Itai-itai disease: Lessons from the investigations of environmental epidemiology conducted in the 1970's, with special reference to the studies of the Toyama Institute of Health.

The outbreak of itai-itai disease, which is the most severe stage of chronic cadmium poisoning, has occurred in the cadmium-polluted Jinzu River basin in Toyama. In this area, the river was contaminated by slags from a mine upstream; consequently, the soil in rice paddies became polluted with heavy metals including cadmium through irrigation water streams from around 1910 to the 1960s. The inhabitants of the Jinzu River basin used the river water for drinking and cooking until around 1960. In this paper, we review the geographical features of the Jinzu River basin and the endemic area of itai-itai disease, and reevaluated the studies conducted in 1970's by the Toyama Institute of Health, because these studies have revealed a clear relationship between renal dysfunction or occurrence of itai-itai disease and exposure to cadmium through irrigation water streams.

Attenuation of Urinary Cadmium in Inhabitants of the Environmentally Exposed Jinzu River Basin Determined by Applying a Mixed Linear Model.

Half-life of urinary cadmium level (U-Cd) was estimated in inhabitants whose initial U-Cd was ≥5 µg/L (131 men and 177 women) or ≥5 µg/gcr (195 men and 246 women), using a linear mixed model adjusted for the baseline age. To clarify the effect of initial U-Cd, the target participants were divided into higher or lower initial U-Cd group. In the higher groups, the half-lives were 15.4 and 13.1 years for unadjusted U-Cd and 19.0 and 23.0 years for creatinine-adjusted U-Cd, in men and women, respectively. In the lower groups, the half-lives were 38.0 and 26.0 years for unadjusted U-Cd in men and women. For creatinine-adjusted U-Cd, it was 42.9 years in men. For attenuation of U-Cd, there were an early fast component shown in the higher group and late slow component shown in the lower group. The attenuation of U-Cd is slower in the longer time compared to that previously reported.

Histopathological analysis for osteomalacia and tubulopathy in itai-itai disease.

BACKGROUND & AIMS: Cadmium (Cd) is a widespread environmental contaminant that causes both renal tubulopathy and osteomalacia. Osteomalacia is thought to be a result of renal tubulopathy, but there are few studies about the histopathological relationship between the two pathoses. Therefore, in the present study, we examined specimens from cases of itai-itai disease (IID), the most severe form of chronic cadmium poisoning, to evaluate the relationship between them. METHODS: We analyzed kidney and bone specimens of 61 IID cases and the data regarding Cd concentration in kidney and bone. Tubulopathy was graded on the basis of a three-step scale (mild, moderate, and severe) using the following three items: the degree of proximal tubular defluxion, thickness of renal cortex, and weight of the kidney. Osteomalacia was evaluated using the relative osteoid volume (ROV). RESULTS: There were 15 cases of mild, 19 cases of moderate, and 27 cases of severe tubulopathy. The average ROV was 24.9 ± 2.0%. ROV tended to increase as tubulopathy advanced in severity, and ROV was significantly higher in cases with severe tubulopathy than those with mild or moderate tubulopathy. ROV had a negative correlation with Cd concentration in the kidney but no correlation with that in the bone. CONCLUSIONS: Our results suggest that the development of osteomalacia was related to the development of tubulopathy.

The liver in itai-itai disease (chronic cadmium poisoning): pathological features and metallothionein expression.

Cadmium (Cd) is a highly hepatotoxic heavy metal, which is widely dispersed in the environment. Acute Cd hepatotoxicity has been well studied in experimental animals; however, effects of prolonged exposure to Cd doses on the liver remain unclear. In the present study, to evaluate chronic Cd hepatotoxicity, we examined specimens from cases of itai-itai disease, the most severe form of chronic Cd poisoning. We compared 89 cases of itai-itai disease with 27 control cases to assess Cd concentration in organs. We also examined 80 cases of itai-itai disease and 70 control cases for histopathological evaluation. In addition, we performed immunohistochemistry for metallothionein, which binds and detoxifies Cd. Hepatic Cd concentration was higher than Cd concentration in all other organs measured in the itai-itai disease group, whereas it was second highest following renal concentration in the control group. In the liver in the itai-itai disease group, fibrosis was observed at a significantly higher rate than that in the control group. Metallothionein expression was significantly higher in the itai-itai disease group than that in the control group. Prolonged exposure to low doses of Cd leads to high hepatic accumulation, which can then cause fibrosis; however, it also causes high expression of metallothionein, which is thought to reduce Cd hepatotoxicity.

[Itai-itai disease: cadmium-induced renal tubular osteomalacia].

