Effects of chronic exposure to low-level cadmium on renal tubular function and CYP2A6-mediated coumarin metabolism in healthy human subjects

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

Significance of cadmium concentrations in blood and hair as an indicator of dose 15 years after the reduction of environmental exposure to cadmium

To evaluate the significance of cadmium (Cd) concentrations in blood (B-Cd) and hair (H-Cd) as an indicator of dose, a cross-sectional study was performed on 40 residents in a Cd-polluted area, Nagasaki Prefecture, Japan, in 1996. In the study area, soil replacement of Cd-polluted rice fields ended in 1981. B-Cd and H-Cd were significantly higher in the study population than in the control subjects. B-Cd was positively correlated with urinary Cd (U-Cd) (Spearman r=0.50, P=0.06 for males and r=0.72, P=0.0001 for females), while H-Cd was weakly or moderately correlated with U-Cd. After adjustment for gender using logistic regression analysis, log(B-Cd) and log(U-Cd), but not log(H-Cd), were significantly associated with the prevalence of increased urinary beta2-microglobulin (P for trend <0.05). These findings suggest that B-Cd is a good indicator of cumulative dose many years after the reduction of environmental exposure to Cd. H-Cd may be weakly or moderately correlated with body burden.     

Burden of cadmium in early childhood: Longitudinal assessment of urinary cadmium in rural Bangladesh

Chronic cadmium exposure is associated with many adverse health effects in adults, but little is known about the scenario early in life. This study assessed cadmium exposure and body burden in young children, born to women with known cadmium exposure via rice. As part of our ongoing population-based, longitudinal study of health effects of early-life toxicants exposure in rural Bangladesh, we measured cadmium in urine of about 350 children at 1.5 and 5 years of age, and in 92 children at 3 months of age. Median cadmium concentrations in urine were 0.30, 0.16 and 0.30 μg/L at 3 months, 1.5 and 5 years of age, respectively (0.6 μg/L in mothers). Cadmium concentrations in infant's urine correlated with concentrations in maternal breast milk, saliva, and urine. As expected, concentrations in urine increased from 1.5 to 5 years of age. Rice (median 47 μg Cd/kg) is most likely the main source of exposure. In conclusion, we found unexpectedly high cadmium exposure among children in rural Bangladesh. Urinary cadmium concentrations were particularly elevated at 3 months of age, indicating limited reabsorption and accumulation of cadmium in the kidneys, known to be the main site of cadmium burden in older children and adults.     

The relationship between itai-itai disease among inhabitants of the Jinzu River basin and cadmium in rice

Women over 50 years of age in 32 cadmium(Cd)-polluted and 16 nonpolluted hamlets were studied. Itai-itai disease patients and proteinuria with glucosuria were used as indices of the effect of Cd on health. Unpolished rice samples were collected from 568 households in the same area and analyzed for Cd. The hamlet's average Cd concentration in rice was used as an index of Cd exposure. A close relationship between Cd exposure and health effects was found to exist when the women were classified according to their hamlet average rice-Cd concentrations. It is demonstrated that a dose-response relationship between Cd exposure and itai-itai disease exists.     

Comprehensive study of the effects of age, iron deficiency, diabetes mellitus, and cadmium burden on dietary cadmium absorption in cadmium-exposed female Japanese farmers

The absorption rate of dietary cadmium (Cd) was investigated among 38 female farmers who had been exposed to Cd at levels close to the current provisional tolerable weekly intake (PTWI); these levels were much higher than those examined in previous studies. The study group composed of 7 diabetics and their 13 age-matched controls and 6 anemic subjects and their 12 controls. With their informed consent, the study participants were confined in an inn for 7 nights and 8 days to collect all feces and urine and duplicates of all food consumed. The dietary Cd absorption rate was calculated for each subject from her total Cd intake and fecal excretion. The means and 95% confidence intervals (CI) of the diabetic group and the anemic group did not differ significantly from those of their respective controls. By individual analysis using all 38 subjects, however, significant Pearson's correlation coefficients were observed between Cd absorption rate and age, serum ferritin, serum iron, and blood and urine Cd levels. Among these, multiple regression analysis revealed that only age was a significant factor contributing to Cd absorption rate. The actual Cd absorption rate in the youngest age group (20-39 years) was 44.0%, which was highly accelerated compared with the rate in the total subject group of 6.5%, while zero to negative balance was observed in the older subjects. These results demonstrate that age, rather than iron deficiency, diabetes mellitus (DM), or Cd burden, is the only independent factor affecting the Cd absorption rate, suggesting that young women are always at high risk.     

