Relationship between urinary ß2 -microglobulin concentration and mortality in a cadmium-polluted area in Japan: A 35-year follow-up study.

The relationship between urinary ß2 -microglobulin (ß2 -MG) and the risk of all-cause mortality and cause-specific mortality in a cadmium (Cd)-polluted area was investigated in 3139 inhabitants (1404 men and 1735 women) of the Kakehashi River basin in Japan at 35-year follow-up. The subjects had been participants in the 1981-1982 health impact survey that assessed Cd-induced renal dysfunction, as measured by the urinary ß2 -MG concentration. Hazard ratios were calculated to assess the risk of all-cause and cause-specific mortality according to the urinary ß2 -MG concentrations. Risk ratios (RRs) were assessed using the Fine and Gray regression model to account for competing risks of cause-specific mortality. The mortality rate was significantly higher in participants with urinary ß2 -MG concentrations >1000 µg/g creatinine (Cr) for men and >300 µg/g Cr for women. In the proportional hazard model, higher urinary ß2 -MG concentrations were associated with higher risks of circulatory disease, digestive system diseases, and kidney and urinary tract diseases in men and women, and with senility for women. However, when competing risk was accounted for, the RRs were significantly higher only for kidney and urinary tract diseases in men and women (RR for each increment of 1000 µg/g Cr [95% confidence interval]: 1.02 [1.00-1.04] for men, and 1.01 [1.00-1.02] for women). The long-term prognosis of participants with renal tubular dysfunction was poor, most likely due to kidney and renal tract diseases.

Environmental cadmium exposure and noncancer mortality in a general Japanese population in cadmium nonpolluted regions.

The objective of this study was to assess the effect of environmental cadmium exposure according to urinary cadmium concentration (U-Cd) on noncancer mortality in a general Japanese population. We conducted a longitudinal study for 19 years in 2804 inhabitants (1107 men and 1697 women) in some cadmium nonpolluted regions in Japan. The participants were classified into quartiles based on U-Cd (µg/g cre) adjusted for urinary creatinine. Hazard ratio (HR) and 95% confidence interval (95% CI) for continuous U-Cd or the quartiles of U-Cd were calculated for noncancer mortality. By applying a Fine and Gray competing risk model, continuous U-Cd (+1 µg/g cre) showed significant HR for cardiocerebrovascular diseases (HR 1.05, 95% CI: 1.00-1.11), cerebrovascular diseases (HR 1.08, 95% CI: 1.01-1.16), and cerebral infarction (HR 1.11, 95% CI: 1.04-1.20) in men. However, notable significant HR for continuous and quartered U-Cd were not observed in women. In this study, U-Cd was associated with increased cardiocerebrovascular mortality in a general Japanese population, suggesting that environmental cadmium exposure is detrimental to the life prognosis in cadmium nonpolluted regions in Japan.

The modifying effect of kidney function on the association of cadmium exposure with blood pressure and cardiovascular mortality: NHANES 1999-2010.

OBJECTIVE: We hypothesized that the associations of urinary Cd with blood pressure and cardiovascular disease (CVD) mortality may be modified by renal function. METHODS: We tested these hypotheses using data from the National Health and Nutrition Examination Survey (NHANES, 1999-2010). RESULTS: Both systolic blood pressure (SBP) and diastolic blood pressure (DBP) were positively associated with blood Cd. DBP was positively related to urinary Cd whereas SBP was inversely associated with urinary Cd. In the stratified analyses by level of eGFR, the associations between SBP and urinary Cd were not statistically significant among those with normal renal function and those with mildly reduced renal function whereas SBP significantly positively associated with urinary Cd among those with moderately or severely decreased renal function (p for trend, 0.0004). Renal function appeared to be a modifying factor of the association between urinary Cd and mortality. CVD mortality risks (p for trend, 0.04) were significantly increased with increasing urinary Cd with hazard ratios (HRs) (95% CIs) of 2.18 (0.68-7.01) for the highest quartile of urinary Cd compared to the lowest. The association between urinary Cd and CVD mortality became stronger in the stratified analyses by renal function and these associations became more consistent in those who never smoked. CONCLUSIONS: The inverse association between urinary Cd and blood pressure observed in previous studies may be due to lack of consideration of renal function as an effect modifier. The strength of the association between urinary Cd and CVD mortality may be underestimated without considering renal function.

