The association between hemoglobin level and osteoporosis in a Chinese population with environmental lead and cadmium exposure.

Low hemoglobin (Hb) level or anemia is associated with osteoporosis and bone fracture. Cadmium (Cd) and lead (Pb) exposure are also risk factors of osteoporosis and anemia. However, the role of anemia in Cd/Pb related bone loss remains unclear. The aim of present study was to investigate the association between Hb level and bone loss in a population with environmental lead and cadmium exposure. One hundred and ninety-four women and 108 men with different levels of Cd/Pb exposure were included in our study. The Cd/Pb exposure was determined using graphite-furnace atomic absorption spectrometry. Forearm bone mineral density (BMD) was determined by peripheral dual-energy X-ray absortiometry. Hb concentration was determined using an automatic blood cellcounter. A logistic model was established to predict the risk of osteoporosis. The BMDs of women that had the highest quartile BCd and BPb were markedly lower than that with the lowest quartile (p < 0.05). The BMD and the prevalence of osteoporosis in men with anemia were lower and higher than that with normal Hb (p < 0.05), respectively. In men, age, BPb and anemia were independent risk factors for osteoporosis. The odds ratio (OR) of men with anemia was 11.28 (95%confidence interval (CI):1.94-65.54) and 19.56 (95%CI: 2.98-128.78) compared to those with normal Hb after adjusting for potential cofounders. No such association was found in women. The area under the curve was 0.88 (95%CI: 0.82-0.96) in predicting osteoporosis using the logistic model in men. Linear discriminant analysis also showed that 90.7% of osteoporosis was correctly classified. Our data show that anemia is associated with incident of osteoporosis in men but not in women that environmentally exposed to Pb and Cd.

The association between life-time dietary cadmium intake from rice and chronic kidney disease.

The association between internal cadmium exposure and chronic kidney disease (CKD) has been investigated before. However, few studies have shown the association between dietary cadmium intake and CKD. In this study, we show the association between life-time dietary cadmium intake and CKD based on a follow-up study. At baseline, we collected blood and urine samples for assays of cadmium and renal effect biomarkers. A questionnaire and food survey was given to each subject to collect diet and lifestyle information for the estimation of cadmium intake. Dietary cadmium, cadmium in blood and urine were regarded as exposure markers. Life-time dietary cadmium intake was estimated based on an individual's daily cadmium intake and exposure time. At follow-up, 467 persons (163 men and 304 women) were finally included. CKD at follow-up was considered if the estimated glomerular filtration rate (eGFR) was less than 60 mL/min/1.73 m2. The eGFR level in subjects in the highest quartile of total dietary cadmium intake (>9.34 g) was significantly lower than in those with a moderate or low intake (p < 0.01). eGFR was negatively associated with total dietary cadmium intake (ß = -0.42, 95% confidence interval (CI): -0.77 to -0.07) after adjustment with confounders. Logistic regression further showed that the risk of CKD in subjects with a high total dietary cadmium intake (>2.2 g) was higher than in those with a low intake (odds ratio (OR) = 18.16, 95%CI: 1.75-188.85). A similar association was found between the baseline urinary albumin (UALB) level and CKD incidence. A predictive model based on UALB and life-time dietary cadmium intake showed an acceptable performance (the area under the curve was 0.77 (95%CI: 0.65-0.88)). Our data show that high dietary cadmium exposure was associated with CKD after controlling for renal tubular dysfunction and internal cadmium exposure.

A nomogram for predicting the renal dysfunction in a Chinese population with reduction in cadmium exposure based on an 8 years follow up study.

