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Background and Aim: Cadmium (Cd) is an ubiquitous environmental toxic pollutant. As daily foods are an almost exclusive source of exposure for general populations, it is of public health importance to know the level of dietary intake of cadmium (Cd-D). The purpose of this study is to examine whether Cd in blood (Cd-B) or urine (Cd-U) correlates with Cd-D in East Asia, and in case it is, whether it is possible to estimate Cd-D from Cd-B or Cd-U. It should be added that the measurement of Cd-D is quite hand-consuming in practice., Materials and Methods: Literature was retrieved for publication on Cd-B and Cd-U in combination with Cd-D. Twenty three data sets thus obtained for East Asia were subjected to regression analysis to investigate the possibility to estimate Cd-D from Cd-B or Cd-U., Results: In Japan and Korea, large correlation coefficients (p > 0.7) were observed between Cd-B and Cd-D, as well as between Cd-U and Cd-D. In China, the coefficient was >0.7 between Cd-B and Cd-D. Furthermore, correlation was significant for Cd-B and Cd-D, as well as Cd-U and Cd-D, when 19 sets for Japan, Korea and China were combined for analysis., Discussion: Major reasons for successful analysis may be predominant use of women-based data. Women have been less smoking than men in East Asia, and possible confounding effects of smoking on Cd exposure might be minimized., Conclusion: Based on significant correlations, Cd-D can be estimated from Cd-B or Cd-U in East Asia., (Copyright © 2018 Elsevier GmbH. All rights reserved.)

Objectives: The aim of this study was to elucidate past and current levels of cadmium (Cd) intake among the general populations in Korea., Methods: For this purpose, publications reporting dietary intake of cadmium (Cd-D), cadmium concentration in blood (Cd-B) and that in urine (Cd-U) in Korea were retrieved through literature survey for a period from 1975 to 2015., Results: In practice, 9, 21 and 14 articles were available on Cd-D, Cd-B and Cd-Ucr (Cd-U as corrected for creatinine concentration), respectively. Linear regression analyses of the reported values as a function of years (i.e., the year when each survey was conducted) showed steady decreases in all of the three exposure markers of Cd-D, Cd-B and Cd-U(cr). Factors possibly contributing for the reduction were discussed including the government-set guideline of 0.2 mg/kg for rice and changes in food habits among general populations., Conclusions: There have been steady decreases in Cd-D, Cd-B and Cd-U(cr). The current estimates for Cd-D, Cd-B and Cd-Ucr were 6.0-7.4 μg/day, 0.73-0.83 μg/L and 0.60-0.95 μg/g cr, respectively.

Objectives: It would be quite convenient if daily dietary cadmium intake (Cd-D) can be estimated either from Cd in blood (Cd-B) or from Cd in urine (Cd-U). The aim of the study was to examine if Cd-D can be estimated from Cd-B or Cd-U., Methods: The data available in a previous publication were employed for regression analyses between Cd-D and Cd-B, and between Cd-D and Cd-U. 30 sites in various prefectures throughout Japan were surveyed and 20 adult women/site on average provided food duplicate, peripheral blood, and second morning urine samples. Geometric means were taken as representative values and employed in regression analyses., Results: Cd-D, Cd-B, and Cd-U(cr) [i.e., Cd-U after correction for creatinine (cr) concentration] distributed in ranges of 12.5-70.5 μg/day, 0.46-3.98 μg/l, and 1.16-11.02 μg/g cr, respectively. A close correlation was observed between Cd-D and Cd-B, and also between Cd-D and Cd-U(cr) with r = 0.76 and r = 0.79 (p < 0.001 for both), respectively. Both regression lines passed close to the origins. Application of 1.23 μg Cd/l blood and 1.26 μg Cd/g cr in urine (average levels for adult Japanese women) to the regression equations gave 16.5 and 11.5 μg Cd/day., Conclusions: The analyses suggested that it may be possible to estimate Cd-D from Cd-B or Cd-U. Cd-B-based estimation should be more respected. As variations in the estimation parameters and estimated values are inherent to field surveys, care should be taken in the application of the study results. Application on a group basis (and not on an individual basis) should be considered.

Objectives: This study was initiated to elucidate the extent of dietary exposure of children in Korea to two pollutant metals of cadmium (Cd) and lead (Pb). Possible urban-rural difference was also examined., Methods: Food duplicate and morning spot urine samples were collected from 108 children in 4 kindergartens (KG) (1 KG in Seoul and 3 KGs in Jeju Island), as reported in a previous publication. The samples were analyzed for Cd and Pb by ICP-MS., Results: Cd and Pb in food duplicate and urine samples were distributed approximately log-normally. Geometric means for Cd and Pb in food duplicate samples were 12.4 and 5.8 μg/day, or 0.58 and 0.27 μg/kg body weight/day, respectively, and the values for Cd and Pb in urine (as observed, i.e., with no correction for urine density) were 0.91 and 1.64 μg/L, respectively. 2.41 and 0.30 μg/day of Cd and Pb (accounting for 19.5 and 5.1%) came from boiled rice, the staple food. The levels of Cd and Pb burden among the children in the present survey were essentially the same with the levels reported for children in Pusan. The reasons for difference in the rank in Cd-D and Cd-U among the 4 KGs need further study., Conclusions: The observed levels of Cd and Pb exposure were more or less similar to what were reported for children in Pusan. No apparent urban-rural difference could be detected.

This survey was initiated to examine possible coastal-inland differences in cadmium (Cd) burden in general Korean populations. In total, 268 healthy non-smoking middle-aged women (30 to 49 years; 88 residents in 8 coastal areas and 180 residents in 15 inland areas) participated in the study. They offered peripheral blood and spot urine samples so that cadmium in blood (Cd-B) and urine (Cd-U) were taken as exposure markers. Determination of Cd-B and Cd-U was carried out by graphite furnace atomic absorption spectrophotometry. With regard to Cd burden, geometric means for the coastal and inland residents were 1.70 and 1.72 μg/L for Cd-B, 1.54 and 1.00 μg/L for Cd-U as observed (Cd-U), 2.59 and 1.81 μg/g creatinine for Cd-U as corrected for creatinine (Cd-Ucr), respectively. Cd-U and Cd-Ucr were higher in the coastal areas than in inland areas. Reasons for higher Cd-U in the coastal areas than in the inland areas were are discussed in relation to major sources of Cd in daily life of the residents. Attention was paid to consumption of fish and shellfish in the coastal areas as major sources of dietary Cd intake. This study shows that Cd burdens were higher in coastal areas than in inland areas in Korea.