Cadmium in blood and urine among smokers and non-smokers with high cadmium intake via food

In New Zealand a species of oyster (Ostrea lutaria) consumed widely contains on an average 5 micrograms Cd/g wet weight. In this study we have investigated the cadmium intake, and blood and urinary cadmium levels in a group of 78 people with a known high oyster consumption. A second group of 17 non-smoking men and women who did not eat oysters were used as a control group. Each subject was interviewed and information on smoking habits, diet, medical and occupational history was obtained. The results show that in spite of a very high intake of cadmium via oysters the concentration of the toxic metal in whole blood and urine was not elevated greatly in proportion to the intake. It is clearly demonstrated that cigarette smoking had a more pronounced and significant effect on whole blood cadmium levels than the intake of cadmium via oysters.     

Electrothermal atomic absorption spectrometric determination of cadmium and nickel in urine

This paper describes two relatively simple methods for the microdetermination of urinary cadmium (U-Cd) and urinary nickel (U-Ni) using electrothermal atomic absorption spectrometry. Reduction of nonspecific absorption interferences was achieved by temperature programming and background correction using a deuterium arc lamp. Within-run CVs were less than 5% for both U-Cd and U-Ni. Day-to-day variation was less than 8.1% for U-Cd and less than 8.0% for U-Ni. The typical limit for detection was 0.08 micrograms/L for U-Cd and 0.1 micrograms/L for U-Ni. The methods described are useful for mass screening of low level exposure to Cd or Ni.     

Current status of cadmium as an environmental health problem

Cadmium is a toxic metal occurring in the environment naturally and as a pollutant emanating from industrial and agricultural sources. Food is the main source of cadmium intake in the non-smoking population. The bioavailability, retention and toxicity are affected by several factors including nutritional status such as low iron status. Cadmium is efficiently retained in the kidney (half-time 10-30 years) and the concentration is proportional to that in urine (U-Cd). Cadmium is nephrotoxic, initially causing kidney tubular damage. Cadmium can also cause bone damage, either via a direct effect on bone tissue or indirectly as a result of renal dysfunction. After prolonged and/or high exposure the tubular injury may progress to glomerular damage with decreased glomerular filtration rate, and eventually to renal failure. Furthermore, recent data also suggest increased cancer risks and increased mortality in environmentally exposed populations. Dose-response assessment using a variety of early markers of kidney damage has identified U-Cd points of departure for early kidney effects between 0.5 and 3 μg Cd/g creatinine, similar to the points of departure for effects on bone. It can be anticipated that a considerable proportion of the non-smoking adult population has urinary cadmium concentrations of 0.5 μg/g creatinine or higher in non-exposed areas. For smokers this proportion is considerably higher. This implies no margin of safety between the point of departure and the exposure levels in the general population. Therefore, measures should be put in place to reduce exposure to a minimum, and the tolerably daily intake should be set in accordance with recent findings.     

Influence of body iron store status and cigarette smoking on cadmium body burden of healthy Thai women and men