Cadmium exposure is associated with renal dysfunction. However, the outcome of renal function in subjects who have had a reduction in cadmium exposure for years has not been completely clarified, particularly for individuals with normal baseline renal function. In this study, we used a nomogram model to predict renal dysfunction after a reduction in cadmium exposure in subjects with normal baseline renal function. In 1998, a survey was performed in 790 subjects living in control and cadmium-polluted areas. A total of 497 subjects was followed up in 2006. 404 subjects with normal baseline urinary ß2-microglobulin (UBMG), 373 subjects with normal baseline urinary N-acetyl-ß-d-glucosaminidase (UNAG) and 407 subjects with normal baseline urinary albumin (UALB) were included in this analysis. Cadmium in the blood (BCd) and urine (UCd) was detected using graphite-furnace atomic absorption spectrometry. A logistic regression model was used to identify potential predicting factors of renal function at follow-up. Nomograms were developed based on those predictive factors. Bootstrap self-sampling, calibration curves and receiver operating characteristic (ROC) curves were performed to quantify our modeling strategy. Adjusted and unadjusted logistic regression models both showed that age, BCd and UBMG or UNAG at baseline were independent risk factors for renal tubular dysfunction. Baseline age, sex, BCd and UNAG or UBMG or UALB were used to construct the nomogam. The internal validation showed that the C-index was 0.70-0.74 for predicting renal dysfunction. The area under the curve of the nomogram was 0.70-0.74. Decision curve analysis verified the predictive value of the nomogram. A nomogram may be a useful risk assessment tool for predicting the progress of renal function in a cadmium-exposed population with normal baseline kidney function.

FairCs-Blockchain-Based Fair Crowdsensing Scheme using Trusted Execution Environment.

Crowdsensing applications provide platforms for sharing sensing data collected by mobile devices. A blockchain system has the potential to replace a traditional centralized trusted third party for crowdsensing services to perform operations that involve evaluating the quality of sensing data, finishing payment, and storing sensing data and so forth. The requirements which are codified as smart contracts are executed to evaluate the quality of sensing data in a blockchain. However, regardless of the fact that the quality of sensing data may actually be sufficient, one key challenge is that malicious requesters can deliberately publish abnormal requirements that cause failure to occur in the quality evaluation process. If requesters control a miner node or full node, they can access the data without making payment; this is because of the transparency of data stored in the blockchain. This issue promotes unfair dealing and severely lowers the motivation of workers to participate in crowdsensing tasks. We (i) propose a novel crowdsensing scheme to address this issue using Trusted Execution Environments; (ii) offer a solution for the confidentiality and integrity of sensing data, which is only accessible by the worker and corresponding requester; (iii) and finally, report on the implementation of a prototype and evaluate its performance. Our results demonstrate that the proposed solution can guarantee fairness without a significant increase in overhead.

The association between dietary cadmium exposure and renal dysfunction - the benchmark dose estimation of reference levels: the ChinaCad study.

The tolerable dietary intake of cadmium was recommended at provisional tolerable monthly intake of 25 µg kg-1 body weight. However, several studies indicated that this tolerable level should be re-evaluated for sufficient health protection. In this study, we show the reference levels of dietary cadmium intake for renal dysfunction by using a benchmark dose (BMD) approach. A total of 790 subjects (302 men and 488 women) living in control and cadmium-polluted areas were included. The dietary cadmium intake was estimated by a food survey. Blood cadmium, urinary cadmium and renal function markers (microalbuminuria, N-acetyl-ß-d-glucosaminidase [NAG] and its isoform B [NAGB], ß2 -microglobulin and retinol binding protein) in urine were measured. We calculated the 95% lower confidence bounds of BMD (BMDLs) of cumulative cadmium intake. In control and two polluted areas, the median cumulative cadmium intake was 0.5, 2.1 and 11.1 g. The odds ratio of the intermediate (1.0-3.0 g), second highest (3.0-11.0 g) and the highest cumulative cadmium intake (>11.0 g) compared with the lowest cumulative cadmium intake (<1.0 g) were 2.8 (95% CI: 1.4-5.8), 8.1 (95% CI: 3.8-17.2) and 11.4 (95% CI: 6.5-26.4) for urinary NAG and 6.6 (95% CI: 3.2-13.8), 14.8 (95% CI: 6.8-32.2) and 22.5 (95% CI: 10.7-47.5) for urinary NAGB. The BMDLs of cumulative cadmium intake were 1.1-1.2 g (benchmark response [BMR] = 5%) for urinary NAG, and were 0.7-0.9 g (BMR = 5%) for urinary NAGB, and were 1.3-1.4 g (BMR = 5%) for urinary ß2 -microglobulin. The BMDLs of cumulative cadmium intake in a Chinese population were lower than the critical standard previously reported. Further evaluations are needed for sufficient health protection.

Hypermethylations of RASAL1 and KLOTHO is associated with renal dysfunction in a Chinese population environmentally exposed to cadmium.