Background: Cadmium (Cd) is a wide-spread environmental pollutant with insidious toxicity to kidneys, and children are considered to be a high-risk group. Lead (Pb) is suspected to induce retardation in mental development in children. Daily foods are an important source of both Cd and Pb exposure for general population. Nevertheless, data on dietary exposure of children to Cd and Pb are still scarce in Japan., Objectives: This study was initiated to clarify the extent of exposure of children to Cd. Exposure to Pb, another environmental pollutant element, was also studied in combination., Methods: Twenty-four-hour food duplicates and the first morning urine samples were collected from 296 children (159 boys and 137 girls at the ages of 3-6 years) in 15 kindergartens in Miyagi prefecture on the Pacific coast in north-east Japan; no environmental pollution with Cd has been known in the prefecture. Cd, Pb and iron in food duplicates and Cd in urine were analyzed by inductively coupled plasma-mass spectrometry. α(1)-Microglobulin (α(1)-MG) in urine was measured by the latex method. Log-normal distributions were confirmed for these analytes., Results: The geometric mean (GM) values for dietary intake of Cd and Pb were 11.8 and 2.28 μg/day, or 4.20 and 0.84 μg/kg body weight/week, respectively, for total children studied. No significant difference was detected in dietary Cd and Pb intake between boys and girls of the same age (except for Pb on a μg/day basis at 6 years) as well as of all ages in combination. Trends of increase in Cd and Pb intake were observed parallel to age when calculated on a daily intake basis, but the trends disappeared after correction for body weight. No age-dependent increase was observed in α(1)-MG, despite there was an age-dependent increase in Cd., Conclusions: The dietary intake of Cd and Pb for children studied were 4.20 and 0.84 μg/kg body weight/week, respectively. International comparison of the present results with values reported in literature suggested that exposure of children in Japan was higher with regard to Cd, and lower regarding Pb, reproducing the observation in adult Japanese populations. For better health of children, efforts may be necessary to reduce high dietary exposure to Cd.

Background and Objectives: Cd absorption may be enhanced in association with iron (Fe) deficiency. Women have increased risks of Fe loss at the time of child birth as well as breast-feeding of children. Possible effects of these two factors were investigated in the present study., Methods: Data were drawn from previous publications from this group on Cd and tubular dysfunction markers (i.e., α1-microglobulin, β2-microglobulin, and N-acetyl-β-D-glucosaminidase) in urine of adult women in non-polluted areas in Japan. Information including age, smoking, number of children, and types of child feeding was obtained by self-administered questionnaires at the time of urine sampling. In practice, 17,468 cases were available, from which 12,869 cases were employed in the present analyses after exclusion of smokers, former or current patients of anemia or hypertension, and those with incomplete answers. Lactation burden was scored after coding of breast, mixed, and bottle feeding with 2, 1, and 0 for each child followed by summation for all children born to a mother. In order to exclude possible effect of aging, women were stratified by 5 years of age to randomly select equal numbers of cases and controls, followed by summation for all ages for comparison., Results: The arithmetic mean age and the geometric mean Cd (as observed) were 49.7 years and 1.13 μg/l urine. The number of children was 0-7, and lactation burden score ranged from 0-12. Multiple regression analyses were conducted with age and either number of children or lactation burden scores as independent variables and Cd as a dependent variable. The results showed that age was an influential variable. Comparison after matching for age showed that having 1, 2, or 3 children or lactation burden score up to 2 were associated with a significant increase in Cd. Lactation burden score up to 2 was also associated with increased Cd in urine and such trend persisted up to the highest score of 5-12. The results of trend tests were generally in agreement with these observations. Further comparison after age-matching showed that women having 2 or 3 children but no lactation burden had higher Cd than those with no children. In contrast, Cd was not higher for those having 2 or 3 children with substantial lactation scores (i.e., 2-4 or 3-6) than for those with the same number of children without lactation burden., Conclusions: Giving birth to 1-3 children was associated with an increase in urinary Cd, suggesting that child birth might be associated with elevation in Cd body burden. The effect of lactation is probably attributable to that of number of children. Further studies are necessary to examine whether the association is also observable in mothers who have 3 or more children.

Background and Objectives: Whereas information has been accumulating on the association of anemia and other diseases with cadmium (Cd) burden, histories of past diseases of the examinees are often not taken in account when the results of health examination are evaluated for cadmium exposure-related health effects on general populations. The present study was initiated to examine the possible association of previous diseases with Cd exposure parameters, taking advantage of compiled data on adult women., Methods: Data were cited from previous publications of this research group on Cd, α1-microglobulin (α1-MG), β2-microglobulin (β2-MG), N-acetyl-β-D-glucosaminidase (NAG) and urine density makers (i.e., creatinine and specific gravity) in the urine of more than 17,000 adult women in non-polluted areas in Japan. Information on previous disease history together with age and smoking habits was obtained by self-administered questionnaires, and 13,031 never-smoking women were selected for the present analyses. To compare the cases with disease history, control cases were randomly selected after stratification by 5 years of age at a ratio of one case to three controls from those with no disease history; summation for all age strata made up the control groups for the disease group in concern. The random sampling to set up control groups was repeated three times in total. The difference between the disease group and control groups was considered valid in cases the difference was statistically significant (p ≦ 0.05), in all three cases after correction (or non-correction) for urine density, and the same results were obtained when compared with the three different control groups., Results: In the anemia group, Cd-U was higher over corresponding three control groups, although none of α1-MG-U, β2-MG-U or NAG-U showed significant changes. In the diabetes mellitus group, NAG-U was higher than in the controls, but such differences were not observed in Cd-U or β2-MG-U. The elevation in α1-MG-U was not reproducible. In the case of the hypertension group, the elevations in Cd-U, α1-MG-U, and β2-MG-U were observed, but changes in NAG-U could not be confirmed. In the analysis of dose-response relationship, the diabetes mellitus group showed increases in the slope for β2-MG-U and in the intercept for NAG-U. No changes in dose-response relationship were observed in other disease groups as compared with the corresponding control groups., Conclusions: Care should be taken in evaluating Cd-related health examination results for those with history of diseases such as hypertension, anemia and diabetes mellitus in particular.

