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Objective To clarify the causes of deaths among patients with Itai-itai disease and severe cadmium (Cd) poisoning. Design Nested case-control analysis of a populationbased cohort study. Setting Database of patients with Itai-itai disease and residents of Cd-polluted areas, maintained by the Ministry of Environment, Japan. Participants Subjects included 142 women with Itaiitai disease, 111 women with Cd-induced renal tubular dysfunction and 253 controls matched for sex, age and occupation. All subjects participated in a health impact survey between 1979 and 1984 and were followed until 30 November 2005. Main outcomes and measures Adjusted HRs with 95% CIs for cause of death in women with Itai-itai disease and screened female cases with tubular dysfunction were compared with matched pair controls, using Cox's proportional hazard model. Vital statistics data were used to determine cause of death. Direct causes of death from autopsy records were used in 29 patients who died from Cd poisoning. Results The most common cause of death among patients with Itai-itai disease was pneumonia, with a significantly increased adjusted HR of 4.54 (95% CI 2.65 to 7.76). Renal diseases were the most common cause of death in renal tubular dysfunction cases, with an increased HR of 12.0 (95% CI 3.92 to 36.8). The adjusted HR for renal diseases was also significantly increased in patients with Itai-itai disease (19.49 (95% CI 6.43 to 59.09)), with a greater impact on mortality of patients with Itai-itai disease than screened cases. The HR for gastrointestinal (GI) diseases was significantly increased (13.79 (95% CI 3.87 to 49.10)) in patients, especially in the first 10 years (37.1 (4.81 to 286.0)). Conclusions Among patients with Itai-itai disease, pneumonia and GI diseases contributed to increased mortality risk. Renal disease is also a significant mortality risk in patients with Itai-itai disease and women with renal tubular dysfunction. [ABSTRACT FROM AUTHOR]

Objectives: The present cohort study investigated the relationship between serum ferritin levels and indices of insulin resistance and β-cell dysfunction in a normoglycemic population without iron overload disorders. Methods: The study participants included 575 normoglycemic Japanese men aged 35-57 years with serum ferritin levels of 400 µg/L or less. Insulin resistance and β-cell dysfunction were estimated at baseline and after 3 years by the homeostasis model assessments of insulin resistance and β-cell function (HOMA-IR and HOMA-β, respectively). To compare the subsequent changes in HOMA-IR and HOMA-β over a 3-year follow-up period among 3 groups based on tertiles of baseline serum ferritin levels (4.9-87.1, 87.2-140.5, and 140.6-396.8 µg/L), the geometric mean HOMA-IR and HOMA-β values at year 3 were calculated for each group using analysis of covariance, incorporating the respective log-transformed parameters at baseline in addition to age, body mass index and major confounding factors. Results: The multivariate-adjusted geometric mean HOMA-IR at year 3 was significantly higher in those in the highest and middle serum ferritin tertiles (1.24 and 1.22, respectively), compared with the lowest tertile (1.07) (p = 0.009). When the total study participants were stratified by median body mass index (22.72 kg/m²), similar positive relationships were observed between serum ferritin levels and HOMA-IR for both obese and non-obese participants. However, the adjusted geometric mean HOMA-β at year 3 was similar among the 3 serum ferritin groups. Conclusions: Elevated serum ferritin levels predicted a subsequent increase in HOMA-IR in normoglycemic Japanese men without iron overload disorders. [ABSTRACT FROM AUTHOR]

This study looked to identify determinants of exposure to dioxin in breast milk from breast-feeding women in a hot spot of dioxin exposure in Vietnam. Breast milk was collected from 140 mothers 1 month after delivery. The risk factors investigated included length of residency, drinking of well water and the frequency of animal food consumption. Cluster analysis was performed to identify dietary patterns of fish and meat portions, fish variety and egg variety. Residency, age and parity were clearly associated with increased dioxin levels. Drinking well water and the consumption of marine crab and shrimps were related to higher levels of furans in breast milk. The consumption of quail eggs also appeared to be associated with increased levels of some dioxin isomers in this area. Some mothers who ate no or less meat than fish and mothers who consumed more freshwater fish than marine fish had lower levels of dioxins in their breast milk. However, the type of water and the eating habits of mothers contributed only partly to the increased dioxin levels in their breast milk; the length of residency was the most important risk factor associated with increased dioxin body burdens of mothers. [ABSTRACT FROM AUTHOR]