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

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

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.

Cadmium-related mortality and long-term secular trends in the cadmium body burden of an environmentally exposed population.

BACKGROUND: Few population studies have reported on the long-term changes in the internal cadmium dose and simultaneously occurring mortality. OBJECTIVE: We monitored blood cadmium (BCd), 24-hr urinary cadmium (UCd), and mortality in an environmentally exposed population. METHODS: Starting from 1985, we followed BCd (until 2003), UCd (until 1996), and mortality (until 2007) among 476 and 480 subjects, randomly recruited from low- exposure areas (LEA) and high-exposure areas (HEA). The last cadmium-producing plant in the HEA closed in 2002. RESULTS: From 1985-1989 to 1991-1996, BCd decreased by 40.3% and 18.9% in the LEA and HEA, respectively (p < 0.0001 for between-area difference). From 1991-1996 until 2001-2003, BCd remained unchanged in the HEA (+ 1.8%) and increased by 19.7% in the LEA (p < 0.0001). Over the entire follow-up period, the annual decrease in BCd averaged 2.7% in the LEA (n = 258) and 1.8% in the HEA (n = 203). From 1985-1989 to 1991-1996, UCd fell by 12.9% in the LEA and by 16.6% in the HEA (p = 0.22), with mean annual decreases of 2.7% (n = 366) and 3.4% (n = 364). Over 20.3 years (median), 206 deaths (21.5%) occurred. At baseline, BCd (14.6 vs. 10.2 nmol/L) and UCd (14.1 vs. 8.6 nmol/24-hr) were higher in deaths than in survivors. The risks (p < or = 0.04) associated with a doubling of baseline UCd were 20% and 44% for total and noncardiovascular mortality, and 25% and 33% for a doubling of BCd. CONCLUSIONS: Even if zinc-cadmium smelters close, historical environmental contamination remains a persistent source of exposure. Environmental exposure to cadmium increases total and noncardiovascular mortality in a continuous fashion without threshold.

Causes of death in patients with Itai-itai disease suffering from severe chronic cadmium poisoning: a nested case-control analysis of a follow-up study in Japan.

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 population-based 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 Itai-itai 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.

[Choice of safety criteria during accidents occurring at the dangerous industrial objects during work using cadmium and metallic mercury]. / O vybore kriteriev bezopasnosti pri vozniknovenii avarii na opasnykh proizvodstvennykh ob"ektakh v protsesse raboty s kadmiem i metallicheskoi rtut'iu.

Based on the systematization of the experimental and epidemiological data on the toxicity of the compounds of mercury and cadmium and on the concept of a reasonable risk, the author has developed qualitative indices (criteria) required to analyze the safety of work associated with metallic mercury and cadmium at the dangerous industrial objects while declaring their safety. The fulfillment of these criteria ensures the high level of safety of mercury- and cadmium-associated work; it is in accord with the current trends in approaches to evaluating the safety of devices using toxically dangerous substances. The criteria considers the risk of human death due to the simultaneous intake of mercury vapors and cadmium oxide aerosols during accidents, as well as the level of chronic intake of these substances in different groups of persons on secondary dust formation (evaporation) after an accident.

Differential hepatotoxicity induced by cadmium in Fischer 344 and Sprague-Dawley rats.