Cadmium (Cd) is one of the endocrine disrupter and is a well-known testicular toxicant. Recently, we reported that Cd-induced mortality was markedly different by injection timing. In this report, we investigated whether severity of testicular toxicity was affected by injection timing of Cd. C57BL/6J mice (male, 7 w) were received single intraperitoneal injection of CdCl(2) (4.5 mg/kg) at zeitgeber time 6 (ZT6) or ZT18; these injection timings showed highest (ZT6) or lowest (ZT18) mortality in our previous study (Miura, 2012). After one week of the injection, several parameters for testicular toxicity such as epididymal sperm motility and numbers of sperm head both in cauda epididymidis and testis were measured. At ZT6 injection group, all parameters examined were significantly reduced compared to the control group. However, very interestingly, no significant changes were observed at ZT18 injection group. We obtained similar results by another experiment in which mice were received single subcutaneous injection of CdCl(2) (4 or 6 mg/kg) followed by measuring the parameters ten days after the injection. This diurnal variation was not contradictory to the result of the lethal toxicity which we showed earlier. Therefore, our results indicate that the testicular toxicity of Cd is also influenced by the injection timing.

Background: The use of benchmark dose (BMD) and the 95% lower confidence limit of benchmark dose (BMDL) have been gaining popularity not only in experimental studies but also in epidemiological studies including those on toxicology of cadmium (Cd), a ubiquitous hazardous element in the environment. However, the reproducibility of BMD and BMDL values has seldom been examined., Objectives: This study was initiated to determine whether consistent BMD and BMDL values are obtained for similar non-exposed populations, i.e., the populations with no anthropogenic exposure to Cd in a single nation of Japan., Methods: Cd (an exposure marker), α(1)-microglobulin (α(1)-MG), β(2)-microglobulin (β(2)-MG) and N-acetyl-β-D-glucosaminidase (NAG) (three effect markers of tubular dysfunction) levels in the urine of adult Japanese women from five previous publications of this study group were examined. Overall, data were available for 17,375 cases (in 16 prefectures) regarding Cd, α(1)-MG and β(2)-MG, and 6,409 cases (in ten prefectures) regarding NAG. The data were used to calculate BMD and BMDL values taking advantage of the hybrid approach (Budtz-Jǿrgensen et al. in Biometrics 57:698-706, 2001). It was possible to calculate BMD and BMDL values for α(1)-MG and β(2)-MG for all of the 16 prefectures with 17,375 cases, whereas the values for NAG were successfully calculated for nine prefectures with 5,843 cases., Results: The application gave BMD values of 1.92, 2.46 and 2.32 μg Cd/g cr for α(1)-MG, β(2)-MG and NAG, respectively, and BMDL values of 1.83, 2.32 and 2.09 μg Cd/g cr. Large inter-prefectural variations were observed in the BMD and BMDL; there was about fourfold difference both in BMD and in BMDL calculated for α(1)-MG and β(2)-MG in 16 prefectures, and the variation was greater (i.e., by about sevenfold) in BMD and BMDL for NAG in nine prefectures. A survey of relevant literature revealed variation in BMD and BMDL values of similar folds as observed in the present analyses in five studies of Japanese populations. Multiple regression analyses taking BMD or BMDL as a dependent variable and age, CR concentration and Cd concentration as independent variables showed both BMD and BMDL were significantly influenced by Cd concentration in cases of α(1)-MG and β(2)-MG, whereas BMD and BMDL for NAG was by CR., Conclusions: Even when the analysis was conducted in a single nation, both BMD and BMDL for the Cd effect markers varied by ca. fourfold when examining α(1)-MG or β(2)-MG and the values varied by ca. sevenfold for NAG among Cd-non-exposed populations. The most influential factors in the study population may include urine density and Cd levels in the urine.

Background and Objectives: Previous findings suggest that the dose (e.g., cadmium in urine)-response (e.g., tubular dysfunction markers in urine) relationship after environmental exposure to cadmium (Cd) may be in a shape of a hockey stick with a steep slope when Cd exposure exceeds a certain level, i.e., the point of flexion. However, less attention has been paid to the relation below the flexion point whether it is linear or not. The present study was initiated to examine through epidemiological analyses whether the assumption of linearity holds true when Cd exposure is low., Methods: Data were cited from previous publications of this research group on Cd, α(1)-microglobulin (α(1)-MG), β(2)-microglobulin (β(2)-MG), N-acetyl-β-D: -glucosaminidase (NAG), and creatinine (CR) in urine from more than 17,000 adult Japanese women. The cases were selected for age (50-59 years), urine specific gravity (1.010-1.030) and CR (0.3-3.0 g/l), and 5,306 cases were available after selection (the group selected in terms of age and urine density, or the AD-selected group)., Results: Statistical analyses of the AD-selected group revealed that the relation was not linear. In case of β(2)-MG, the slope of the regression line between Cd as an independent variable and β(2)-MG a dependent variable was steeper at lower Cd level (i.e., <2.5 μg/l) and shallower when Cd was higher, showing a clear trend of leveling off. The same was also the case for α(1)-MG and NAG. When Cd was 2.0-2.1 μg/l or higher, α(1)-MG, β(2)-MG, and NAG were in excess of the 95%-tile values for the markers in more than 5% of the population. The significance of the observation was discussed in reference to existing criteria for Cd such as 2.5 or 5.2 μg/g cr or for β(2)-MG of 300 μg/g cr., Conclusions: When the present observation of bilinear relation at low Cd exposure levels was combined with the previous observation of very sharp increase in responses among heavily exposed cases, it appeared likely that the overall relationship is tri-phasic in Cd dose-response relationship in humans. A substantial fraction (>5%) of the populations had the marker levels in excess of the 95%-tile values when Cd was ≥2 μg/l. Comparison with findings in reported literature suggests that the presence of such cases by itself may not necessarily mean a risk of tubular dysfunction and that other factors including Cd levels in urine should be considered together.

