary NAG and its isoenzymes could serve as a sensitive biomarker of renal dysfunction in cadmium-exposed populations. The mechanisms underlying the increase in NAG and its isoenzymes after cadmium exposure need to be studied further.

The cadmium-metallothionein (CdMT) injection model was used to examine whether multiple short-interval injections of CdMT, instead of a single dose, could better reproduce the features of chronic exposure to inorganic cadmium. Male Wistar rats were given an initial CdMT dose and four subsequent doses subcutaneously at 2-h intervals. A control group, given saline, was compared with a low dose group (0.2 + 4 x 0.1 mg Cd/kg b.w.) and high dose group (0.4 + 4 x 0.1 mg Cd/kg b.w.). Nephrotoxic effects were seen at the high dose. A marked proteinuria began 6-12 h after the first injection and extended to day 9. A progressive, unreversed calciuria appeared at 6 h and reached its maximum at day 13. This was a marked increase in duration compared with the transient peaks of proteinuria and calciuria observed in previous single dose studies. The unreversed calciuria and the marked proteinuria are suggestive of residual tubular damage, which may be irreversible. In conclusion, the model with multiple short-interval CdMT injections more closely reproduces the situation in long-term exposure to inorganic cadmium, compared to the single dose models previously employed.

Two experiments (I and II) were performed to study aluminium accumulation in brain as well as in several other tissues in male Wistar rats. A single intraperitoneal injection of cadmium-metallothionein (CdMT, 0.1-0.4 mg Cd/kg b.wt.) was used to compromise kidney function 12 hr before the final aluminium injection in both experiments. In experiment I, rats were maintained on diets deficient (0.01%, w/w) in calcium (-Ca) or providing adequate (+Ca) dietary calcium (0.9%) for 6 weeks. Among animals given a daily intraperitoneal dose of aluminium chloride (10.8 mg Al/kg per day) on 6 consecutive days there was a tendency towards higher aluminium level in brains of rats with compromised kidney function from CdMT (in -Ca rats: the geometric mean [G] = 288 versus 205 ng/g wet weight [w., wt.], P = 0.07, and in +Ca rats: G = 242 versus 164, P < 0.05) as compared to animals given no CdMT. The results from experiment II (all rats were given aluminium 5.6 mg Al/kg 2 and 12 hr after CdMT injection) demonstrated a higher level of aluminium (G: 41 ng/g w. wt., P < 0.05) in brains of rats with only slightly damaged kidney function (0.1 mg Cd/kg) than in those given no CdMT (G: 29 ng/g w. wt.). It was also observed that 1) calcium deficiency had a statistically significant effect (P < 0.05) in increasing kidney retention of intraperitoneal aluminium (G: 327 micrograms/g w. wt.) as compared to rats with a normal calcium supply in the diet (G: 54 micrograms/g w. wt.); 2) when aluminium concentration in kidney was at and above 54 micrograms/g wet tissue, kidney damage was observed. The above results indicate that compromised kidney function including tubular damage induced by a low-dose of CdMT may play a crucial role in the accumulation of aluminium in brain and other tissues. Since tubular function decreases with age in human populations, these findings in rats may be of considerable importance if a similar phenomenon would occur in humans. Therefore, the possibility of increased aluminium retention in persons with low calcium and high aluminium intakes may need to be further investigated.

Primary cell culture was utilized to study the relationships between stress protein induction by zinc in vivo and cadmium toxicity in vitro. Effects of cadmium on cell viability were evaluated by the alamar blue assay, in conjunction with the ultrastructural morphology of cells by transmission electron microscopy. The expression of stress protein gene products was evaluated by 35S two-dimensional gel electrophoresis. The results showed cytotoxicity of CdCl2 at and above 129 microM (14.55 micrograms cadmium/mL medium) following 4 h of exposure. Prior zinc administration (20 mg zinc/kg, s.c., two daily doses) in vivo significantly protected the cells in vitro as demonstrated by improved cell viability. The 35S labeling of proteins induced by CdCl2 exposure clearly demonstrated for the first time that gene product of the 70-kDa family was induced in cultured rat proximal tubule cells which are the target cells for cadmium toxicity in vivo. Zinc in vivo pretreatment of animals induced proteins in the 90-, 70-, and 38-kDa families, which may act together with metallothionein to protect cells against cadmium toxicity. The results also indicate that the protective effect of zinc remains after the cells have been put in culture and thus provides a system in which we can study the changes that occur as a result of zinc exposure that decreases cadmium toxicity.