A number of reports document that Fischer 344 (F344) rats are more susceptible to chemically induced liver injury than Sprague-Dawley (SD) rats. Cadmium (CdCl2), a hepatotoxicant that does not require bioactivation, was used to better define the biological events that are responsible for the differences in liver injury between F344 and SD rats. CdCl2 (3 mg/kg) produced hepatotoxicity in both rat strains, but the hepatic injury was 18-fold greater in F344 rats as assessed by plasma alanine aminotransferase (ALT) activity. This difference in toxicity was not observed when isolated hepatocytes were incubated with CdCl2 in vitro, indicating that other cell types contribute to Cd-induced hepatotoxicity in vivo. Indeed, the sieve plates of hepatic endothelial cells (EC) in F344 rats were damaged to a greater degree than EC in SD rats. Additionally, Kupffer cell (KC) inhibition reduced hepatotoxicity in both strains, suggesting that this cell type is involved in the progression of CdCl2-induced hepatotoxicity. Moreover, enhanced synthesis of heat shock protein 72 occurred earlier in the SD rat. Maximal levels of hepatic metallothionein (MT), a protein associated with cadmium tolerance, were greater in SD rats. These protective factors may limit CdCl2-induced hepatocellular injury in SD compared with F344 rats by reducing KC activation and the subsequent inflammatory response that allows for the progression of hepatic injury.

Association between cadmium concentration in rice and mortality in the Jinzu River basin, Japan.

A follow-up survey on 2101 inhabitants (1566 men, 535 women), who participated in a 1967 health survey and had resided in their present rural community since birth was conducted to determine the influence of environmental cadmium exposure on the mortality of the general population in the Jinzu River basin. The survey was conducted over 6128 days from August 1, 1967 to May 10, 1984. The rural communities were divided into two groups, one with a cadmium concentration in rice of < 0.30 ppm and the other > or = 0.30 ppm. The influence of cadmium concentration in rice on mortality was analyzed using SMRs and a Cox's proportional hazards model. In both sexes, SMRs tended to be greater in the > or = 0.3 ppm group as compared to < 0.3 ppm group. The Cox hazard ratios for males and females in the > or = 0.30 ppm group, to those in the < 0.30 ppm group, were 1.42 and 1.10, respectively (significant in the men). Since the mean cadmium concentration in rice in each rural community was closely related to the development of renal injury, in regions with high cadmium concentrations in rice, the development of renal injury induced by cadmium is believed to be the factor underlying the increased mortality observed.

Skeletal changes in multiparous, nulliparous and ovariectomized mice fed either a nutrient-sufficient or -deficient diet containing cadmium.

As a simulation of the etiological factors known for Itai-Itai disease, a syndrome characterized by osteomalacia and renal dysfunction in its Japanese victims, female mice were subjected to the individual and combined stresses of dietary cadmium, nutrient-deficient diet, multiparity and ovariectomy; the calcium-depleting effect of each factor was evaluated by determining Ca levels in femur and lumbar vertebrae. At age 68 days, female mice were given nutrient-sufficient (+) or -deficient (-), purified diets containing either 0.25 (environmental), 5, or 50 ppm Cd as CdCl2; the nutritional composition of (-) diet simulated that of food consumed by Japanese victims of Itai-Itai disease. At age 70 days, half of the females began a breeding regimen of six consecutive, 42-day rounds of pregnancy/lactation (PL mice); the remainder were maintained as virgin, non-pregnant controls (NP mice). Limited numbers of PL and NP mice were sacrificed at the end of each reproductive round. PL(+) mice taken at the end of round (R)-6 had successively borne litters in all six rounds, while PL(-) counterparts had nonsuccessively borne only three. At the conclusion of the 252-day reproductive period, remaining females entered the 392-day, post-reproductive phase of the experiment. At age 546 days (mid-R-12), PL females having successfully borne at least three litters were ovariectomized (OV) to mimic human menopause; at the same time, NP females were either ovariectomized or sham-operated (SO). After surgery, all females were maintained to age 714 days (mid-R-16), then sacrificed. During the post-reproductive period, food consumption by females of the same reproductive status was unaffected by elevated levels of Cd or nutrient-deficiencies in diet. However by R-16, Cd at 50 vs. 0.25 ppm had reduced body mass by 11% in both NP and PLOV females, femur and lumbar vertebral calcium content (TCa) by 20 and 25% in the respective groups, and femur and vertebral calcium/dry weight ratios (Ca/DW) by 12 and 11%. Alternative R-16 comparisons indicated that (-) diet also diminished skeletal Ca, but that the additional factors of (prior) multiparity and ovariectomy generated only small and non-significant effects. Comparison of skeletal status between the ends of the reproductive and post-reproductive periods indicated that (1) individual NP groups, regardless of Cd exposure, generally sustained small decreases in TCa and CaDW over time (consistent with aging), but PL groups without exception secured significant gains (consistent with cessation of multiparous activity), (2) skeletal integrity of PL groups was significantly more compromised by the combination of Itai etiological factors at the end of R-6 than R-16, and (3) among those factors, the most demineralizing over lifetime were chronic exposure to Cd followed by ingestion of (-) diet. Despite these findings, skeletal degeneration characteristic of the Itai-Itai syndrome was ultimately not duplicated in this mouse model suggesting that the full-blown disease required primary and profound skeletal demineralization secondarily supported and enhanced by renal dysfunction.