This study was initiated to examine accumulation of cadmium (Cd) and other metals in kidney and liver in autopsy samples and to compare the levels between those in an area with heavy Cd exposure and those in no-polluted areas in Japan. Data on Cd and other metals in kidney (cortex and medulla) and liver in 95 cases (87 women and eight men; the exposed) in a Cd-polluted area and 43 cases (21 women and 22 men; the controls) in non-polluted areas were cited from 15 previous publications to be summarized together with six unpublished cases. Cd levels in kidney cortex and medulla were significantly lower in the exposed (31.5 and 23.8 μg/g wet tissue as GM, respectively) than in the controls (82.7 and 36.4 μg/g, respectively), whereas Cd levels in liver was higher in the exposed (60.2 μg/g) than in the controls (8.1 μg/g). Exposed women had lower Cd in the cortex (29.9 μg/g) and medulla (22.7 μg/g) than exposed men (55.4 and 38.1 μg/g, respectively) as well as in cortex of control women (92.9 μg/g). Comparison with worldwide data other than Japan for non-exposed populations [19.1, 9.3, and 1.3 μg/g in cortex, medulla, and liver, respectively, as the inverse variance-weighted averages (IVWA) of GM values for each of 22 reports] suggests that the levels for the non-exposed Japanese (123.3, 33.5, and 3.9 μg/g as IVWA) tended to be higher than the levels in other countries, possibly reflecting high dietary Cd intake in the past.

Successful trials were made to estimate the dietary daily intake of lead (Pb) and cadmium (Cd) via foods from the levels of the metals in blood or urine. In practice, 14 and 15 reports were available for Pb and Cd in blood (Pb-B and Cd-B), urine (Pb-U and Cd-U) and 24-h diet duplicates (Pb-D and Cd-D), respectively, from which 68 pairs each of Pb or Cd in blood and food duplicates [each being geometric mean (GM) values for the survey sites] were obtained. Regression analysis revealed that there was a significant correlation between Pb-B and Pb-D, and also between Cd-B and Cd-D, suggesting that it should be possible to estimate both Pb-D and Cd-D from Pb-B and Cd-B, respectively. For Cd-U, the number of available cases was limited (20 pairs), but a significant correlation was detected between Cd-U (as Cd-U(cr), or Cd levels in urine as corrected for creatinine concentration) and Cd-D. Care should be taken in estimating Pb-D from Pb-B, as the ratio of Pb-D over Pb-B may decrease as a function of increasing Pb-B levels. The Pb-D (μg/day) for typical Japanese women with Pb-B of 15 μg/l was best estimated to be 13.5 μg/day. No Cd-B- or Cd-U(cr)-dependent change was detected in case of Cd. The best estimate of Cd-D for Cd-B at 1.5 μg/l should be about 19.4 μg/day.

Recent publications in Japan suggest that Cd in river beds and locally harvested rice tend to be higher in seven prefectures in the north-eastern part on the coast of the Sea of Japan (the high-Cd zone). The present study was initiated to investigate the current level of exposure to Cd and possible health effects among local populations in the zone. Thus, levels of Cd and three tubular dysfunction markers [i.e., α(1)-MG, β(2)-MG, and N-acetyl-β-D-glucosaminidase (NAG)] were examined in urine of local residents (700 and 704 adult women, respectively) in two prefectures (prefecture 1 and prefecture 7), which were located in the north-east (prefecture 1) and south-west ends (prefecture 7) of the high-Cd zone. Urinary Cd levels [e.g., 0.99 and 0.78 μg/l as geometric mean (GM) for observed (non-corrected) values, respectively] in prefecture 1 and prefecture 7 were comparable to the levels in other parts of Japan (All Japan-A; 0.99 μg/l). Correspondingly, GM values for α(1)-MG (2.29 and 1.99 mg/l vs. 2.17 mg/l for All Japan-A) and for β(2)-MG (87 and 80 μg/l vs. 99 μg/l for All Japan-A) were not elevated, and NAG also stayed unchanged (2.89 and 2.87 units/l for prefecture 1 and prefecture 7, respectively). Evaluation in combination with the findings in other five prefectures in the zone suggests that Cd exposure is equal to the national average both in prefecture 1 and in prefecture 7, whereas Cd exposure appeared to be elevated in the central part of the zone. The observation appears to be on line with geographical location of the two prefectures that they are on the two ends of the zone of high natural Cd background.

Objectives: The objectives of the present study are to investigate whether cadmium in blood (Cd-B) and cadmium in urine (Cd-U) correlate with each other irrespective of age among general populations and which one of Cd-B or Cd-U correlates more closely with three renal tubular dysfunction markers in urine of α₁-microglobulin (α₁-MG-U), β₂-microglobulin (β₂-MG-U) and N-acetyl-β-D-glucosaminidase (NAG-U)., Methods: Data on two exposure markers (Cd-B and Cd-U) and three effect markers (α₁-MG-U, β₂-MG-U and NAG-U) were collected for 1,403 adult women in non-polluted areas all over Japan. Possible significance of correlation between the parameters and dependency on age was examined by simple and multiple regression analysis., Results: Both Cd-B and Cd-U increased as a function of age. The two exposure markers correlated significantly with each other, and the Cd-U over Cd-B ratio also increased as a function of age. Although both Cd-B and Cd-U correlated significantly with the three effect markers, the correlation was closer for Cd-U than for Cd-B., Conclusions: Cd-U rather than Cd-B should be recommended as an exposure marker of choice in Cd biological monitoring of general populations. Effects of aging should be taken into account when evaluating study results.