The influence of cigarette smoking, body iron store status and gender on cadmium (Cd) body burden was examined in a group of 197 healthy Thais with overall mean age of 30.5 year (19-47 year). The lowest, geometric mean, and the highest urinary Cd excretion rate was 0.04, 0.46 and 3.84 microg/g creatinine, respectively. The prevalence of low iron stores (serum ferritin <20 microg/l) was 16% and 2% in women and men, respectively. All women (n = 99) were non-smokers, but they had the same Cd body burden as did men (n = 47) who on average smoked 8.7 cigarettes per day for 9 years. These women and men had 1.9-fold greater body Cd burden than did non-smoking men (t = 4, P < 0.001). In addition, the women Cd body burden was found to be inversely correlated with serum ferritin (r = -0.39, P < 0.001) and those with low iron stores showed a 3.4-fold greater Cd body burden than did women whose serum ferritin being between 101 and 200 microg/l (F = 6.2, P = 0.003, one-way ANOVA). In contrast, men's Cd body burden did not show a significant correlation with serum ferritin, but it did show a positive correlation with cumulative cigarette smoking index (r = 0.29, P = 0.02). Thus, iron status and cigarette smoking were found to be determinants of Cd body burden in young adult Thai women and men.     

Evaluation of urinary cadmium and lead as markers of background exposure of middle-aged women in Korea: dietary intake as an influential factor.

The study was conducted to examine the validity of urinary cadmium (Cd) and lead (Pb) in comparison with the metals in blood as a biological marker of non-occupational exposure of general populations. Participants in four survey sites in Korea (107 non-smoking Korean women aged 30-49 years) offered peripheral blood, morning spot urine, and 24-h total food duplicate samples. Analysis of Cd and Pb was accomplished by graphite furnace atomic absorption spectrophotometry. The analyse levels were evaluated on an individual basis (n = 107) and also on a survey site basis, i.e. in terms of geometric means for the groups in the survey sites (n = 4). Cd in urine (as observed, or after correction for creatinine concentration or a specific gravity) correlated with Cd in blood on an individual as well as survey site basis, and tended to correlate with Cd in food duplicates on the survey site basis. Correlation of Pb in urine with Pb in blood was weaker than that of Cd in urine with Cd in blood both on the individual and survey site basis. Pb in urine correlated with Pb in food duplicates either weakly or even negatively when examined on a survey site basis. It was concluded that Cd in urine can be most probably employed as a biological marker of environmental Cd exposure of general population, whereas less support was obtained for Pb in urine as an exposure marker.     

Background exposure to toxic metals in women adversely influences pregnancy during in vitro fertilization (IVF)

Low-level environmental exposure to Hg, Pb and Cd may interfere with pregnancy during in vitro fertilization (IVF). The aim of this study was to generate hypotheses concerning associations between background exposures and pregnancy. In modified Poisson regression models including 24 women and adjusted for urine Cd and creatinine, blood Pb, age, race and smoking, 1μg/L increases in blood Hg are associated with decreases of 35% (P=0.03) and 33% (P=0.01) in clinical and biochemical pregnancies, respectively. In alternate Poisson models including 26 women and adjusted for blood Pb, blood Hg, age, race and smoking, 1μg/L increases in blood Cd are associated with decreases of 94% (P=0.01) and 82% (P=0.04) in clinical and biochemical pregnancies, respectively. No effects are detected in 15 men, although inverse associations are suggested for urine cadmium and pregnancy. These data suggest that low-level, background exposures to Hg and Cd may interfere with pregnancy following IVF.     

All‐cause mortality increased by environmental cadmium exposure in the Japanese general population in cadmium non‐polluted areas

The aim of the present study was to evaluate the effect of environmental cadmium (Cd) exposure indicated by urinary Cd on all‐cause mortality in the Japanese general population. A 19‐year cohort study was conducted in 1067 men and 1590 women aged 50 years or older who lived in three cadmium non‐polluted areas in Japan. The subjects were divided into four quartiles based on creatinine adjusted U‐Cd (µg g^?1 cre). The hazard ratio (HR) and 95% confidence interval (CI) for continuous U‐Cd or the quartiles of U‐Cd were estimated for all‐cause mortality using a proportional hazards regression.The all‐cause mortality rates per 1000 person years were 31.2 and 15.1 in men and women, respectively. Continuous U‐Cd (+1 µg g^?1 cre) was significantly related to the all‐cause mortality in men (HR 1.05, 95% CI: 1.02–1.09) and women (HR 1.04, 95% CI: 1.01–1.07). Furthermore in men, the third (1.96–3.22 µg g^?1 cre) and fourth quartile (≥3.23 µg g^?1 cre) of U‐Cd showed a significant, positive HR (third: HR 1.35, 95% CI: 1.03–1.77, fourth: HR 1.64, 95% CI: 1.26–2.14) for all‐cause mortality compared with the first quartile (<1.14 µg g^?1 cre). In women, the fourth quartile of U‐Cd (≥4.66 µg g^?1 cre) also showed a significant HR (1.49, 95% CI 1.11–2.00) for all‐cause mortality compared with the first quartile (<1.46 µg g^?1 cre).In the present study, U‐Cd was significantly associated with increased mortality in the Japanese general population, indicating that environmental Cd exposure adversely affects the life prognosis in Cd non‐polluted areas in Japan. Copyright © 2014 John Wiley & Sons, Ltd.     