Exposure to cadmium (Cd) can affect both DNA methylation and renal function, but there are few examples of the association between epigenetic markers and Cd-induced kidney damage. It has been suggested that hypermethylation of the genes RASAL1 and KLOTHO is associated with renal fibrogenesis. To investigate whether hypermethylation of RASAL1 and KLOTHO in peripheral blood DNA can be associated with Cd exposure and/or Cd-induced renal dysfunction, the degrees of methylation of RASAL1 and KLOTHO in peripheral blood DNA from 81 residents in Cd-polluted and non-polluted areas were measured using bisulfate-PCR-pyrosequencing. Changes in blood cadmium (BCd), urinary cadmium (UCd), and kidney parameters were measured, and the glomerular filtration rate (eGFR) was estimated. The levels of BCd and UCd correlated positively with the levels of DNA methylation in RASAL1 and in KLOTHO. The more heavily exposed residents (BCd, 4.23-13.22µg/L; UCd, 8.65-32.90µg/g creatinine) exhibited obvious renal dysfunction. Notably, when Cd concentration in blood and urine was adjusted, the increased methylation level in RASAL1 was inversely correlated with eGFR (P<0.01) but the relationship between hypermethylation of KLOTHO and eGFR was not statistically significant. The methylation of RASAL1 increased along with the increased abnormal prevalence of eGFR. Our findings suggest that Cd exposure can induce the hypermethylation of RASAL1 and KLOTHO. Hypermethylation of RASAL1 may be an indicator of the progress for chronic kidney disease.

Exposure assessment of dietary cadmium: findings from Shanghainese over 40 years, China.

BACKGROUND: Environmental exposure to cadmium causes renal dysfunction and bone damage. Cadmium contamination in food is regarded as the main environmental source of non-occupational exposure. The aim of this study was to assess the contribution of dietary cadmium exposure in environmental cadmium exposure and its health risk among adults in Shanghai, China. METHODS: A cross-sectional survey about food consumption was conducted in 2008 among 207 citizens aged over 40 years in Shanghai, China. The food frequency questionnaire was combined with food, tobacco and water cadmium exposure to estimate the daily environmental cadmium exposure in both point and probabilistic estimations. Urine and blood samples of the participants were analyzed for internal exposure to total cadmium. Correlation analysis was conducted between the internal cadmium exposure and environmental cadmium exposure. RESULTS: According to the point estimation, average daily environmental cadmium exposure of the participants was 16.7 µg/day and approached 33.8% of the provisional tolerable daily intake (PTDI). Dietary and tobacco cadmium exposure approached 25.8% and 7.9% of the PTDI, respectively. Males had higher levels of dietary cadmium exposure than females (p?=?0.002). The probabilistic model showed that 93.4% of the population did not have any health risks from dietary cadmium exposure. By sensitivity analysis, tobacco consumption, tobacco cadmium level, cadmium in vegetables and cadmium in rice accounted for 27.5%, 24.9%, 20.2% and 14.6% of the total cadmium exposure, respectively. The mean values of urinary and blood cadmium among the study population were 0.5 µg/L and 1.9 µg/L, respectively. Positive correlations were observed between environmental cadmium exposure and blood cadmium (R?=?0.52, P<0.01), tobacco cadmium intake and blood cadmium excluding non-smokers (R?=?0.26, P?=?0.049<0.05), and urine cadmium and age (R?=?0.15, P?=?0.037). CONCLUSIONS: It has been suggested that there is no increased health risk among adult residents in Shanghai, China because of recent total cadmium exposure. Vegetables and rice were the main sources of dietary cadmium intake. Tobacco cadmium exposure, which accounted for approximately 25% of the total dietary cadmium exposure, was another important source of non-occupational cadmium exposure.

Skin Ageing: A Progressive, Multi-Factorial Condition Demanding an Integrated, Multilayer-Targeted Remedy.