Cadmium in blood (Cd-B) is an important indicator, next to Cd in urine, in biological monitoring of exposure to Cd. The present study was initiated to examine compatibility in results of analysis for Cd-B between graphite furnace atomic absorption spectrophotometry (GFAAS) and inductively-coupled plasma mass-spectrometry (ICP-MS). For this purpose, 1,159 blood samples were collected from adult women (with no occupational exposure to Cd) in eight prefectures nation-widely in Japan. The samples were analyzed by the two methods; geometric mean (the maximum) concentrations were 1.22 (6.90) μg/l by ICP-MS, and 1.47 (7.40) μg/l by GFAAS. Statistical analyses showed that there was a close correlation between the results by the two methods. The regression line (with ICP-MS and GFAAS results as an independent variable and a dependent variable, respectively) had a slope close to one and an intercept next to zero to suggest that ICP-MS gave values compatible with that of GFAAS. Further analysis with the ratio of Cd-B by GFAAS over that by ICP-MS revealed that the two results were close to each other, and that the agreement was even closer when Cd-B was >2 μg/l. Thus, the two methods can be employed inter-convertibly when Cd-B is relatively high, e.g. >2 μg/l. Care may need to be practiced, however, for possible 'between methods' difference when Cd-B is low, e.g., ≤2 μg/l.

Objectives: Literature survey has suggested that cadmium (Cd) in the general environment is more abundant in the northern part of the coast on the sea of Japan. The present survey was initiated to examine if the exposure to Cd in the area has been higher than other parts of Japan, and if so, the higher exposure has been associated with tubular dysfunction among the local residents., Methods: In three prefectures of Akita, Yamagata and Ishikawa in the region, adult women (about 700 subjects per prefecture) were invited to participate in the survey. Each of the participants provided informed consents, offered spot urine samples and filled questionnaires (on age etc.). The urine samples were analyzed for Cd, alpha(1)-microglobulin (alpha(1)-MG), beta(2)-microglobulin (beta(2)-MG) and N-acetyl-beta-D: -glucosaminidase, together with creatinine and specific gravity. The results were combined with published data on two other prefectures of Niigata and Toyama (both in the area), as well as Japan as a whole (all Japan-A excluding Niigata prefecture, which was studied separately in the present study), and subjected to analysis for possible difference from all Japan-A in terms of the levels of internal Cd burden, and prevalence of beta(2)-MG-uria., Results: Geometric means (GMs) for urinary Cd in the five prefectures were in a range from a low of 1.20 to a high of 2.65 microg/l, being higher than the GM (0.99 microg/l) for all Japan-A. GMs for alpha(1)-MG (2.15-2.80 mg/l) and beta(2)-MG (99-107 microg/l) were only slightly higher or even lower than all Japan-A values depending on the prefectures. Elevation in the prevalence of beta(2)-MG-uria was significant in Akita prefecture, but the elevation in beta(2)-MG was not associated with elevation in Cd in urine. Literature survey on general population Cd epidemiology showed that Cd, alpha(1)-MG and beta(2)-MG levels in urine of the residents in the five prefectures were within the levels reported for non-polluted areas, and such was also the case for prevalence of beta(2)-MG-uria., Conclusions: In an over-all evaluation, no clear-cut evidence was available for increased prevalence of Cd exposure-associated renal tubular dysfunction among general populations in the five prefectures in the northern part on the coast of Sea of Japan than in other prefectures in Japan, despite moderate elevation in urinary Cd levels.

Objectives: Cadmium is a ubiquitous hazardous element with nephro-toxicity after long-term exposure. The present study was initiated to examine possible effects of dietary cadmium (Cd) intake on health of local residents across Japan. For this purpose, Cd in locally harvested brown rice (Cd-BR) was taken as the parameter of Cd exposure, and two measures of mortality, i.e., standardized mortality ratio (SMR) and age-adjusted renal insufficiency mortality rate (AARIMR) were employed as parameters of over-all health effects including effects on kidney., Methods: Japan consists of 47 prefectures. Data on Cd in 37,250 brown rice samples harvested in 1997-1998 in the 47 prefectures were made available from the Ministry of Agriculture, Forestry and Fisheries, Japan. SMR and AARIMR data (for the year 2000) by two genders in the 47 prefectures were cited from publications of the Ministry of Health, Labour and Welfare, Japan. Possible correlation of Cd in brown rice (Cd-BR) with SMR and AARIMR was examined by Poisson regression analysis., Results: The geometric mean (GM) Cd-BR for Japan as a whole was 0.040 mg/kg with a geometric standard deviation (GSD) of 2.72. Prefectural GM values varied from a low of <0.01 mg/kg to a high of 0.089 mg/kg. Nevertheless, SMR (in a range of 89.9-119.5 for men and 87.1-111.7 for women) did not correlate with Cd-BR significantly. AARIMR (in a range of 5.3-11.9 and 3.2-8.4 for men and women, respectively) tended to decrease as a function of increasing Cd-BR both in men and women, although the correlation was insignificant in both genders., Conclusions: No evidence was obtained in the present analysis to suggest that either mortality as a whole or the mortality due to renal failure is affected by dietary intake of Cd in rice.

This study was initiated to examine if variations in the concentrations of cadmium (Cd) and lead (Pb) in water environment may affect metal levels in local foods and body burden of local residents in non-polluted areas in Japan. Two nationwide databases have been made available on concentrations of Cd in locally harvested brown rice and of Cd and Pb in sediments in local river beds. These data were combined with published data on metal concentrations in polished rice, food duplicates, and blood and urine from the residents. Cd in river sediments correlated significantly with those in brown rice, food duplicates, blood, and urine. Cd in food duplicates correlated with Cd in rice. In contrast, Pb concentrations in the river sediments either did not correlate or correlated only weakly with Pb in biological materials or food duplicates. Possible implication of the different behavior between Cd and Pb regarding the intensity of correlation was discussed with reference to the different routes of exposure to the elements. In conclusions, the Cd body burden on local residents in Japan is significantly influenced by Cd levels in water in the general environment, whereas water-borne Pb did not show clear correlation with the Pb body burden.