Nephrotoxic effects of cadmium exposure are well established in humans and experimental animals. An early manifestation of such toxicity is calciuria a few hours after injection of CdMT in rats. Protection against calciuria and other adverse effects such as proteinuria (occurring later) is offered by pretreatment with Cd, which effectively induces metallothionein synthesis. In the present experiment, one group of animals was given pretreatment with CdCl2 to induce metallothionein synthesis. The comparison group was left without pretreatment. The distribution of Cd from a normally nephrotoxic dose of 109CdMT was studied by gel chromatography in subcellular fractions of kidney cortex in both groups. In the pretreated animals, 109Cd in the plasma membrane and microsome fractions of renal cortical cells was mainly bound to metallothionein and other low molecular weight proteins at 4 hr. In nonpretreated animals the major part of 109Cd was bound to high molecular weight proteins. These findings indicate that membrane proteins may be important targets for Cd when inducing nephrotoxicity and that sequestering of Cd by metallothionein (and other low molecular weight proteins) may be a mechanism of protection.

Only a few studies have investigated the effects of the interaction between Cu, Zn, and Cd on the toxicity of Cd in vivo and the metabolism of these metals. The present study is concerned with these effects. Observations of the distribution of these metals in liver and renal cortex and of their excretion in urine were made. Sixty male Wistar rats were divided into 10 groups of six (a full factorial design complemented by a center point and a control group) and were administered Zn (0 or 25 mg/kg body mass), Cu (0 or 12.5 mg/kg), and CdMT (cadmium--metallothionein; 0.1 or 0.4 mg Cd/kg) by sc injection. The rats were given Zn and/or Cu 24 hr prior to the CdMT injection. The data were analyzed by linear multiple regression. After CdMT injection, the Cd retention level was markedly reduced in renal cortex and increased in liver by Cu pretreatment, while the urinary excretion of Cd was significantly lower in these rats. The levels of endogenous Zn in renal cortex and liver increased significantly in rats pretreated with Cu. The production of MT in liver and renal cortex was induced more efficiently by Cu than by Zn. The results obtained may be of importance in understanding the mechanism of CdMT toxicity and the potential influence of Zn and Cu on the chronic nephrotoxicity of cadmium.

Factorial experimental design was used to study the protective effects of Zn and Cu on cadmium-metallothionein(CdMT)-induced nephrotoxicity in male Wistar rats. In the factorial design two levels of Zn (0 and 25 mg/kg body weight), two levels of Cu (0 and 12.5 mg/kg), and two levels of CdMT (0.1 and 0.4 mg of Cd/kg) were used as varied factors. The factorial design was complemented with a center point with all three variables at an intermediate setting, i.e., Zn at 12.5 mg/kg, Cu at 6.25 mg/kg, and CdMT at 0.25 mg Cd/kg. Each of the nine combinations of settings was administered to one of nine groups with six rats in each. Zn and Cu were injected sc 24 hr prior to the injection of CdMT. The concentrations of protein and Ca in urine and Ca in renal cortex were used as effects. The relationship between the experimental design settings and the effects were modeled with multiple regression. The multiple regression analysis revealed that for the high dose of CdMT (i) the enhanced values of protein in urine caused by CdMT injection could be more efficiently reduced by Zn than by Cu, and (ii) excessive Ca in urine and renal cortex could be more efficiently reduced by Cu than by Zn. No significant synergism or antagonism between Cu and Zn was found. These models can be used to estimate the dose levels of Zn and cu which will reduce the toxic effects of CdMT. The treatment of 20.4 mg/kg Zn, for example, will reduce the effects of 0.4 mg Cd/kg as CdMT on protein in urine, and 2.8 mg/kg Cu will reduce the Ca in urine to the levels of those caused by 0.25 mg Cd/kg (no Zn and Cu). Similarly, the effect of 0.4 mg Cd/kg on Ca level in renal cortex can be reduced to that of 0.28 mg Cd/kg as CdMT by 7.98 mg Cu/kg, which is three times as efficient as Zn. The obtained results might be of importance in understanding the mechanism of cadmium toxicity and the potential risk to the health of the population exposed to cadmium occupationally or environmentally.