Relationship between mortality and rice cadmium concentration in inhabitants of the polluted Jinzu River basin,Toyama, Japan: A 26 year follow‐up

The aim of this study was to investigate the relationship between mortality and rice cadmium (Cd) concentration in inhabitants of a polluted area in Japan. The target subjects were inhabitants of the Jinzu River basin who participated in health examinations for screening of renal dysfunction from 1979 to 1984. The mean rice Cd concentration in each hamlet was used as an index of the Cd exposure. We conducted a 26 year follow‐up survey in 3281 inhabitants (1544 men and 1737 women) whose data regarding the rice Cd concentration were available. Mortality risk ratios for all and specific causes were estimated after adjustments for age at baseline, smoking status and history of hypertension using a Cox hazard model or Fine and Gray competing risks regression model. The mortality risk ratios of rice Cd concentration (+0.1 ppm) for all causes in women were significantly increased (risk ratio: 1.04). Furthermore, the relative risks of rice Cd concentration for kidney and urinary tract disease, renal diseases, renal failure and toxic effects of cadmium were significantly increased in both sexes. These findings indicated that increased rice Cd concentration decreased the prognosis for life over a long‐term observation in women. This result provides important information for determining the worldwide standard for allowable rice Cd concentration.     

Estimation of benchmark doses as threshold levels of urinary cadmium, based on excretion of beta2-microglobulin in cadmium-polluted and non-polluted regions in Japan

The threshold level of urinary cadmium (Cd) for beta2-microglobulin (MG)-uria was calculated using a benchmark dose (BMD) approach. Total number of subjects was 3103 for Cd-polluted areas and 2929 for non-polluted areas. Multiple logistic regression analysis was employed to fit the dose-response model taking into consideration an age effect. Cut-off values for urinary beta2-MG were defined as those corresponding to the 84th and 97.5th percentile of beta2-MG levels in the controls, and 1000 microg/g creatinine (cr). The BMD low (BMDL) was calculated using the profile likelihood method. When the benchmark response was 5%, the BMD/BMDL of Cd for the 84th percentile of beta2-MG for mean age, 55, 65, and 75 years was 3.0/2.7, 4.6/4.2, 2.8/2.6, and 1.8/1.6 microg/g cr in men and 3.4/3.2, 5.8/5.5, 3.2/3.1, and 1.8/1.7 microg/g cr in women, respectively. The value for the 97.5th percentile for each age was 4.9/4.5, 7.6/7.0, 4.6/4.3, and 2.6/2.4 microg/g cr in men and 5.9/5.6, 9.7/9.2, 5.6/5.3, and 2.8/2.6 microg/g cr in women. Namely it became clear that the margin between the threshold level and average excretion level of urinary Cd was small in the older population in Japan. To prevent the adverse health effects caused by exposure to Cd, it is important to establish the threshold level of Cd exposure at each age.     

Sister-chromatid exchanges in the lymphocytes of people exposed to environmental cadmium

Sister-chromatid exchanges (SCEs) were analyzed from peripheral lymphocyte cultures of 8 men and 16 women who had been exposed to environmental cadmium (Cd), and 6 controls. Average Cd concentrations in blood of the Cd-polluted group were 8.9 micrograms/l for men and 10.0 micrograms/l for women. These were no significant differences in SCE rates between the Cd-polluted and nonpolluted groups. There were no significant correlations between SCE rates and blood or urinary Cd concentrations. Cadmium alone may be an insignificant agent in producing chromosomal damage to peripheral blood lymphocytes.     