Alpha(1)-microglobulin (alpha(1)-MG), beta(2)-microglobulin (beta(2)-MG) and N-acetyl-beta-D-glucosaminidase (NAG) are tubular dysfunction markers often used in cadmium (Cd) epidemiology. The purpose of the present study was to identify the best maker among the above-referred three that correlates most closely with Cd in urine of residents with no known Cd pollution. Survey was conducted in 2007-2008 in three prefectures in Japan. Adult women, 2163 in total, participated in the survey; they provided informed consents, offered spot urine samples and filled questionnaires on possible confounders of Cd burden. Urine samples were analyzed for Cd, alpha(1)-MG, beta(2)-MG and NAG together with calcium (Ca), magnesium (Mg), creatinine (CR) and specific gravity (SG). The analyte levels, as observed (e.g., Cd(ob)) or after correction for CR (e.g., Cd(cr)) or SG (e.g., Cd(sg)) were subjected to simple and multiple regression analysis. Correlation matrix analysis with observed values for total cases showed that the coefficients of correlation with Cd were highest for NAG, followed by alpha(1)-MG, and lowest for beta(2)-MG. Multiple regression analysis by three prefectures either separately or in combination (thus four analyses) disclosed that Cd was the independent variable most influential to NAG (as the dependent variable) throughout the four analysis conditions with high R(2) values (>0.3), whereas the most influential variables were not the same depending on the analysis conditions in cases with alpha(1)-MG and beta(2)-MG. When coefficients of correlation for the three dysfunction markers with Cd were compared among the observed, CR- and SG-corrected values, the coefficients for the observed values were higher than the counterpart values for CR- or SG-corrected values. In conclusion, NAG rather than alpha(1)-MG or beta(2)-MG should be recommended for monitoring Cd exposure-related tubular effects among general populations. Observed (i.e., un-corrected) values rather than CR- or SG-corrected values should be used.

Objectives: This study was initiated to investigate the extents of biological variations in cadmium and three common tubular dysfunction marker levels in blood and urine through repeated sampling., Methods: A 12-month survey and a 10-week survey were conducted in an area with no known cadmium pollution. In the 12-month survey, five adult women offered urine samples once every month and blood samples once in every season, respectively. In the 10-week survey, 17 adult women gave urine samples once every week. Blood and urine samples were analyzed for cadmium (Cd-B and Cd-U) by graphite-furnace atomic absorption spectrometry, and urine samples were analyzed also for alpha 1-microglobulin (alpha 1-MG-U), beta 2-microglobulin (beta 2-MG-U) and N-acetyl-beta-D-glucosaminidase (NAG-U) by conventional methods, all under strict quality control. The results were subjected to statistical analysis to examine the extents of biological variations through-out the study periods., Results: Variations in geometric means (GMs) for Cd-B, Cd-U, alpha 1-MG-U, beta 2-MG-U, and NAG-U were all small; the ratio of the largest GM over the lowest GM was 1.1 for Cd-B, 2 for Cd-U and 2 to 3 for alpha 1-MG-U, beta 2-MG-U, and NAG-U in the 12-month survey, and 1.7 at largest for all parameters in the 10-week survey. The within-subject variations during the 12-month or 10-week periods were however large, i.e., more than 4-5-fold difference between the smallest and the largest values obtained for the same subject. Effects of the correction for urine density to reduce the variations were limited. In contrast, within-subject variation in Cd-B was small with a ratio of 1.3., Conclusions: Variations in GM values for Cd-U, alpha 1-MG-U, beta 2-MG-U, and NAG-U at different time of sampling are small so that single measurement would be acceptable as far as the evaluation on a group basis is the study objective. Within-subject variations are wide however, the ratio of the largest value over the smallest value being 4-5 or more, irrespective of correction for urine density. Therefore, care should be practiced when evaluation on an individual basis is intended. Very low within-subject variation in Cd-B may suggest the advantage of Cd-B over Cd-U for individual evaluation among general populations if blood sampling is accepted.

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

Objective: The objective of this study is to examine if overall correlation exists among cadmium levels (Cd) in the general environment, dietary Cd intake, and Cd body burden of local residents., Methods: Eleven prefectures in Japan were selected as the areas where large-scale data on Cd levels in urine of adult women (40-49 and 50-59 years of age, respectively) were available to calculate geometric mean (GM) values for each of the prefecture. Other data were cited from published or previously established databases on Cd in the sediments of river bottoms (as a representative of Cd in the environment), Cd in rice for local consumption, and Cd in daily food duplicate samples collected from local women populations, and calculated for GM values for the prefectures. The GM values were subjected to correlation matrix and regression analysis., Results: Marginally significant (P < 0.10) correlation was detected between Cd in sediment and Cd in rice. Furthermore, correlation of Cd in sediment was significant with Cd in total foods (P < 0.05) and possibly with Cd in urine (P < 0.05-0.10). Importance of data on Cd in rice paddy soil as a missing link is discussed., Conclusions: Correlation was demonstrated in the flow of Cd transport from the environment (expressed as Cd contents in river sediments) to humans (in terms of Cd in urine) among general populations in Japan.

Cadmium (Cd) is a toxic element ubiquitous in the environment, and general populations have been exposed to this element primarily via foods. Thus, the critical level of non-occupational Cd exposure to cause any health effects among general populations is of public health as well as toxicological concern. The objectives of the present study were to examine the quantitative relationship between cadmium (Cd-U) and beta2-microglobulin in urine (beta2-MG-U) as a marker of exposure to Cd and as a marker of renal tubular dysfunction, respectively, and to identify a threshold Cd-U, if present, in causing a substantial increase in beta2-MG-U. Thus, paired data on geometric mean (GM) Cd-Ucr (i.e., Cd-U as corrected for creatinine [cr] concentration) and GM beta2-MG-Ucr (beta2-MG-U as corrected for cr) of residents in polluted as well as nonpolluted areas in Japan were retrieved in international and domestic sources. In practice, 245 cases of the data pairs were obtained in 51 articles published since 1975. Statistical analysis on ordinary scales disclosed that beta2-MG-Ucr increased markedly when Cd-Ucr exceeded a certain level. The relation between the two parameters after double-logarithmic conversion was in a shape of the letter J or a stick for ice hockey. Analysis for Cd-Ucr at the flexion point gave Cd-Ucr of 4 (on double logarithmic scales) or 7 microg/g cr (on ordinary scales). Cd-Ucr levels that correspond to a beta2-MG-Ucr of 1,000 microg/g cr were estimated to be 8-9 microg/g cr, by ordinary and logarithmic assumption as well as by the 3rd degree regression analysis. Thus, it is concluded that there is a threshold Cd-Ucr level that leads to a substantial increase in beta2-MG-Ucr, and that the threshold level is greater than 4 microg/g cr.