Occupational exposure to lead may cause kidney damage. This study was carried out on a cohort of 70 active and 30 retired long term exposed lead smelter workers. Their kidney function was compared with 31 active and 10 retired truck assembly workers who had no occupational exposure to lead. The lead workers had been regularly followed up with measurements of lead concentration in blood since 1950. Previous exposure to lead was calculated as a time integrated blood lead index for each worker. Blood and urine samples were obtained from all subjects. The concentration of lead in blood (B-Pb) and urine (U-Pb) was analysed. The urinary concentrations of several sensitive indicators of early tubular (U-beta 2-microglobulin (U-beta 2-m); U-N-acetyl-beta-glucosaminidase (U-NAG)) and glomerular kidney damage (U-albumin) were determined. The B-Pb and U-Pb values were significantly higher among active and retired lead workers compared with their corresponding control groups. The highest concentrations were found among the active lead workers. The concentrations of the parameters of kidney function investigated were of the same magnitude for exposed workers and controls. No clinical signs of renal impairment were found among the workers. No correlations of clinical importance existed between concentrations of U-albumin, U-beta 2-m, and U-NAG activity on the one hand and the concentrations of B-Pb, cumulative blood lead index, U-Pb, and lead concentrations in the calcaneus and tibia on the other, among lead workers and controls. Despite many years of moderate to heavy exposure to lead, particularly for the retired lead workers, no signs of adverse effects on the kidney such as early tubular or glomerular malfunction were found. Reversible changes in kidney function during the 1950s and 1960s could not be excluded, however, due to a greater exposure to lead during that time.

We investigated the role of metallothionein (MT) in tissues after cessation of cadmium (Cd) exposure. Wistar rats of both genders were given CdCl(2) in drinking water at daily doses of 0, 2.5, 5.0 or 10.0 mg Cd/kg body-weight for 12 weeks. Half of the animals were then killed; the others were given Cd-free water for the following 16 weeks, i.e. until 28 weeks after start of the experiment (28-week rats). We observed dose-dependent increases in the levels of MT in the tissues of rats 12 weeks after beginning the experiment (12-week rats). After the exposure ceased, levels of MT in the 28-week rats changed in three ways: an increase in the liver, persistence in the kidney cortex and a decrease in the medulla, relative to those levels in their 12-week counterparts. Biomarkers of kidney dysfunction were determined to be urinary MT (UMT) and urinary N-acetyl-beta-D-glucosaminidase (UNAG). After 12 weeks, we observed dose-related statistically significant increases in UMT and UNAG in all of the Cd-exposed groups. A statistically significant decrease for UNAG between the 12- and 28-week rats occurred among males at the lowest Cd dose and for UMT in all of the Cd-exposed groups. The unchanged tissue levels of MT in the kidney cortex suggest that decreased UMT is a sign either of (i) decreased transport of Cd-MT from the liver via blood plasma to the renal tubules or (ii) increased tubular reabsorption and recovery of renal tubular function.

Mercuric chloride (HgCl2) is a classic nephrotoxic agent. While it is well established that HgCl2 can induce metallothionein synthesis in the kidney and also cause damage to the pars recta region of the renal tubule, the urinary losses of essential elements like calcium (Ca) and magnesium (Mg) probably related to this process, have not been described. In this study, calcium, magnesium, metallothionein (MT), as well as sodium (Na) and potassium (K) in urine, kidney cortex and liver were measured in male Wistar rats after two daily injections of HgCl2 (0.5 or 1.0 mg Hg/kg body weight intraperitoneally). As compared with controls, there was a significant 3-4-fold increase in calcium excretion which reached its maximum at 8-12 and 32-36 hr after treatment with 1.0 mg Hg/kg. Urinary magnesium excretion was also increased in a similar way as the calcium excretion. At 12-16 hr, urinary magnesium in the 1.0 mg Hg/kg dose group was 3.4 times higher than that of the controls. Urinary MT level in HgCl2 treated rats was much higher than that in the controls, the maximum excretion was between 24-28 and 32-36 hrs preceeded by the peak of Hg in urine. Na and K concentrations in urine decreased significantly in rats treated with HgCl2. The present study thus demonstrates that increases of urinary calcium and magnesium excretion are early toxic effects of HgCl2 on the kidney. It gives support to the hypotheses implying these ion imbalances in the mechanism of elicitation of renal toxicity by mercury. These findings are also of interest because they indicate the possibility that perturbations of Ca and Mg metabolism as a result of environmental (including occupational) mercury exposure might occur; such ion imbalances might subsequently increase risks of adverse health effects.