Cadmium (Cd) is one of the most toxic elements to which humans could be exposed at work or in the environment. The outbreak of itai-itai disease, which is the most severe stage of chronic Cd poisoning, occurred in the Cd-polluted Jinzu River basin in Toyama. In this area, the river was contaminated by slag from a mine upstream; as a consequence, the soil in rice paddies was polluted with heavy metals including Cd through irrigation water from around 1910 to the 1960s. The government of Toyama prefecture carried out an extensive survey on Cd concentration in rice and soil of the paddy fields and declared that the upper layer of a total of 1500 ha of paddy fields should be replaced by nonpolluted soil. Then, an intervention program of soil replacement in the polluted paddy fields was continually carried out from 1980 to 2011. As a result, Cd concentration in rice markedly decreased. The kidney is the organ critically affected after long-term exposure to Cd. Proximal tubular dysfunction (RTD) has been found among the inhabitants of the Jinzu River basin. The very recent report by the Environmental Agency in Japan in 2009 has disclosed that b2-microglobulinuria with RTD is still found at a high prevalence among the inhabitants of the Jinzu River basin of both sexes. Twenty patients with itai-itai disease (1 male and 19 females), who attended our hospital and received medical examination during 2000 to 2008, had applied for recognition as itai-itai disease patients to the government of Toyama prefecture. In this paper, the recent epidemiological and clinical features of itai-itai disease are discussed on the basis of a review of the cases of these 19 female patients.

Latest status of cadmium accumulation and its effects on kidneys, bone, and erythropoiesis in inhabitants of the formerly cadmium-polluted Jinzu River Basin in Toyama, Japan, after restoration of rice paddies.

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

Gene expression signatures in peripheral blood cells from Japanese women exposed to environmental cadmium.

The objective of this study was to examine the effects of environmental cadmium (Cd) exposure on the gene expression profile of peripheral blood cells, using an original oligoDNA microarray. The study population consisted of 20 female residents in a Cd-polluted area (Cd-exposed group) and 20 female residents in a non-Cd-polluted area individually matched for age (control group). The mRNA levels in Cd-exposed subjects were compared with those in respective controls, using a microarray containing oligoDNA probes for 1867 genes. Median Cd concentrations in blood (3.55 microg/l) and urine (8.25 microg/g creatinine) from the Cd-exposed group were 2.4- and 1.9-times higher than those of the control group, respectively. Microarray analysis revealed that the Cd-exposed group significantly up-regulated 137 genes and down-regulated 80 genes, compared with the control group. The Ingenuity Pathway Analysis Application (IPA) revealed that differentially expressed genes were likely to modify oxidative stress and mitochondria-dependent apoptosis pathways. Among differentially expressed genes, the expression of five genes was positively correlated with Cd concentrations in blood or urine. Quantitative real-time PCR (RT-PCR) analysis validated the significant up-regulation of CASP9, TNFRSF1B, GPX3, HYOU1, SLC3A2, SLC19A1, SLC35A4 and ITGAL, and down-regulation of BCL2A1 and COX7B. After adjustment for differences in the background characteristics of the two groups, we finally identified seven Cd-responsive genes (CASP9, TNFRSF1B, GPX3, SLC3A2, ITGAL, BCL2A1, and COX7B), all of which constituted a network that controls oxidative stress response by IPA. These seven genes may be marker genes useful for the health risk assessment of chronic low level exposure to Cd.

Biological variations in cadmium, alpha 1-microglobulin, beta 2-microglobulin and N-acetyl-beta-D-glucosaminidase in adult women in a non-polluted area.

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.

Elevated urinary levels of vitamin D-binding protein in the inhabitants of a cadmium polluted area, Jinzu River basin, Japan.

Environmental cadmium (Cd) pollution and its effects on human health are still important issues. The most severe and representative manifestation of chronic Cd intoxication is Itai-itai disease, which is a syndrome that includes renal tubular dysfunction, osteomalacia, and generalized pain due to multiple bone fractures. The whole mechanism of how renal dysfunction relates to the development of bone lesions is unresolved. Vitamin D-binding protein (DBP) binds, transports and activates vitamin D, which plays a major role in calcium homeostasis and bone turnover. In this study, we measured urinary DBP levels and investigated their relationship to the markers of renal tubular dysfunction in the inhabitants of a Cd-polluted Jinzu River basin in Toyama Prefecture, Japan (Cd group). We also investigated age-matched subjects from an area known to have lower levels of Cd pollution (reference group). Urinary DBP was measured by a fluorometric enzyme-linked immunosorbent assay (ELISA), which was established in our laboratory. Significantly higher levels of urinary DBP were observed in the Cd group compared to the reference group. We observed significant positive correlations between urinary levels of DBP and renal tubular dysfunction markers in both groups. In the Cd group, urinary levels of DBP had a negative correlation with serum phosphate value. These results indicate that excretion of urinary DBP is increased after long-term Cd exposure and that the loss of DBP in urine may be linked to renal tubular dysfunction and possibly bone lesions in the inhabitants of Cd-polluted areas.

[Renal effects of environmental exposure to cadmium in middle-aged population of Jinzu River basin in Toyama, Japan: 2000-2002 study].