The present study was initiated to assess current level of general population exposure to lead (Pb) in terms of Pb in urine (Pb-U). For this purpose, spot urine samples were collected from 2,332 never-smoking adult women in 10 areas all-over Japan, and were subjected to analysis for Pb-U by graphite furnace atomic absorption (GFAA). Data on cadmium in urine (Cd-U) as measured by GFAA were cited from a previous publication). The grand geometric means (GM) for Pb-U as observed, as corrected for creatinine (cr) and as corrected for a specific gravity of 1.016 were 1.06 microg/l, 1.28 microg/g cr and 1.14 microg/l, respectively, with small intra- and inter-variations with geometric standard deviations of about 2 or less. Arithmetic means of the 10 GMs (one each for the 10 areas) were 1.05 microg/l, 1.19 microg/g cr and 1.18 microg/l, respectively. The levels observed appeared to be lower than levels reported for other populations in the world. Chronological comparison within Japan suggested a gradual decrease in Pb-U in past over 20 yr. No close correlation was detected between Pb-U and Cd-U.

Objective: The purpose of this data compilation is to overview past and current dietary exposure (primarily via rice) of general populations to cadmium (Cd) in environmentally polluted and non-polluted areas in Japan, and to compare the levels with counterpart levels in other areas in Asia., Methods: A literature survey was conducted for publications on this subject, in either Japanese or international languages, since the early 1970s. Most of the studies identified employed the food-duplicate method in combination with atomic absorption spectrometry for Cd determination, although a few studies utilized other methods, such as the market basket method and dithizon-colorimetry., Results: The highest estimate of dietary Cd intake (Cd-D), 600 microg Cd/day, was reported in the late 1960s for the local population in the Jinzu river basin, where Itai-itai disease had been endemic, and the Cd-D levels were 300 microg/day or higher in other polluted areas. Cd-D dropped to well below 100 microg/day when the polluted soil was replaced in the late 1970s and thereafter. In non-polluted areas, the Cd-D was reported to be approximately 100 microg/day in 1969, followed by a gradual decrease to approximately 40 microg/day in the late 1970s, to reach the current level of less than 30 microg/day. There is a trend of gradual reduction at the rate of 0.3 to 0.6 microg/day per year. Cd from rice accounted for 30 to 40% of the Cd-D in non-polluted areas, but a higher contribution was observed in some polluted areas. Nevertheless, the current Cd-D is still higher than the levels in other rice-dependent populations in east and south-east Asia., Conclusion: The Cd-D levels reported for polluted areas were in excess of 300 microg Cd/day. Substantial reduction in Cd-D to the level below 100 microg/day was observed after remediation, such as replacement of polluted paddy soil. In non-polluted areas, there has been a gradual decrease in Cd-D in the past 25 years. Nevertheless, the levels in the current intake of the general population in Japan (25 to 30 microg/day, or <1/10 of the levels in polluted areas in the past) is still higher than the levels in other rice-dependent areas in Asia.

Objectives: The present study was initiated to examine the dietary intake, blood level and urinary concentration of lead (Pb) and cadmium (Cd) among children in Korea, in comparison with the findings in their mothers., Methods: Peripheral blood, spot urine and 24-h food duplicate samples were collected in Busan, Korea, from 38 pairs of children (4-10 years of age) and their mothers (28-46 years, non-smoking, mostly housewives), who provided informed consent. Samples were wet-ashed by being heated in the presence of mineral acids, and Pb and Cd in the wet-ashed samples were analyzed by graphite furnace atomic absorption spectrometry. Pb and Cd in food (Pb-F, Cd-F), blood (Pb-B, Cd-B) and urine [observed value (Pb-Uob, Cd-Uob), and values corrected for creatinine (Pb-Ucr, Cd-Ucr) or a specific gravity (1.016; Pb-Usg, Cd-Usg)] were presented in terms of geometric mean (GM) and geometric standard deviation (GSD)., Results: Pb-F and Cd-F in the children were 0.337 microg Pb and 0.457 microg Cd/kg body weight per day as GM, respectively. Pb-B and Cd-B were 38.0 microg Pb and 1.51 microg Cd/l, and Pb-U and Cd-Uob were 5.44 microg Pb/l and 1.33 microg Cd/l, respectively. Pb-F and Pb-B for children were not significantly different from the values for their mothers. In contrast, Cd-F and Cd-B were significantly different between children and their mothers. Cd-F for children correlated with Cd-F for mothers, but no significant correlation was observed in Cd-B, Cd-U, Pb-F, Pb-B or Pb-U between children and their mothers. The dietary intake of Pb in total Pb intake (i.e., respiratory and dietary intake) accounted for 51.7 and 64.8% in children and their mothers, respectively, whereas the corresponding proportions were 97.8 and 98.2%, respectively, for Cd., Conclusion: Cd intake was exclusively from food, both in children and mothers. Dietary Cd intake of children significantly correlated with that of their mothers. Dietary Pb intake in children, however, did not correlate with that of their mothers. Pb uptake from ambient air tended to be higher in children than in their mothers.

The objective of the present study is to examine whether rice is still a leading source of cadmium (Cd) burden among general populations in Japan. For this purpose, 10 prefectures were selected from all over Japan (including the northern- and southern-most Hokkaido and Okinawa prefecture, respectively). Cadmium levels in urine of never-smoking women (corrected for creatinine; Cd-Ucr) were compared with the rice- and wheat product-based Cd intake, which were estimated from Cd contents in rice and wheat (in the forms of bread, noodle and flour) consumed by residents in the areas, and per-capita daily consumption of rice and wheat. Stepwise multiple regression analysis taking Cd-Ucr as a dependent variable and rice- or wheat product-based Cd intakes as independent variables showed that rice was the most influential and almost exclusive variable with a partial correlation coefficient of 0.770-0.832, explaining 59-69% of total variation in Cd-Ucr. The effects of other sources including wheat were essentially negligible.