Of the human organs, skin is the most visible one that displays the manifestations of ageing. It has a very intricate microanatomical structure and performs several key physiological functions. The pathophysiology of cutaneous ageing is characterized by deterioration of structural stability and functional integrity, implying a continuous reduction in maximal function and reserve capacity, as a result of the accumulating damage due to both intrinsic and extrinsic factors. Elimination of unfavorable expressions associated with facial and cutaneous ageing is the key patient demand in aesthetic dermatology. Even though the progress has been made in nonsurgical therapies like fillers and lasers, non-invasive interventions by using skin care products designed for rejuvenation at an early stage are the most popular and accessible solution among people. In this review, we have scrutinized the ageing-associated cutaneous changes at molecular, cellular and tissue levels. To optimize the ageing process towards a healthy skin, we propose an integrated, multilayer-targeted intervention, which involves both topical application of anti-ageing formulations from outside and oral supplementation from inside. Additionally, several promising naturally derived ingredients are reviewed from an anti-aging perspective. Most of them possess various bioactivities and may contribute to the development of the mentioned anti-ageing remedy.

The association between estimated glomerular filtration rate and cadmium exposure: An 8-year follow-up study.

BACKGROUND: The associations between cadmium exposure and chronic kidney disease have rarely been reported in longitudinal studies. In this study, we investigated the associations between the estimated glomerular filtration rate and cadmium exposure in a cross-sectional study in a longitudinal cohort. MATERIALS AND METHODS: In total, 790 subjects (≥35 years of age) living in southeastern China were included at 1998. Cadmium in blood (BCd) and urine (UCd) as well as renal dysfunction biomarkers, urinary N-acetyl-ß d-glucosaminidase (UNAG) and albumin (UALB), were determined. 497 subjects were followed at 2006 and a total of 456 subjects were finally included after excluding subjects that did not have exposure or effects biomarkers. The BCd, UCd, UNAG and UALB were determined using baseline methods. At follow-up, the estimated glomerular filtration rate (eGFR) was computed using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. Single nucleotide polymorphisms (SNPs) in metallothioneins 1A (MT1A) rs11076161 and MT2A rs28366003 in blood sample were detected using TaqMan allelic discrimination assays. RESULTS: The median of UCd and BCd at baseline was 5.38 µg/g cr and 4.69 µg/L, respectively, and the median UCd and BCd at follow-up was 4.88 µg/g cr and 2.20 µg/L at follow-up. The mean eGFR at follow-up was 88.0 mL/min/1.73 m2 and 15 subjects had new onset of eGFR <60 mL/min/1.73 m2. The eGFR at follow-up was associated with baseline age (ß = -0.66, 95% confidence interval (CI): 0.80 to -0.52), BCd (ß = -0.46, 95% CI: 0.68 to -0.25) and UALB (ß = -0.29, 95% CI: 0.41 to -0.16) after adjusting for confounders. Subgroup analysis in subjects who had low baseline UALB or subjects with or without hypertension showed similar results. A logistic regression model further showed that baseline BCd and UALB were independent risk factors for follow-up CKD. The odds ratios (ORs) were 1.09 (95% CI:1.03-1.16) for UALB, 1.16 (95% CI:1.01-1.33) for BCd, and 6.74 (0.87-29.63) for current hypertension. Baseline BCd, UALB and current hypertension were used to construct the nomogram. Linear discriminant analysis (LCA) showed that 87.6% of CKD was accurately predicted based on the three factors. CONCLUSION: Baseline age, BCd and UALB were associated with follow-up eGFR, and baseline BCd and UALB were predictive factors for incidence of CKD.

Changes in bone mineral density 10 years after marked reduction of cadmium exposure in a Chinese population.

The main focus of this study was to evaluate the long-term effects of Cd on forearm bone mineral density after the cessation of the ingestion of Cd-polluted rice. A total of 458 persons (294 women, 164 men) from three Cd exposure areas (low, moderately, and heavy) participated in this study. Those living in the moderate and heavy exposure areas ceased ingesting Cd-polluted rice (0.51 and 3.7mg/kg, respectively) in 1996 (10 years prior to present analysis). The participants completed a questionnaire and bone mineral density (BMD) was measured by dual energy X-ray absorptiometry (DXA) at the proximal radius and ulna. The changes and change percentage in forearm bone density and the prevalence of osteoporosis between 1998 and 2006 were used as markers of bone recovery. The Cd concentrations in urine (UCd) and blood (BCd) in 1998 were used as Cd exposure markers. The values of the BMD change and change percentage of groups in which UCd was above 5microg/g creatinine (microg/g crea) and BCd was above 10microg/L were significantly higher than those of the low-exposure groups (in women, p<0.001; in men, p>0.05). The BMD change and change percentage correlated positively with the UCd and BCd (in women, p<0.01; in men, p>0.05). Analysis of the Z-score revealed that the prevalence of osteoporosis in 2006 was higher than that in 1998 and increased along with the level of UCd and BCd in both women and men, especially for those subjects with the higher BCd [BCd>5microg/L, OR=3.45 (0.95-13.6); BCd>10microg/L, OR=4.51(1.57-13.54)] and UCd [UCd>10microg/g crea, OR=4.74 (1.82-12.81)] in women. It is concluded that decreasing dietary cadmium exposure at the population level is not associated with bone recovery at the individual level, and the adverse bone effects of Cd exposure persisted after the main source of Cd exposure had been blocked, especially in women.