Background: We aimed to investigate the mortality and causes of deaths of inhabitants with renal dysfunction induced by cadmium (Cd) exposure caused by heavy environmental contamination. Methods: We conducted a 26-year follow-up survey targeting 7529 inhabitants of the Cd-polluted Jinzu River basin and 2149 controls from non-polluted areas who participated in urinary examinations for proteinuria and glucosuria conducted in 1979 to 1984. When the residents were divided into 4 groups, no finding group, glucosuria group, proteinuria group, glucoproteinuria group, mortality risk ratios for all and specific causes of these groups in the polluted area were compared with that of controls without glucosuria and/or proteinuria after adjustments for age at baseline, smoking status, and history of hypertension using Cox’s proportional hazard model. Results: The mortality risk ratios for all causes of proteinuria and glucoproteinuria in men and glucosuria, proteinuria, and glucoproteinuria in women of the polluted areas significantly increased compared with those of the controls with no urinary findings. Respiratory, renal, and cardiovascular diseases and diabetes in men, and all diseases except cerebrovascular diseases in women contributed toward an increased mortality of exposed glucoproteinuria groups, which involved chronic Cd toxicosis with renal tubular dysfunction. In women, the mortality risks for cancer of the colon and rectum, uterus and kidney and urinary tract were significantly higher in the exposed proteinuria and glucoproteinuria groups, suggesting associations between renal damage and cancer risk. In exposed women, the no finding group and glucoproteinuria group also showed increased mortality from ischemic heart diseases, indicating that all exposed women may be at risk for ischemic heart diseases. Although the control glucosuria and/or proteinuria group also showed high mortality for diabetes and renal diseases, the increased risk ratio for renal disease mortality was much higher in exposed subjects with urinary findings, particularly in women. Conclusions: These findings indicate that inhabitants with renal effects caused by Cd exposure had a poor life prognosis over long-term observation in both genders. Particularly in women, renal tubular dysfunction indicated by glucoproteinuria may increase mortality from cancer, ischemic heart diseases, and renal diseases. [ABSTRACT FROM AUTHOR]

Objectives Dioxin levels in the breast milk of mothers residing near hot spots of dioxin contamination areas in South Vietnam remain much higher than in unsprayed areas, suggesting that fetuses and breast-fed infants may be exposed to high levels of dioxins. The present study investigated the association of infant neurodevelopment in early infancy and dioxin exposure during the perinatal period. Methods The study involved 216 mother-infant pairs living near the Da Nang airbase, a dioxin contaminated area in Vietnam. Mothers and infants were followed from birth until infants were 4 months old. Dioxin levels in breast milk were measured to estimate the perinatal dioxin exposure, including the infant daily dioxin intake (DDI) via breastfeeding. Infant neurodevelopmental parameters, including cognitive, language and motor domains were assessed at approximately 4 months using the Bayley Scales of Infant and Toddler Development, third edition (Bayley-III). Results The level of 2,3,7,8-tetrachlorodibenzo-p-dioxin and polychlorinated dibenzo-p-dioxins/furans-toxic equivalents in breast milk and the infant DDI showed significant inverse correlations with neurodevelopmental scores. When the subjects were divided into four groups according to dioxin levels in breast milk, the moderate and high DDI groups had significantly lower cognitive, composite motor and fine motor scores, and the high polychlorinated dibenzo-p-dioxins/furans-toxic equivalents group had significantly lower fine motor score than the low exposure group. For all domains, neurodevelopmental scores were decreased with increase in the level of 2,3,7,8-tetrachlorodibenzo-p-dioxin. Conclusion The present study demonstrates a considerable impact of perinatal dioxin exposure on neurodevelopment in 4-month-old infants living in contaminated areas in Vietnam. [ABSTRACT FROM AUTHOR]

Effects of dioxins on cognitive functions were reported in previous studies conducted in humans and animals. In the present study, we investigated the influence of dioxin exposure during pregnancy on social interaction and on the activity of offspring, which are related to neurodevelopmental disturbances. In addition, we analyzed neurochemical alterations of the limbic system of rat brains to suggest one mechanism of dioxin effects on brain function. We believe that this manuscript is suitable for publication in "Environmental Health Insights" because it provides an interesting topic for a wide global audience. To clarify the relationships between maternal dioxin exposure and socioemotional functions of rat offspring, dams were given TCDD (1.0 μ g/kg) on gestational day 15. Social interactions and forced swimming time were compared between TCDD-exposed and control offspring in each gender. Frequency and duration of locomotion were higher, and durations per one behavior of proximity and social contact were significantly lower in the exposed males, while only the duration of proximity was lower in the exposed females. Forced swimming time on the first day was significantly longer in the exposed males. In the limbic system of the rat brain, the levels and/or activity of CaMKIIα were decreased in males and were increased in females in the exposed offspring. These results suggest that prenatal TCDD exposure induces hyperactivity and socioemotional deficits, particularly in the male offspring due to alterations in CaMKIIα activity in the limbic system of the brain. [ABSTRACT FROM AUTHOR]

