Koji Nogawa

Progress of renal dysfunction in inhabitants environmentally exposed to cadmium

The reversibility of beta 2-microglobulinuria, glucosuria, and aminoaciduria was examined in 74 inhabitants (32 males and 42 females) over 50 yr of age, who lived in a cadmium-polluted area. The subjects participated in two examinations conducted just after the cessation of cadmium exposure and 5 yr later. All urinary parameters did not show reversible changes. During the 5 yr the geometric mean concentrations of beta 2-microglobulinuria, glucosuria, and aminoaciduria indicated significant increases in excretion. In cases where greater than 1,000 micrograms/g creatinine of beta 2-microglobulinuria was observed (at the time cadmium exposure ended), almost all individuals exposed to cadmium showed deterioration of beta 2-microglobulinuria, whereas in the case of less than 1,000 micrograms/g creatinine of beta 2-microglobulinuria, no significant changes were observed. The present study indicates that cadmium-induced renal dysfunction in individuals environmentally exposed to cadmium is irreversible.

A dose-response analysis of cadmium in the general environment with special reference to total cadmium intake limit

An epidemiological study on the dose-response relationship of cadmium was performed on 1850 Cd-exposed and 294 nonexposed inhabitants of the Kakehashi River basin in Ishikawa Prefecture. beta 2-microglobulinuria was used as an index of the effect of cadmium on health and the average cadmium concentration in locally produced rice was employed as an indicator of cadmium exposure. Cadmium exposure was found to affect health in a dose-related manner when the subjects were classified according to the average cadmium concentration in their village rice and their length of residence in the polluted area. Based on the available data, the total cadmium intake that produced an adverse effect on health was calculated as approximately 2000 mg for both men and women.

Mechanism for bone disease found in inhabitants environmentally exposed to cadmium: decreased serum 1α, 25-dihydroxyvitamin D level

SummaryTo investigate the mechanism for bone disease caused by exposure to cadmium serum samples were collected from 5 itai-itai disease patients, 36 Cd-exposed residents with renal tubular damage and 17 non-exposed individuals and analyzed for 1α,25-dihydroxyvitamin D[1α, 25(OH)2D], parathyroid hormone, β2-microglobulin, calcium and inorganic phosphorus. Measurement of percentage tubular reabsorption of phosphate (%TRP) were performed only on the Cd-exposed subjects. Serum 1α, 25(OH)2D], levels were lower in itai-itai disease patients and cadmium-exposed subjects with renal damage than in non-exposed subjects. Parathyroid hormone and β2-microglobulin concentrations in serum were higher in the Cd-exposed subjects. Decrease in serum 1α,25(OH)2D levels were closely related to serum concentrations of parathyroid hormone, β2-microglobulin and %TRP. This study suggests that cadmium-induced bone effects were mainly due to a disturbance in vitamin D and parathyroid hormone metabolism, which was caused by the cadmium-induced kidney damage.

The association between renal dysfunction and osteopenia in environmental cadmium-exposed subjects.

Two hundred and three cadmium (Cd)-exposed subjects with renal dysfunction and 80 non-exposed subjects were examined to reveal the relationship between Cd-induced renal dysfunction and osteopenia. As biological indicators of renal function, urinary beta 2-microglobulin (beta 2-mg), and serum creatinine, calcium, and phosphorus were selected. Cd in the urine and blood was also measured. The results indicated that significant differences exist between both sexes in Cd-exposed as well as nonexposed subjects. To evaluate the degree of osteopenia, a microdensitometrical (MD) method was used. The relationships between biological parameters and each index of the MD method were analyzed using multivariate analysis. Age, urinary beta 2-mg, and serum creatinine were significantly associated with indices of osteopenia in Cd-exposed men. In contrast, age showed the most significant association with MD indices in women of both groups. However, urinary beta 2-mg was significantly associated with MD indices only in Cd-exposed women. In Cd-exposed subjects, after the number of predictor variables was increased, urinary beta 2-mg was also strongly associated with osteopenia. These results suggest a causal relationship between renal dysfunction and osteopenia in Cd-exposed subjects.

Urinary metallothionein as a new index of renal dysfunction in "Itai-Itai" disease patients and other Japanese women environmentally exposed to cadmium.

The significance of elevated excretion of metallothionein in urine of women living in cadmium-polluted and non-polluted areas of Japan was studied with respect to renal dysfunction. The relationships between the concentrations of metallothionein in urine and those of other non-specific urinary indices of renal dysfunction, i.e., total protein, glucose, β2-microglobulin, retinol-binding protein, α-amino nitrogen and proline were examined. In addition, the relationships between urinary metallothionein and urinary cadmium and copper were also evaluated. It was found that the logarithm of the metallothionein concentration in urine was significantly correlated with the logarithm of the concentrations of each of the above parameters. When subjects with signs of renal dysfunction, including “itai-itai” disease patients and patients suspected of the disease, were compared with subjects with normal renal functions, as a group, the former excreted significantly higher concentrations of metallothionein in their urine than the latter. The results suggest that the elevated excretion of metallothionein is not only an index of excessive cadmium exposure, but also of renal dysfunction caused by chronic exposure to this metal.