Estimation of benchmark dose for renal dysfunction in a cadmium non-polluted area in Japan

Previously, the association between urinary cadmium (Cd) concentration and indicators of renal dysfunction, including beta(2)-microglobulin (beta(2)-MG), total protein and N-acetyl-beta-D-glucosaminidase (NAG) were investigated in 1270 inhabitants > or = 50 years of age (547 men, 723 women) in a Cd non-polluted area in Japan and showed that a dose-response relationship existed between renal effects and Cd exposure in the general environment without any known Cd pollution. However, the threshold levels of urinary Cd could not be estimated at that time. In the present study, the threshold levels of urinary Cd were estimated as the benchmark dose low (BMDL) using the benchmark dose (BMD) approach. Urinary Cd excretion was divided into 6-7 categories, and an abnormality rate was calculated for each. Cut-off values for urinary substances were defined as corresponding to the 84% upper limit values, which were calculated from 2034 persons who had been living in the non-polluted areas and did not smoke. Then the BMD and BMDL were calculated using a log-logistic model. The values of BMD and BMDL for all urinary substances could be calculated. The BMDL for the 84% cut-off value of beta(2)-MG, setting an abnormal value at 5%, was 2.0 microg g(-1) creatinine (cr) in men and 1.6 microg g(-1) cr in women. In conclusion, the present study demonstrated that the threshold level of urinary Cd could be estimated in people living in the general environment without any known Cd-pollution in Japan, and the value was inferred to be almost the same as that in Belgium and Sweden.     

The reference dose for subchronic exposure of pigs to cadmium leading to early renal damage by benchmark dose method

Pigs were exposed to cadmium (Cd) (in the form of CdCl(2)) concentrations ranging from 0 to 32mg Cd/kg feed for 100 days. Urinary cadmium (U-Cd) and blood cadmium (B-Cd) levels were determined as indicators of Cd exposure. Urinary levels of β(2)-microglobulin (β(2)-MG), α(1)-microglobulin (α(1)-MG), N-acetyl-β-D-glucosaminidase (NAG), cadmium-metallothionein (Cd-MT), and retinol binding protein (RBP) were determined as biomarkers of tubular dysfunction. U-Cd concentrations were increased linearly with time and dose, whereas B-Cd reached two peaks at 40 days and 100 days in the group exposed to 32mg Cd/kg. Hyper-metallothionein-urinary (HyperMTuria) and hyper-N-acetyl-β-D-glucosaminidase-urinary (hyperNAGuria) emerged from 80 days onwards in the group exposed to 32mg Cd/kg feed, followed by hyper-β2-microglobulin-urinary (hyperβ2-MGuria) and hyper-retinol-binding-protein-urinary (hyperRBPuria) from 100 days onwards. The relationships between the Cd exposure dose and biomarkers of exposure (as well as the biomarkers of effect) were examined, and significant correlations were found between them (except for α(1)-MG). Dose-response relationships between Cd exposure dose and biomarkers of tubular dysfunction were studied. The critical concentration of Cd exposure dose was calculated by the benchmark dose (BMD) method. The BMD(10)/BMDL(10) was estimated to be 1.34/0.67, 1.21/0.88, 2.75/1.00, and 3.73/3.08mg Cd/kg feed based on urinary RBP, NAG, Cd-MT, and β(2)-MG, respectively. The calculated tolerable weekly intake of Cd for humans was 1.4 μg/kg body weight based on a safety factor of 100. This value is lower than the currently available values set by several different countries. This indicates a need for further studies on the effects of Cd and a re-evaluation of the human health risk assessment for the metal.     