Abstract  Using a general linear mixed model, we conducted a 10-year follow-up investigation of 29 persons requiring observation in the cadmium (Cd)-polluted Kakehashi River basin to determine serial changes in biological parameters after removal of Cd-polluted soil present in rice paddies. In particular, we investigated changes in urinary Cd, urinary total protein, biological acid–base balance based on arterial blood pH, carbon dioxide tension (PaCO2), base excess (BE), serum chloride ion (SCl−), and renal glomerular function based on serum creatinine (SCr) and creatinine clearance (CCr). In both sexes, urinary Cd concentrations decreased and total protein concentrations increased with increasing number of years elapsed, with the partial regression coefficients statistically significant in the women. Partial regression coefficients showed positive values for SCl−, with statistical significance in both sexes. The value for PaCO2 was significantly negative in men. Given the serial changes in arterial blood pH, PaCO2, BE, SCl−, it is suggested that the biological acid–base balance will progress to metabolic acidosis with hyperchloremia. Moreover, glomerular dysfunction as indicated by an increase in SCr and a decrease in CCr will continue to progress even after soil replacement. Interventions such as soil replacement appear to be too late to prevent progressive renal failure in Cd-exposed populations. [ABSTRACT FROM AUTHOR]

Abstract  There are more than 50 cadmium (Cd) polluted areas in Japan. The severest general environmental Cd polluted area in Japan was the Jinzu River basin in Toyama Prefecture where Itai-itai disease had been endemic. The present study aimed to compare organ Cd concentrations of inhabitants who had been exposed to different levels of environmental Cd and to clarify the health effects of the environmental Cd exposure in Japan. Since 1960 we have measured tissue Cd concentrations of inhabitants with a history of living in a different Cd polluted areas. Study population living in Cd polluted areas were 36 (1 male, 35 females) patients with Itai-itai disease, 20 (7 males, 13 females) subjects suspected of having Itai-itai disease, 8 (2 males, 6 females) inhabitants in Cd polluted areas other than the Jinzu River basin. Subjects who had lived in Cd non-polluted area were 72 inhabitants. Cd concentrations in liver, pancreas and thyroid of those living in Cd polluted areas were as high as those of patients with Itai-itai disease, and their Cd concentrations in renal cortex were as low as those of patients with Itai-itai disease. The present study demonstrated that tissue Cd concentrations of some inhabitants in Cd polluted areas other than Jinzu River basin are equal to those of the patients with Itai-itai disease and that patients with Itai-itai disease were present even in these areas. [ABSTRACT FROM AUTHOR]

We examined how the influence of smoking on blood and urinary cadmium (Cd) concentrations was modified by the level of environmental Cd. We measured blood and urinary Cd concentrations of 1134 men over 50 yr of age in three areas in Japan that were exposed to different levels of environmental Cd. Analysis of variance was used to compare Cd concentrations in blood and urine of smokers with those of nonsmokers living in the three areas. Correlation coefficients between the number of cigarets smoked per day or smoking indices (the number of cigarets smoked per day multiplied by the number of years smoked) and blood and urinary Cd concentrations were calculated. No significant difference in Cd concentrations between smokers and nonsmokers was observed in areas where the average Cd concentration in blood was over approx 2.4 ng/g, 2.0 μg/L in urine, and 2.3 μg/g creatinine in urine, respectively. Therefore, it was suggested that an influence of smoking on blood and urinary Cd concentrations was notobserved in areas exposed to relatively high levels of environmental Cd. [ABSTRACT FROM AUTHOR]

A 15-year follow-up study of 3178 inhabitants (1424 men and 1754 women) living in the cadmium (Cd) polluted Kakehashi River basin was conducted. The results clarified effects on mortality of renal dysfunction induced by Cd indicated by urinary beta-2-microglobulin (β2-MG), total protein, glucose, and total amino acids. This study used Cox's proportional hazard model.The mortality risk ratio of urinary β2-MG positive (>=1000 μg/gCr) subjects was significantly increased in both sexes: 1.35 for men and 1.73 for women. The increased mortality ratio of the urinary protein positive (>=10 mg/dl) subjects was also significant for both sexes, with risk ratios of 1.82 for men and 2.01 for women. Only the women showed significantly increased mortality of the urinary glucose positive (>=20 mg/dl) subjects and amino acids positive (>=300 μg/gCr) subjects. When the subjects were divided into four categories according to urinary β2-MG, <300, 300–1000, 1000–10000, >=10000 μg/gCr, the mortality risk ratios were increased in proportion to the increase of urinary β2-MG in both sexes. These results suggest that mortality of Cd-exposed subjects increased with increasing excretion of four urinary markers of renal tubular dysfunction, and in proportion to increases in the amount of urinary β2-MG excretion including under 1000 μg/gCr. [ABSTRACT FROM AUTHOR]