Renal effects evolution in a Chinese population after reduction of cadmium exposure in rice.

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.

Preliminary ecotoxicity hazard evaluation of DOPO-HQ as a potential alternative to halogenated flame retardants.

Recent regulatory and environmental pressures have led to increasing demands for environmentally friendly flame retardants as alternatives to halogenated flame retardants (HFRs). A new flame retardant alternative, 10-(2, 5-dihydroxyl phenyl)-9, 10-dihydro-9-oxa-10- phosphaphenanthrene-10-oxide (DOPO-HQ), was applied due to its high thermal stability and glass transition temperature. However, there is little information available for its ecotoxicology. For this purpose, the preliminary ecotoxicity of DOPO-HQ was investigated and evaluated, using aquatic, terrestrial and microorganism toxicity according to Organization for Economic Co-operation and Development (OECD) guidelines under the framework of the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) regulation. No effect was observed on Pseudokirchneriella subcapitata, Daphnia magna and Gobiocypris rarus at the saturation water solubility. For active sludge, Eisenia foetida and seedling emergence, no effect was observed at the limited highest concentration of 1000 mg/L or 1000 mg kg-1 dw. However, moderate effect on the shoot weight is observed with the maximum inhibition rate of 46.3% when exposed to 1000 mg kg-1 dw. Comparing the ecotoxicity of DOPO-HQ with that of HFRs and their typical alternatives, the toxicity of DOPO-HQ is markedly lower than those of triphenyl phosphate (TPP) and HFRs such as tris(2-chloro-1-methylethyl) phosphate (TCPP), tris(1,3-dichloro-2-propyl) phosphate (TDCCP), tris(2-chloroethyl) phosphate (TCEP) and tetrabromobisphenol A (TBBPA). Similar low effect levels were observed for resorcinol bis (biphenyl) phosphate (RDP), bisphenol A bis (biphenyl) phosphate (BDP) and its parent chemical 9, 10-dihydro-9-oxa-10-phosphaphenanthrene -10-oxide (DOPO). DOPO-HQ could be a potential alternative to HFRs from an environmental perspective.

Benchmark dose estimation of cadmium reference level for hypertension in a Chinese population.

Cadmium exposure can cause high blood pressure or hypertension. Benchmark dose has been used to estimate the reference point of cadmium for kidney and bone damage. In this study, we observed the association of blood pressure and cadmium in blood (BCd) and evaluated the reference level of cadmium for hypertension using benchmark dose (BMD) approach. A total of 441 subjects were included in this study. Blood samples were collected from each individual for BCd determination. Blood pressure was measured by electronic sphygmomanometer. BMD and BMDL were calculated using BMD software corresponding to additional risk of 10%. The systolic blood pressure (SBP), diastolic blood pressure (DBP) and prevalence of hypertension increased with the increasing of BCd, especially for SBP (χ(2)=3.9, p=0.047 in men; χ(2)=4.3, p=0.037 in women). With a benchmark response of 10%, the BMDL10 for hypertension (high SBP) was 0.95µg/L and 1.02µg/L for women and men, respectively; the BMDL10 for hypertension (high DBP) was 1.8µg/L and 1.66µg/L for women and men, respectively. Our data evidenced that BCd was associated with elevation in blood pressure and hypertension, especially for women. The reference level of cadmium for hypertension with high SBP was lower than that of high DBP.