A global perspective on cadmium pollution and toxicity in non-occupationally exposed population.

Cadmium is a non-essential element that has high rates of soil to plant transference compared with other non-essential elements, and certain plant species accumulate large amounts of cadmium from low cadmium content soils. In this paper, levels of cadmium found in major food groups are highlighted together with cadmium levels found in liver and kidney samples from non-occupationally exposed populations. Data on human kidney cadmium levels identified recently, including the study in our own laboratory, are compared with older studies. Human-tissue cadmium contents showed large variations among individuals, but sources of the variation remain unknown. Exposure levels of 30-50 microg per day have been estimated for adults and these levels have been linked to increased risk of bone fracture, cancer, kidney dysfunction and hypertension. Increased mortality was found among individuals showing signs of cadmium renal toxicity compared with those without such signs, suggesting that renal toxicity may be an early warning of complications, sub-clinical or clinical morbidity.

Association between urinary calcium excretion level and mortality in inhabitants of the Jinzu River basin area of Japan.

A follow-up study on 5442 inhabitants (2699 men, 2743 women) was conducted to determine the association between urinary Ca excretion level and mortality of the general population of three different areas of the Jinzu River basin area, namely, non-Jinzu River, mixed, and the Jinzu River water systems, over a period of 6127 d. More than 98% of the subjects were followed completely in each area. In comparison with the low- and high-Ca-excretion groups (cutoff values; 25.1 mg/dL in men, 20.4 mg/dL in women), the mortality rates per 1000 person-years and standardized mortality ratios (SMRs) tended to be greater in the low-Ca-excretion groups than in the high-Ca-excretion groups in both sexes for each of the three areas. Moreover, Cox's hazard ratios in men and women of the three areas exhibited negative values, 0.99 except for men of the mixed water system. These values were statistically significant in both sexes for the Jinzu River water system and in women for the non-Jinzu River water system. We conclude that the life-span becomes shorter as urinary Ca excretion levels become lower.

[Health effects of air pollutants]. / Gesundheitliche Auswirkungen von Luftschadstoffen.

Air pollutants can exhibit both acute and chronic effects. Acute effects mainly occur during smog situations in industrial areas when atmospheric concentrations of hazardous substances are extremely high. This leads to an increase of morbidity and mortality especially in old and ill people. Chronic effects are the consequence of a longlasting exposition to low doses of noxious substances. Epidemiological studies have shown that frequency of respiratory diseases is higher in air polluted areas; this effect is particularly evident in smokers. Biological monitoring is used to determine the individual heavy metal burden. Lead is a danger especially for the developing central nervous system. Cadmium accumulates in the renal cortex during lifetime and may cause disturbances of renal function if a certain concentration is reached. The risk groups for heavy metals are young children and pregnant women in the case of lead and old people in the case of cadmium, respectively. Lung cancer incidence is higher in large cities than in rural areas. Carcinogenicity of city smog extracts was proved in vitro and in vivo. These findings suggest that urban air pollution may play a role as a causal factor in respiratory cancer.

Urinary beta 2-microglobulin concentration and mortality in a cadmium-polluted area.