Co-exposure of cadmium and lead on bone health in a southwestern Chinese population aged 40-75 years

Both cadmium (Cd) and lead (Pb) are associated with bone health, but studies exploring the effects of Cd and Pb co-exposure on bone health are rare. This study aimed to assess the interactive effects of Cd and Pb co-exposure on bone health. In total, 799 participants, living in the targeted areas (located in southwestern China) for more than 15 years, aged 40-75 years, and subsisted on homegrown rice and vegetables were investigated. Cd and Pb levels in urine and blood samples, as well as bone mineral density, T- and Z-score were determined. After being adjusted for covariates, the T-score was negatively correlated with blood Pb in men (P < .05); for women and non-smoking women, the T-score was negatively correlated with urinary Pb (P < .05). Moreover, after being adjusted for covariates, the Z-score was negatively correlated with urinary Pb in non-smoking women (P < .05). No positive association of prevalence of osteoporosis with Cd and Pb exposure was found. However, at an additive scale, positive interactions of urinary Cd and Pb on the prevalence of osteoporosis for women and non-smoking women, and the same interactions to blood Cd and Pb for men were found. There was also a positive interaction of urinary Cd and Pb for women at a multiplicative scale. This study suggests Cd and Pb exposure could exert detrimental effects on bone health, with possible underlying interactions. Nevertheless, more studies are needed to explore the interactive effects of heavy metal co-exposure.     

Effects of aging on cadmium concentrations and renal dysfunction in inhabitants in cadmium‐polluted regions in Japan

The absorption of cadmium (Cd) may lead to Cd‐related diseases such as renal tubular dysfunction and bone disease, and it is known to take around 10–30 years to reduce Cd concentrations to half their original levels. Urinary β₂‐microglobulin (β₂‐MG), N‐acetyl‐β‐D‐glucosaminidase (NAG), protein, glucose and albumin were used as indicators of renal dysfunction caused by Cd exposure. Our previous study found that urinary Cd concentrations had increased recently and that age was more strongly associated with urinary β₂‐MG concentration than recent Cd body burden. Therefore, the purpose of the present study was to investigate the effect of aging on Cd concentrations and renal dysfunction. The Cd, β₂‐MG, NAG, protein, glucose and albumin concentrations in the urine of 40 Japanese subjects (20 females and 20 males) environmentally exposed to Cd were collected. They lived in the Kakehashi River basin and were divided into three age categories: 50–69, 70–79 and 80–99 years. Significant differences in urinary Cd and β₂‐MG concentrations were found among age groups, with urinary Cd levels tending to increase with age in both sexes. No significant correlations were found between urinary Cd and any indicators of renal dysfunction. The correlation between age, Cd and indicators of renal dysfunction was observed more clearly in females than in males. Age is more strongly correlated with indicators of renal dysfunction than Cd body burden. Copyright © 2017 John Wiley & Sons, Ltd.     

Dose-response relationship between total cadmium intake calculated from the cadmium concentration in rice collected from each household of farmers and renal dysfunction in inhabitants of the Jinzu River basin,Japan

The association between total cadmium (Cd) intake and abnormal urinary findings was investigated in the Cd-polluted Jinzu River basin. In 1967 and 1968 the most systematic and large-scale health examinations were conducted among the entire population aged over 30 years of this region. We performed this study by targeting the subjects participating in the 1967 health survey conducted mainly in the heavily polluted area. From subjects who had eaten household rice of known Cd concentration, 1,075 inhabitants who had either resided in their current household since birth or who had moved there from a non-polluted area (group A), and 780 inhabitants who had resided in the current household since birth (group B), were selected as the target population. The total Cd intake for each person was calculated from the Cd dose ingested from rice and other foods. Logistic regression analysis was performed using the prevalence of abnormal urinary findings (proteinuria, glucosuria and proteinuria with glucosuria) as the criterion variable and the total Cd intake and age as explanatory variables. In subjects of groups A and B the odds ratios became higher as the dose of total Cd intake increased. Odds ratios in subjects of group A were statistically significant except for glucosuria of men and proteinuria of women. In subjects of group B the odds ratios were also significant for proteinuria + glucosuria of men and glucosuria of women. It was demonstrated that the greater the increase in total Cd intake, the greater the increase in abnormal urinary findings in the Jinzu River basin, and the association of the two factors was very close.