Effects of lead and cadmium co-exposure on bone mineral density in a Chinese population.

It has been indicated that both cadmium (Cd) and lead (Pb) may have adverse effects on the bone. However, most studies have only focused on a single factor. The primary and main and interactive effects of Cd and Pb on bone mineral density (BMD) in a Chinese population were observed in this study. A total of 321 individuals (202 women and 119 men), aged 27 years and older, living in control and polluted areas, were recruited to participate in this study. The BMD was measured through dual energy X-ray absorptiometry (DXA) at the proximal radius and ulna. The samples of urine and blood were collected to determine the levels of Cd and Pb in the urine (UCd and UPb) and blood (BCd and BPb). The Cd and Pb levels of people living in the polluted area were significantly higher than those living in the control area (p<0.05). The BMD of women living in polluted area was significantly lower than that of women living in the control area (p<0.05). Furthermore, the BMD decreased with increasing of BCd (p<0.05), BPb and UPb in women. The likelihood of low BMD was associated with higher BCd in women (OR=2.5, 95% CI: 1.11-5.43) and BPb in men (OR=4.49, 95% CI: 1.37-14.6). The relative extra risk index of low BMD for female and male subjects with both high levels of BCd and BPb was 0.45 and 1.16, respectively. This study strengthens previous evidence that cadmium and lead may influence the bone and also demonstrates that cadmium and lead may have interactive effects on BMD.

Lead concentration in plasma as a biomarker of exposure and risk, and modification of toxicity by δ-aminolevulinic acid dehydratase gene polymorphism.

UNLABELLED: Blood lead concentration (B-Pb), the main biomarker of lead exposure and risk, is curvi-linearily related to exposure. We assessed plasma lead (P-Pb) as a marker for both lead exposure and toxic effects. We examined claims that δ-aminolevulinic acid dehydratase genotype (ALAD) can modify lead toxicity. In 290 lead-exposed and 91 unexposed Chinese workers, we determined P-Pb, B-Pb, urinary lead (U-Pb), ALAD polymorphism (rs1800435, ALAD1/2; TaqMan assay), and also toxic effects on heme synthesis (blood zinc protoporphyrin and hemoglobin, urinary δ-aminolevulic acid), on the kidneys (urinary albumin, ß2-microglobulin and N-acetyl-ß-d-glucosaminidase) and on the peripheral nervous system (sensory and motor conduction velocities). In exposed workers, median P-Pb was 4.10 (range 0.35-27)µg/L, B-Pb 401 (110-950)µg/L, and U-Pb 188 (22-590)µg/g creatinine. P-Pb had a higher ratio between exposed and unexposed workers (median 39, range 18-110) than B-Pb (19, 15-36; p<0.001) and U-Pb (28, 15-36; p<0.001). All three biomarkers were associated with all toxic effects (P-Pb: rS=-0.10 to 0.79; B-Pb: rS=-0.08 to 0.75; all p<0.05). In the exposed workers, B-Pb and U-Pb were significantly higher (p=0.04) in ALAD2 carriers (7% in the exposed population) than in ALAD1 homozygotes. P-Pb values were similar; ALAD1 homozygotes suffered higher kidney toxicity at the same P-Pb. CONCLUSIONS: (i) P-Pb has advantages over B-Pb as a biomarker of high Pb exposure, but it was not significantly better as an index of risk of toxicity. (ii) The ALAD genotype modifies toxicokinetics and toxicodynamics.

Renal function after reduction in cadmium exposure: an 8-year follow-up of residents in cadmium-polluted areas.

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-ß-d-glucosaminidase (NAG), ß2-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 ß2-microglobulin among young individuals. The probability of having ß2-microglobulin levels above the 95th percentile in 2006 was high in those with elevated ß2-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 ß2-microglobulin may be more informative than NAG as an indicator for an individual's future tubular function.

Kidney dysfunction and cadmium exposure--factors influencing dose-response relationships.