A 9-y follow-up study of 3,178 persons who lived in a cadmium-polluted area was conducted to assess the influence of environmental cadmium exposure on long-term outcome. The standardized mortality ratios of the urinary beta 2-microglobulin-positive subjects (> 1,000 micrograms/g creatinine) of both sexes were higher than those of the general Japanese population, whereas the cumulative survival curves were lower than those of the urinary beta 2-microglobulin-negative group. A significant association was also found between urinary beta 2-microglobulin and mortality, using a Cox's proportional hazards model. Moreover, mortality rates increased in proportion to increases in the amount of urinary beta 2-microglobulin excreted. These results suggest that the prognosis for cadmium-exposed subjects with proximal tubular dysfunction is unfavorable. The mortality rate tended to become higher as the severity of renal dysfunction progressed.

High mortality and shortened life-span in patients with itai-itai disease and subjects with suspected disease.

A follow-up study was conducted from 1967 to 1987 for patients diagnosed as having itai-itai disease, subjects who were suspected of having the disease, and controls. Ninety-five subjects per category were selected after matching for age, sex, and residential area. The cumulative survival rate of the patients who had a definite diagnosis of itai-itai disease was significantly lower than that of the control group in every period after the first 3 y. The cumulative survival rate of the subjects who were suspected of having itai-itai disease and who had severe renal dysfunction due to cadmium pollution was significantly lower than that of the control group. These results demonstrate (1) the enduring negative influence of itai-itai disease on prognosis and (2) that the cadmium pollution-induced renal disorder adversely affects the health of the inhabitants of a cadmium-polluted area.

Total cadmium intake and mortality among residents in the Jinzu River Basin, Japan.

This study investigated the relationship between total cadmium intake and mortality among rural inhabitants of the Jinzu River Basin, Japan. A follow-up survey was conducted for 6,128 days on 3,236 inhabitants. The rural communities were divided into 2 groups, one with a total cadmium intake of < 2.0 gm and the other > or = 2.0 gm. Standardized mortality ratios and a Cox's proportional hazard model indicated mortality risk was greater in the > or = 2.0 gm group, compared with the < 2.0 gm group. In the Jinzu River Basin, a total cadmium intake > or = 2.0 gm exerts an adverse influence on life prognosis.

The epidemiological approach to cadmium pollution in Japan.

The study of health problems due to cadmium pollution in Japan originated from an endemic episode of Itai-itai disease in a rural area in north-central Japan after World War II. The disease was defined as osteomalacia with tubular changes in the kidney and considered to be associated with excess intake of cadmium. This episode motivated the Japanese Government to conduct health examinations on the general population in cadmium-polluted and non-polluted areas throughout the country since 1969. Although Itai-itai disease-like bone changes were rarely found, these studies revealed a higher prevalence of renal tubular dysfunction among elderly people in the cadmium-polluted areas. No significant difference was noted in cancer mortality, but mortality from cardiovascular diseases and all causes tended to be lower in cadmium-polluted areas. Clinical and pathological studies in man as well as experiments on primates have recently been made to elucidate the pathogenesis of Itai-itai disease and the health effects of cadmium. The lack of knowledge on the ecological and biological complex of cadmium resulted in the impediment of studies on this problem. The lesson from this experience is that basic research is essential for promoting the study of pollutants such as heavy metals, though pollution problems usually require urgent solutions.

[A study on the survival rates for patients and suspected patients with Itai-itai disease].

A follow-up study was carried out from January 1967 to December 1986 on 148 patients with Itai-itai disease, 130 suspected patients (persons requiring observation), and 212 controls who were living in the same community as patients with Itai-itai disease. The relative survival rates for the three groups were calculated from a life expectancy table. Except for 1973 data, comparison of the annual data from 1968 to 1986 showed that the relative survival rates in the patient group were significantly lower than those in the control group. The relative survival rates in the suspected patient group were significantly lower than those in the control group between 1981 and 1986. Recently the differences of the relative survival rates between the patient group and the suspected patient group have become smaller and are not significant. These results show the long-lasting influence of Itai-itai disease on the prognoses of patients and suspected patients.