OBJECTIVE: In 2000-2002, the effects of environmental cadmium (Cd) exposure on renal tubular function were investigated in men and women born between January 1, 1946 and December 31, 1955, and living in the Cd-polluted Jinzu River basin in Toyama. It is assumed that these generations had been exposed to Cd mainly through the consumption of rice and vegetables grown locally, in contrast to older generations who had been exposed not only through the consumption of rice but also by drinking river water polluted with Cd discharged from a mine. METHODS: Morning urine specimens, self-administered questionnaires and polished rice samples consumed daily were collected from 110 men and 121 women living in the polluted area and from 48 men and 45 women living in the reference area. RESULTS: Urinary Cd excretion level, an indicator of Cd accumulation in the kidneys, significantly increased with increased duration (years) of residence in the Cd-polluted area in both men and women. There was no case of urinary beta2-microglobulin (beta2-MG) level exceeding 1,000 microg/g Cr in either sex, in contrast to the high prevalence of beta2-MGuria observed in older generations. However, urinary beta2-MG and alpha1-MG levels were slightly but significantly increased with increased duration (years) of residence in the Cd-polluted area in women. CONCLUSIONS: The results indicate that men and women born between 1946 and 1955 and living in the Cd-polluted Jinzu River basin had Cd accumulation in the kidneys and a slight increase in urinary low-molecular weight protein level due to this accumulation.

Reduction of erythrocyte catalase and superoxide dismutase activities in male inhabitants of a cadmium-polluted area in Jinzu river basin, Japan.

Cadmium (Cd) is a toxic heavy metal which causes oxidative damage in organisms. In this study, we investigated the activities of the antioxidant enzymes erythrocyte catalase and copper/zinc superoxide dismutase (Cu/Zn-SOD) in 22 male inhabitants of the Cd-polluted Jinzu River basin in Toyama Prefecture, Japan (Cd group). The reference group consisted of 21 male inhabitants from an area that was not polluted with Cd (reference group). Urinary Cd levels and two renal tubular dysfunction markers in urine, alpha1-microglobulin (alpha1-m) level and N-acetyl-beta-D-glucosaminidase (NAG) activity, were significantly elevated in the Cd group. Catalase and Cu/Zn-SOD activities were significantly reduced in the Cd group as compared to the reference group. Significant negative correlation was observed between the activities of these two antioxidant enzymes and urinary Cd levels. We also observed significant negative correlations between activities of these two antioxidant enzymes and the renal tubular dysfunction markers. Our results indicate that erythrocyte catalase and Cu/Zn-SOD activities are reduced as a result of long-term Cd exposure. This may be linked to renal tubular dysfunction in the inhabitants of the Cd-polluted area.

The gender differences in health effects of environmental cadmium exposure and potential mechanisms.

On a viewpoint of gender differences in Cd body burden and its health effects, we reviewed the population-based research including our own which conducted in Japan, Thailand, Australia, Poland, Belgium and Sweden to assess health effects of human exposure to environmental cadmium and their potential mechanisms. As a result, six risk factors in Cd health effects in women have been identified; (1) more serious type of renal tubular dysfunction, (2) difference in calcium metabolism and its regulatory hormones, (3) kidney sensitivity; difference in P450 phenotype, (4) pregnancy, (5) body iron store status, and (6) genetic factors. Further studies of Cd toxicity targeted to women would now appear necessary.

Assessment of bone metabolism in cadmium-induced renal tubular dysfunction by measurements of biochemical markers.

Bone metabolism related to the severity of cadmium (Cd)-induced renal tubular dysfunction (RTD) was assessed by measuring several bone biochemical markers. Fifty-three female subjects with RTD aged 65-76 years (mean 70.0+/-3.3 years) and who lived in the Cd-polluted Jinzu River basin in Toyama, Japan were studied. Bone alkaline phosphatase (bone-ALP), intact bone Gla-protein (intact-BGP) and carboxy-terminal propeptide of type I collagen (PICP) in serum as bone formation markers and pyridinoline (Pyr) and deoxypyridinoline (Dpyr) in urine as bone resorption markers were measured. All markers of bone turnover were increased and significantly correlated with each other, suggesting that bone formation and resorption were coupled and increased in Cd-induced RTD. Fractional excretion of beta(2)-microglobulin (beta(2)-m, FE(beta 2-m)) as an index of severity of Cd-induced RTD was extremely varied ranging from 0.45 to 53%. There were no significant correlations between FE(beta 2-m) and each of the five bone biochemical markers. The bone turnover in Cd-induced RTD appeared to be determined by the glomerular filtration rate (GFR): in subjects with GFRs above 50 ml/min, the levels of bone-ALP or intact-BGP tended to be inversely related to the GFRs, whereas in subjects with GFRs below 40 ml/min, those levels tended to decrease. These results suggest that the bone turnover, in particular the bone formation, was influenced by renal tubular function as assessed by the levels of GFR in Cd-induced RTD.