Our early toxicological studies showed that metallothionein (MT) is a protein that carries cadmium (Cd) to the kidney, explaining why Cd exposures during long time periods may give rise to kidney dysfunction. This dysfunction is usually considered to be the critical effect, i.e. the adverse effect that occurs at the lowest exposure level. MT also provides intracellular protection against cadmium toxicity. In studies of population groups in cadmium contaminated areas in China, we investigated factors that affected the relationship between internal dose of Cd, as indicated by blood Cd (BCd) or urinary Cd (UCd), and the prevalence of kidney dysfunction. We found dose-response relationships between UCd and the prevalence of increased levels of biomarkers of renal tubular dysfunction (urinary beta-2-microglobulin, B2M, or N-acetyl-beta-d-glucosaminidase - NAG) or urinary albumin (UAlb), a biomarker of glomerular kidney dysfunction. Two years after Cd intake from contaminated rice was diminished, renal tubular dysfunction appeared unchanged or aggravated among those with higher UCd; Another 8 years later, i.e. 10 years after Cd intake was decreased, the prevalence of renal tubular dysfunction was still increased but UAlb had returned to normal. Factors that influenced the dose-response relationships were: (1) time after maximum exposure. (2) Concomitant exposure to other nephrotoxic agents such as inorganic arsenic. (3) Cd induced metallothionein mRNA levels in peripheral blood lymphocytes, used as a biomarker of the ability of each person, to synthesize MT. (4) The occurrence of increased levels in blood plasma of autoantibodies against MT. The two last points further support a role in humans of MT as a protective protein against tissue damage from cadmium and gives support to previous ideas developed partly in experimental systems.

Bone mineral density is related with previous renal dysfunction caused by cadmium exposure.

Relationship between bone mineral density (BMD) and previous renal dysfunction caused by cadmium exposure was investigated. A total of 457 persons, living in polluted and control areas, were followed up in this study. The inhabitants living in exposure areas ceased ingesting cadmium-contaminated rice in 1996. Blood and urinary cadmium levels and BMD in 1998 and 2006 were measured. Urinary N-acetyl-ß-d-glucosaminidase and albumin determined in 1998 and 2006 were used to evaluate kidney status. BMD of subjects with tubular damage was significant lower than those without damage in female (p < 0.05). The prevalence of osteoporosis was significantly different between those with and without kidney damage (p = 0.003, in total population; p = 0.039, in female) and those with and without tubular damage (p = 0.0005, in total population; p = 0.007, in female). The results suggested that BMD was correlated with previous kidney impairment caused by cadmium exposure, especially to tubular damage and especially for female.

δ-Aminolevulinic acid dehydratase genotype predicts toxic effects of lead on workers' peripheral nervous system.

There is a wide variation in sensitivity to lead (Pb) exposure, which may be due to genetic susceptibility towards Pb. We investigated whether a polymorphism (rs1800435) in the δ-aminolevulinic acid dehydratase (ALAD) gene affected the toxicokinetics and toxicodynamics of Pb. Among 461 Chinese Pb-exposed storage battery and 175 unexposed workers, allele frequencies for the ALAD1 and ALAD2 alleles were 0.968 and 0.032, respectively. The Pb-exposed workers had a higher fraction of the ALAD1-2/2-2 genotype than unexposed workers (7.8% vs. 2.3%, p=0.01). The Pb levels in blood (B-Pb) and urine (U-Pb) were higher in Pb-exposed workers carrying the ALAD2 allele compared to homozygotes for ALAD1 (median B-Pb: 606 vs. 499 µg/L; U-Pb: 233 vs. 164 µg/g creatinine), while there was no statistically significant difference in the unexposed controls (median: 24 vs. 37 µg/L, and 3.9 vs. 6.4µg/g creatinine, respectively). High B-Pb and U-Pb were associated with statistically significantly lower sensory and motor conduction velocities in the median, ulnar and peroneal nerves. At the same B-Pb and U-Pb, ALAD1 homozygotes had lower conduction velocities than the ALAD2 carriers. There were similar trends for toxic effects on haem synthesis (zinc protoporphyrin and haemoglobin in blood) and renal function (albumin and N-acetyl-d-ß-acetylglucosaminidase in urine), but without statistical significance. There was no difference in Pb toxicokinetics and toxicodynamics associated with VDR BsmI polymorphism. Our results show that the ALAD genotype modifies the relationship between Pb and its toxic effects on the peripheral nervous system. This must be considered in the assessment of risks at Pb exposure.

Increased hepatic and decreased urinary metallothionein in rats after cessation of oral cadmium exposure.

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.