Biomonitoring employs three categories of biomarkers: Biomarkers of exposure, i.e. measurements of metal concentrations in a compartment in the body reflecting external or internal exposure; Biomarkers of effects include early as well as clinical effects. Biomarkers of susceptibility indicate individuals with increased sensitivity of target molecules or metabolism causing increased target dose. The three categories of biomarkers were used in studies of health effects of metal exposures in China. Adverse effects on the kidney tubules with increased levels of the effect biomarkers beta-2-microglobulin in urine (UB2M) and urinary N-acetyl-beta-d-glucosaminidase (UNAG) were found among Cd exposed population groups in China. Among persons exposed to Cd, occupationally or in the general environment, the level of Cd-induced metallothionein mRNA (MTmRNA) in peripheral lymphocytes appeared as a useful indicator of the ability of individuals to synthesize MT. Persons with low MTmRNA levels displayed higher biomarker values of renal tubular damage than persons with high levels of MTmRNA, at comparable levels of urinary Cd. Other studies demonstrated the importance of auto-antibodies against metallothionein in plasma (MTab) in modifying the response to Cd. Persons with high levels of MTab displayed tubular proteinuria at lower levels of urinary Cd than persons with low levels of MTab. Studies in two metal contaminated areas in China demonstrated clear interactions between Cd and inorganic arsenic. Combined exposure, with increased levels of As and Cd in urine, caused considerably higher biomarker values of renal tubular damage, measured as increased urinary levels of B2M or NAG, than each of the exposures alone.

We have previously demonstrated Clara cell protein (CC16) [secretoglobin 1A1] in serum to be a highly sensitive biomarker of altered lung epithelial permeability after ozone challenge. As a previous experimental study has indicated a diurnal variation in serum CC16 in humans, the aims of the present investigation were to confirm this observation and to attempt to model the diurnal variation in CC16 concentrations. In 18 healthy nonsmoking subjects, peripheral blood samples were drawn at six sampling points over a 15-h period and repeated twice within 3 to 4 weeks. A clear within-day variation was revealed in serum CC16 concentrations, falling significantly from baseline levels between the 11:30 am and 10:00 pm time points (p = 0.000). Furthermore, it was shown that this within-day variation was reproducible regardless of subject or day, enabling the diurnal variation in serum CC16 to be modeled and fitted a second-degree polynomial for the observed time span. In conclusion, the present data demonstrate a pronounced time-dependent diurnal variation in serum levels of CC16, which can be mathematically compensated for, when addressing the issue of an air pollution-induced effect on CC16 in field studies.

Cadmium (Cd) is a widely spread toxicant with endocrine disrupting properties. Under experimental conditions it suppresses sex steroid synthesis in the male as well as the female. Testicular steroidogenesis is primarily regulated by gonadotropins, but is also influenced by catecholamines. We have previously shown that Cd exposure affects rat testosterone synthesis by down-regulating luteinizing hormone (LH) receptor mRNA expression. In this study, rats were given 10 micromol/kg Cd subcutaneously and sacrificed 0.48-144 h later. We investigated the effects of Cd on testicular gene expression of two adrenergic receptors. In addition, mRNA levels of the androgen-regulated house keeping gene glyceraldehyde-3-phosphate dehydrogenase (GAPDH) were measured. In contrast to the suppressive influence on LH receptor expression Cd lacked effect on the expression of alpha(1A)- and beta(2)-adrenergic receptors. GAPDH gene expression, on the other hand, was up-regulated 1.6-fold after exposure to 10 micromol/kg Cd. These data suggest that the influence of Cd on testicular gene expression involves a specific effect on the LH receptor and not a general effect on seven-transmembrane-spanning receptors. Also, data indicate that the increased expression of GAPDH may be secondary to Cd-induced testosterone deprivation, suggesting future studies of androgen-regulated genes in the toxicity of Cd.