In the present study, 1476 adult women in 6 prefectures in Japan volunteered to offer peripheral blood and spot urine samples, and to complete questionnaires on social habits and health. Blood samples were analyzed for iron, ferritin and TIBC in serum in addition to RBC, Hb and Cd in whole blood. Urine samples were analyzed for Cd, alpha1-MG, and beta2-MG; the measures were corrected for creatinine and were expressed as e.g., Cd-Ucr. Among 1212 never-smokers, 37 women with < 25 ng ferritin/ml serum and < 10 g Hb/100 ml blood were classified as the anemics, whereas 701 women with > or = 25 ng/ml ferritin and > or = 10 g/100 ml Hb were taken as controls. Matching by age and the prefecture of residence was successful for 34 anemics. Comparison (by paired t-test) of Cd in blood, and Cd, alpha1-MG and beta2-MG in urine (as corrected for creatinine) of the anemics with that of matched controls showed no significant differences. Thus, it appeared likely that the current level of iron insufficiency among general women population in Japan may not induce substantial increase in Cd absorption or Cd-associated kidney dysfunction.

ABSTRACT Cadmium (Cd) is a heavy metal widely used or effused by industries. Serious environmental Cd pollution has been reported over the past two centuries, whereas the mechanisms underlying Cd-mediated diseases are not fully understood. Interestingly, an increase in reactive oxygen species (ROS) after Cd exposure has been shown. Our group has demonstrated that sleep is triggered via accumulation of ROS during neuronal activities, and we thus hypothesize the involvement of Cd poisoning in sleep-wake irregularities. In the present study, we analyzed the effects of Cd intake (1-100 ppm CdCl2 in drinking water) on rats by monitoring sleep encephalograms and locomotor activities. The results demonstrated that 100 ppm CdCl2 administration for 28 h was sufficient to increase non-rapid-eye-movement (non-REM) sleep and reduce locomotor activities during the night (the rat active phase). In contrast, free-running locomotor rhythms under constant dim red light and their re-entrainment to 12:12-h light/dark cycles were intact under chronic (1 month) 100 ppm CdCl2 administrations, suggesting a limited influence on circadian clock movements at this dosage. The relative amount of oxidized glutathione increased in the brain after the 28-h 100 ppm CdCl2 administrations similar to the levels in cultured astrocytes receiving H2O2 or CdCl2 in culture medium. Therefore, we propose Cd-induced sleep as a consequence of oxidative stress. As oxidized glutathione is an endogenous sleep substance, we suggest that Cd rapidly induces sleepiness and influences activity performance by occupying intrinsic sleep-inducing mechanisms. In conclusion, we propose increased non-REM sleep during the active phase as an index of acute Cd exposure. Copyright © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

This study was initiated to investigate the extents of biological variations in cadmium and three common tubular dysfunction marker levels in blood and urine through repeated sampling. A 12-month survey and a 10-week survey were conducted in an area with no known cadmium pollution. In the 12-month survey, five adult women offered urine samples once every month and blood samples once in every season, respectively. In the 10-week survey, 17 adult women gave urine samples once every week. Blood and urine samples were analyzed for cadmium (Cd-B and Cd-U) by graphite-furnace atomic absorption spectrometry, and urine samples were analyzed also for α1-microglobulin (α1-MG-U), β2-microglobulin (β2-MG-U) and N-acetyl-β- d-glucosaminidase (NAG-U) by conventional methods, all under strict quality control. The results were subjected to statistical analysis to examine the extents of biological variations through-out the study periods. Variations in geometric means (GMs) for Cd-B, Cd-U, α1-MG-U, β2-MG-U, and NAG-U were all small; the ratio of the largest GM over the lowest GM was 1.1 for Cd-B, 2 for Cd-U and 2 to 3 for α1-MG-U, β2-MG-U, and NAG-U in the 12-month survey, and 1.7 at largest for all parameters in the 10-week survey. The within-subject variations during the 12-month or 10-week periods were however large, i.e., more than 4–5-fold difference between the smallest and the largest values obtained for the same subject. Effects of the correction for urine density to reduce the variations were limited. In contrast, within-subject variation in Cd-B was small with a ratio of 1.3. Variations in GM values for Cd-U, α1-MG-U, β2-MG-U, and NAG-U at different time of sampling are small so that single measurement would be acceptable as far as the evaluation on a group basis is the study objective. Within-subject variations are wide however, the ratio of the largest value over the smallest value being 4–5 or more, irrespective of correction for urine density. Therefore, care should be practiced when evaluation on an individual basis is intended. Very low within-subject variation in Cd-B may suggest the advantage of Cd-B over Cd-U for individual evaluation among general populations if blood sampling is accepted. [ABSTRACT FROM AUTHOR]

The present study was initiated to examine urinary α1-microglobulin (α1-MG-U) levels among non-smoking women in the general population in Japan. A previously established database on spot urine samples from adult woman volunteers in 10 non-polluted areas all over Japan was re-examined. The data examined were on α1-MG-U, cadmium, calcium, magnesium and zinc levels in urine (Cd-U, Ca-U, Mg-U and Zn-U, respectively), urinary creatinine (CR or cr), urine specific gravity (SG or sg), smoking habits and age. Thus, 8975 never-smoking women were selected for statistical analyses. The grand geometric mean (GM) for α1-MG-U among the population was 2.1 mg/L or 2.5 mg/g cr, depending on the correction for urine density. It was 1.1 µg/L or 1.3 µg/g cr for GM Cd-U. The inter-area difference in α1-MG-U was <1.5 mg/g cr or <0.7 mg/L; the area with the highest or lowest GM Cd-U was not always highest or lowest in GM α1-MG-U. The correlation coefficient (0.53) between log Cd-U and log α1-MG-U (both without urine density correction) became substantially smaller when the analyte levels were corrected for CR (0.25) or SG (0.26). In multiple regression analysis, the power of influence of the five independent variables (log Cd-U, Ca-U, Mg-U, Zn-U and age) in combination was small (R2 ≦ 0.13). In contrast, logistic regression analysis suggested that α1-MG-U might be elevated as a function of an increase in Cd-U, depending on the cut-off values. Discussion was made on dose (Cd-Ucr) and response (α1-MG-Ucr) relationship based on information available in literatures to show that the increment in α1-MG-Ucr per Cd-Ucr was much greater when Cd-Ucr was large, e.g., in excess of 10 µg/g cr. [ABSTRACT FROM AUTHOR]