Long-term observation of serum creatinine and arterial blood pH in persons with cadmium-induced renal dysfunction.

Twenty-one subjects who had cadmium (Cd)-induced renal dysfunction and who lived in a Cd-polluted area in Japan were investigated to determine changes in their renal function. Since 1974, serum creatinine and arterial blood pH were measured annually during the autumn months for 9-14 y. Mean serum creatinine was significantly increased during this period, i.e., from 1.19 +/- 1.28 mg/100 ml to 1.68 +/- 1.56 mg/100 ml. Even after cadmium exposure ceased, significant deterioration of glomerular filtration was found. Eleven subjects showed a greater than 20% serum creatinine increase during this period. The most severe case had a serum creatinine value of 4.4 mg/100 ml at the most recent examination and experienced generalized edema, which suggests a clinical diagnosis of renal failure. The mean arterial blood pH values decreased significantly in all subjects, i.e., from 7.400 +/- 0.023 to 7.361 +/- 0.034. The 11 subjects cited above also showed a significant decrease and progression of tubular dysfunction after Cd exposure ceased. Our findings suggest that Cd-induced renal tubular dysfunction and decreased glomerular filtration are aggravated even after cessation of environmental Cd exposure, and in some cases this renal dysfunction may progress to renal failure.

Cadmium, zinc and copper relationships in kidney and liver of humans exposed to environmental cadmium

Cadmium, copper and zinc have been determined in kidney cortex, kidney medulla and liver from 51 cadmium-polluted and 122 nonpolluted autopsied subjects. Liver cadmium and zinc were significantly higher in the cadmium-polluted subjects than in the nonpolluted subjects. Kidney cadmium, copper and zinc were lower in the cadmium-polluted subjects because of renal damage. Significant correlations of the three metals were found in the kidney. In the liver the correlation coefficients were significant only between cadmium and zinc.

Osteopenia in inhabitants with renal dysfunction induced by exposure to environmental cadmium

SummaryBone density was measured in 28 women with itai-itai disease, 92 men and 114 women with cadmium-induced renal dysfunctions and 44 men and 66 women living in the three different non-polluted areas using a microdensitometer. The values of both indices corresponding to cortical width and bone mineral content were significantly lower in itai-itai disease patients than the cadmium-exposed women with renal dysfunctions and the non-exposed subjects. The cadmium-exposed women also showed a decrease in bone density compared with the non-exposed subjects. A significant decrease in bone density was also observed between cadmium-exposed men and the non-exposed subjects, although the difference was not as clear as in the women. The present study indicates that exposure to cadmium could cause marked osteopenia, particularly in the women.

Critical concentration of cadmium in kidney cortex of humans exposed to environmental cadmium

Cadmium (Cd) was determined in kidney cortex and liver of 173 autopsied Japanese. Subjects consisted of 51 persons from Cd-polluted areas ages between 61-94 years and 122 controls ages between 3-90 years. The mean Cd concentrations for the Cd-polluted group were 35.2 micrograms/g wet wt for kidney cortex and 66.7 micrograms/g wet wt for liver. Corresponding values for the control group aged over 60 were 90.1 and 10.7, respectively. Both liver and kidney cortex Cd were analyzed for 127 subjects (41 Cd-polluted and 86 control subjects). The kidney cortex concentration tended to increase linearly with increasing liver concentrations up to approximately 20 micrograms/g of liver Cd; above this value there was no further increase in kidney cortex level. Only three persons showed kidney cortex Cd levels above 200 micrograms/g. The lowest liver Cd levels of the Cd-polluted subjects with renal damage were around 30 micrograms/g. The critical level of kidney cortex Cd may exist below 200 micrograms/g in humans exposed to environmental Cd. The corresponding value for the liver may be below 30 micrograms/g wet wt.

Leukocytosis and low serum IgA in workers exposed to the epoxy compound, t-methyl-3-phenylglycidate

SummaryForty-nine out of 54 male workers engaged in the production of an epoxy compound, t-methyl-3-phenylglycidate, showed skin symptoms in varing degrees that may be due to the skin-irritative effect of the compound. The exposed workers were also shown to have subjective symptoms which may be related to the irritative property of the compound on surface tissue. Laboratory examinations on the blood obtained from the exposed workers showed significantly higher values of leukocyte concentration as compared with the non-exposed controls. This was chiefly caused by the increase of neutrophilic granulocytes and T-cell lymphocytes. Serum IgA levels of the exposed workers were shown to be significantly lower than those of the control group. Hemoglobin concentration, hematocrit value and red cell count of the exposed workers remained at the same level as those of the control subjects. Liver or kidney damage was not found in biochemical analyses on the sera of exposed workers.