Aims: A study was carried out of informed consent strategies in an epidemiological project approved by the regional research ethics committees in Sweden and China and conducted in three areas south-west of Shanghai. Methods: All participants in the epidemiological project (EP) were included in the research ethical study (RES), which was conducted as a questionnaire-based interview survey in the three areas. Answers were collected by five field interviewers. Results: All participants included answered the questionnaire. Almost all perceived the information provided as rather good or quite good. However, a majority (on average 76%) had the impression that the EP was part of routine healthcare measures, and not a research project. Almost all participants felt free to abstain from participation although 38% in area II stated that they had not been informed about freedom to abstain from participation. A large proportion of participants did not fully understand the nature of the EP. However, almost all participants stated that they would agree to participate in a similar study in the future. Conclusion: Although informed consent procedures are supposed to be internationally applicable our study illustrates that it is not always easy to convey information and obtain consent in the present study setting.

Human exposure to cadmium may occur in both occupational and general environments. We were interested in determining whether a combination of occupational and environmental exposure to cadmium results in different levels of severity of renal dysfunction relative to that arising from environmental or occupational exposure alone. We selected 44 residents, who once were employed in a smelter and lived in a cadmium-polluted area, as group A. Another 88 subjects, who never worked in the plant, but lived in the same area, were selected as group B. Group C consisted of 88 subjects who had no history of occupational exposure to cadmium and lived in a non-cadmium-polluted area. Statistical analysis demonstrated that there was no significant difference in age or gender among the three groups, nor were there significant differences in smoking habits. The prevalence of renal dysfunction as indicated by increased excretion of beta2-microglobulin (B2M), N-acetyl-beta-D-glucosaminidase (NAG) and albumin (ALB), was higher in group A than in group B. This finding suggests that exposure to cadmium both occupationally and environmentally results in a higher prevalence of renal dysfunction, relative to those who are exposed to cadmium only in the general environment. Therefore, this specific population, who once were occupationally exposed to cadmium and lived in polluted areas, should be identified. Furthermore, health examinations of this population should be conducted in time to prevent further health damage induced by cadmium exposure.

Environmental exposure to cadmium may give rise to osteomalacia combined with renal dysfunction, so called 'Itai-Itai disease', which was endemic in the heavily polluted area in Japan. The main focus of this study was to investigate whether environmental exposure to cadmium is associated with low bone mass in a population living near a smelter. A total of 790 persons (302 males and 488 females), who were all over 35 years old and resided in areas near a lead, zinc and cadmium smelter and in a control area in southeast China, completed a questionnaire, and bone mineral density was measured by SPA-4 single photon absorptiometry at the radius and ulna. Cadmium content of urine was determined by graphite-furnace atomic absorption spectrophotometry as a measure of dose. The present study shows that forearm bone densities were negatively correlated with urinary cadmium excretion (p < 0.001) and forearm bone density decreased linearly with age (p < 0.001) and urinary cadmium (p < 0.01), suggesting a dose-effect relationship between cadmium dose and bone mineral density. Based on the World Health Organization criteria, (bone mineral density < -2.5 SDs below the normal young adult), the prevalence of osteoporosis in women increased from 34.0% in the control area to 51.9% in the heavily polluted area (p < 0.01) among subjects over 50 years old, and the odds ratio value was 2.09 (95% CI: 1.08-4.03) for the highly polluted area compared with the control area. A striking observation in the study was a marked increase of the prevalence of fracture in the cadmium-polluted area in both sexes. It was concluded that environmental exposure to cadmium is associated with an increased loss of bone mineral density in both gender, leading to osteoporosis and increased risk of fractures, especially in the elderly and in females.

The aim of the study was to compare bone lead concentrations in cortical and trabecular bones in long-term exposed primary copper and lead smelter workers, and to relate the measured concentrations to the previous lead exposure of the workers. Lead concentrations in seven bones (trabecular: sternum, vertebrae, iliac crest, rib; cortical: femur, left forefinger, and temporal bone) were determined by electrothermal atomic absorption spectrometry in 32 male, long-term exposed copper and lead smelter workers, and compared with levels in 10 male occupationally unexposed reference persons. A time-integrated blood lead index (cumulative blood lead index, CBLI) was calculated for each worker. The lead levels in the seven studied bones were all significantly higher in active and retired lead workers as compared with the reference group (p

In order to study the validity of metallothionein (MT) gene expression in peripheral blood lymphocytes (PBLs) as a biomarker of cadmium exposure and susceptibility to renal dysfunction, MT mRNA levels were measured using reverse transcription polymerase chain reaction (RT-PCR) in PBLs from residents living in a cadmium-contaminated area. MT mRNA levels were found to increase with the increase of blood cadmium (BCd) and urinary cadmium (UCd) levels. Basal MT mRNA levels were significantly correlated with the logarithm of BCd levels and the logarithm of UCd levels confirming that MT expression in PBLs is a biomarker of cadmium exposure and internal dose. An inverse relationship was observed between in vitro induced MT-mRNA level in PBLs and urinary N-acetyl-beta-d-glucosaminidase (UNAG) suggesting that MT gene expression in PBLs may be used as a biomarker of susceptibility to renal toxicity of cadmium.

In order to investigate the effects of cadmium (Cd) on testicular prostaglandin F(2 alpha) (PGF(2 alpha)) production, adult male Sprague-Dawley rats were exposed to CdCl(2) by subcutaneous injections. Dose-response as well as temporal-response experiments were performed, and PGF(2 alpha) levels were determined by radioimmunoassay (RIA). The highest cadmium dose (10 micromol/kg) caused a dramatic elevation of testicular PGF(2 alpha), which was established to occur 48 h after exposure. At this point of time, cadmium-treated animals displayed PGF(2 alpha) levels 16.7 times higher than saline-injected controls. No significant differences were found with the lower doses used (1 and 5 micromol/kg). In addition, the influence of pre-treatment with zinc (Zn) was assessed. The very strong stimulatory effect on PGF(2 alpha) synthesis (22.3-fold) detected after exposure to 20 micromol/kg cadmium, was completely absent in the group given zinc (1 mmol/kg) prior to cadmium exposure. Plasma testosterone concentrations were determined in the three experiments, and all groups with strongly elevated PGF(2 alpha) levels showed drastically lowered concentrations of testosterone. Zinc pre-treatment abolished not only the cadmium-induced rise in PGF(2 alpha) but also the testosterone reduction. Additionally, cadmium was found to inhibit the expression of steroidogenic acute regulatory protein (StAR), which is responsible for the rate-limiting step in steroidogenesis. The present findings establish that cadmium can cause a strong induction of testicular PGF(2 alpha) production, which might help to explain the well-known antisteroidogenic effect of this heavy metal. Such an inhibitory effect could be due to reduced levels of StAR.

Osteoporosis is a common metabolic disease characterized by low bone mass and microarchitectural deterioration of bone tissue. Many factors are involved in the occurrence of osteoporosis. Cadmium can cause both osteomalacia and osteoporosis and these effects have long been investigated through various epidemiological or experimental studies. The present study examines a possible relationship between cadmium nephropathy and its effects on the skeleton in populations living in a polluted area in southeast China. Monophoton absorptiometry was used to measure bone mineral density in the population and the Z score (the number of SD from the difference between the measured bone density of the individual and the group mean value for sex- and age-matched controls) was introduced to define osteoporosis (Z score < -2). Osteoporosis caused by cadmium exposure was demonstrated in this study on a general population environmentally exposed to cadmium in China. It was found that there were significant differences in the prevalence of osteoporosis among the different urinary cadmium groups chi(2) = 18.84, P = 0.0008). The linear trend test gave chi(2) = 16.281, P = 0.00005. There was a dose-response relationship between cadmium exposure (urinary cadmium) and prevalence of osteoporosis. Of 31 subjects with osteoporosis, 23 subjects were suffering from renal dysfunction. The prevalence of renal dysfunction (74.19%) was significantly higher than that in those without osteoporosis (chi(2) = 16.53, P

The objective of this study was to investigate the possible effects of environmental cadmium (Cd) exposure on the levels of serum sex hormones in a Chinese population group. A total of 263 male volunteers were included. Blood samples were collected for the determination of serum testosterone (T), measured by radioimmunoassay, and follicle stimulating hormone (FSH) and luteinizing hormone (LH), both measured by enzyme immunoassays. Urinary and blood Cd were analyzed by atomic absorption spectroscopy (AAS). We found a dose-response relationship between urinary Cd excretion and the prevalence of abnormally high serum T levels, but, through multiple regression analysis, we could not trace exposure to Cd as a significant determinant of serum T levels. Exposure to Cd also failed to influence the levels of FSH and LH in serum. In contrast, we found that age, body mass index (BMI), and smoking habits are significant determinants of FSH and LH and of T and LH, respectively. We conclude that oral Cd exposure is not a critical determinant of hormone homeostasis in males, but lifestyle and some biological factors, such as age and BMI, are important. The relationship found between urinary Cd and high T levels may be of importance for male reproductive morbidity and should be investigated further.

It has been demonstrated that cadmium (Cd) is carcinogenic to rodent prostate. However, the mechanism of its toxicity is far from fully understood. In the present study, the effects of oral Cd exposure (0, 50, 100, 200 ppm in drinking water) on serum sex hormone levels, the expression of MT-I and MT-II mRNA, and the zinc content of rat prostate were assessed. With Cd administration, serum testosterone (T) levels significantly increased in all Cd groups after 3 months and in the 200 ppm Cd group after 6 months. A significant depression in the serum luteinizing hormone (LH) level was seen in the Cd group (200 ppm) after 6 months. It was noted that Cd administration resulted in a significant down-regulation in the expression of MT-I and MT-II mRNA in the rat ventral prostate. However, no Cd-induced changes in the mRNA expression of Metallothioneins (MTs) were detected in the dorsolateral prostate. After Cd administration, the content of Cd in both the ventral and dorsolateral lobes of the prostate significantly increased with increasing dose and duration of Cd administration. In contrast, the Zn content decreased with Cd administration in both the ventral and dorsolateral lobes of the rat prostate. Taken together, these results suggest that oral Cd exposure may disrupt endocrine homeostasis, changing the distribution of Zn and the mRNA expression of MTs in rat prostate, and that such Cd-induced changes may contribute to the susceptibility of prostate to the carcinogenicity of this heavy metal.

Exposure to ozone (O3) impairs lung function, induces airway inflammation and alters epithelial permeability. Whilst impaired lung function and neutrophilia have been observed at relatively low concentrations, altered lung epithelial permeability is only seen after high-dose challenges. The appearance of Clara cell protein (CC16) in serum has been proposed as a sensitive marker of lung epithelial injury. Here, the use of CC16 as an injury biomarker was evaluated under a controlled exposure to O3 and the relationship between this marker of lung injury and early lung function decrements was investigated. Subjects (n=22) were exposed on two separate occasions to 0.2 parts per million O3 and filtered air for 2 h. Blood samples were drawn and lung function assessed at 2 h pre-exposure, immediately before and immediately after exposure as well as 2 and 4 h postexposure. O3 increased CC16 serum concentrations at 2 h (12.0+/-4.5 versus 8.4+/-3.1 microg x L(-1)) and 4 h postexposure (11.7+/-5.0 versus 7.9+/-2.6 microg x L(-1)) compared with air concentrations. Archived samples from O3 studies utilising the same design indicated that this increase was sustained for up to 6 h postexposure (9.1+/-2.6 versus 7.1+/-1.7 microg x L(-1)) with concentrations returning to baseline by 18 h (7.7+/-2.9 versus 6.6+/-1.7 microg x L(-1)). In these studies, the increased plasma CC16 concentration was noted in the absence of increases in traditional markers of epithelial permeability. No association was observed between increased CC16 concentrations and lung function changes. To conclude, Clara cell protein represents a sensitive and noninvasive biomarker for ozone-induced lung epithelial damage that may have important uses in assessing the health effects of air pollutants in future epidemiological and field studies.

OBJECTIVE: In mice, the renal toxicity of arsenic (As) and cadmium (Cd) has been shown to be exacerbated by the simultaneous administration of both elements. To verify the existence of such an interaction in humans, cohorts slightly (Belgian) and moderately (Chinese) exposed to both elements were examined. METHODS: Biological indicators of exposure (Cd in urine and in blood; As in urine) and renal effect parameters (retinol binding protein (RBP); beta(2)-microglobulin (beta(2)M); albumin (ALB); N-acetyl-beta-glucosaminidase (NAG) in urine) were determined and their relationships studied by multiple regression analyses. RESULTS: Changes in renal effect parameters could be ascribed to Cd body burden. RBP and beta(2)M urinary concentration were influenced by exposure to As only in Chinese women, directly and in interaction with Cd exposure. CONCLUSION: A synergistic action of As on the tubular effects of Cd is observed in women moderately exposed to these elements and leads to RBP urinary excretion slightly above normal values.

Recent publications indicate an increased incidence of lung cancer in non-ferrous smelter workers exposed to lead. The present study provides further data on selected subgroups in one such cohort. The cohort was based on 3979 smelter workers employed for at least 1 year between 1928 and 1979, and also exposed to lead and included in the Blood Lead Register that was started at the smelter in 1950. Two subcohorts were formed from the original cohort. One consists of 710 workers employed at the lead departments (Lead subcohort 1), and the other of 383 workers employed at the lead departments (Lead subcohort 2), but never at other works where an excess lung cancer risk was previously identified. Standardized Cancer Incidence Rates (SIR) 1958-1987 were calculated relative to county rates. In the subcohorts, arsenic exposure in lung cancer cases was assessed in detail based on occupational hygiene information from the company. Lung cancer incidence was raised in both subcohorts (Lead subcohort 1: SIR 2.4; 95% CI 1.2-4.5; Lead subcohort 2: SIR 3.6; 95% CI 1.2-8.3). Total cancer incidence in the cohorts was not increased. A detailed study of arsenic exposure in the 10 lung cancer cases in these two subcohorts revealed that all but one of these cases had a significant exposure also to arsenic. An elevated incidence of lung cancer was observed in smelter workers exposed to lead. However, considerable arsenic exposure also occurred in a majority of the lung cancer cases in the investigated subcohorts. In this multifactorial exposure situation it has not been possible to separate the carcinogenic effects of lead and arsenic, but a possible interaction between these metals may be involved in explaining the carcinogenic risks.

High oral intake of cadmium via food or drink in a single dose by humans gives rise to vomiting, abdominal pain, and diarrhea. Concentrations of cadmium in drinks giving rise to such symptoms have been 16 mg/liter and higher corresponding to doses of 3 mg and higher. Longer term intakes of food (rice) with concentrations around 1 mg/kg corresponding to daily intakes of 600 micrograms have given rise to some less pronounced symptoms including signs of malabsorption. Reproductive and developmental effects have been observed in animal experiments at oral and other exposures. The present provisional tolerable weekly intake (PTWI) for Cd is 500 micrograms (a weekly intake of 7 micrograms/kg body wt), corresponding to a daily intake of 70 micrograms or 1 microgram per kg body wt. Recent data demonstrating renal dysfunction in humans at even lower lifelong oral exposures indicate that the PTWI needs to be lowered in the future. An estimated lowest-observed-adverse-effect level (LOAEL) for symptoms from the gastrointestinal tract in humans after intake of a single oral dose is 43 micrograms/kg body wt. If a safety factor of 3-10 is used based on LOAEL, a tolerable single dose would be 0.3-1 mg (4 to 14 micrograms/kg body wt). For longer time exposures (months-a few years) daily intakes of 200 micrograms (3 micrograms/kg body wt) may be tolerated without obvious gastrointestinal symptoms or signs. At present, there is no convincing human evidence that such doses can cause reproductive or developmental effects, but since such effects have been reported in animals, it may be advisable not to exceed a daily intake of 1 microgram/kg body wt for such potentially sensitive subsections of the population as children and women who are pregnant or lactating. Any excursions above the PTWI need to be compensated for by a corresponding period with intake below the PTWI in order for the cumulative dose to be low enough to avoid the long-term effects of cadmium on the kidney.