Ikiko Tsuritani

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 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.

Impact of obesity on musculoskeletal pain and difficulty of daily movements in Japanese middle-aged women.

OBJECTIVE To investigate the impact of obesity on musculoskeletal pain and disability, which impairs well-being, associations between body mass index (BMI), frequency of musculoskeletal pain and difficulty of daily movements were assessed in middle-aged women. METHODS Subjects were 709 Japanese women in a community, aged 40-69. Measured BMI, current smoking habits, frequency of pain (pain score)(rarely (0), occasionally (1) or frequently (2)) during the last 1 month at shoulders, neck, upper back, lower back and legs, difficulty of three daily movements: walking continually for more than a half hour, climbing stairs and sitting on the floor with ones legs bent beneath one another, (score for each movement) (rarely (0), occasionally (1) or frequently (2)) by a questionnaire. The summed score was defined as the difficulty score of daily movements (DS) (0-6). RESULTS BMI increased significantly with age. Lower back pain (occasionally or frequently) was the most common symptom (40.3%) in the subjects. There was a peak in prevalence of frequent pain of shoulders at age 50. Pain score for legs and DS increased significantly with age. Higher BMI was related to increased prevalence of frequent leg pain and DS (>or=3), but there were no significant associations between age or BMI, and scores of back pain. DS was correlated significantly with pain scores at shoulders, upper back, lower back and legs. After adjustment for age and smoking habit using a logistic regression analysis, odds ratios for frequent pain at legs and DS (>or=3) were 4.02 (CI: 1.83-8.80) and 2.92 (CI: 1.56-5.47), respectively, in the obese women (BMI>or=26.4, n=61), compared with 401 women with normal BMI (20-24). CONCLUSION Obesity tended to impair well-being through musculoskeletal pain at legs and difficulty of daily movements in Japanese middle-aged women.

Urinary cadmium excretion is correlated with calcaneal bone mass in Japanese women living in an urban area.

Nine hundred eight women aged 40-88 years living in a non-Cd-polluted area in Japan were analyzed for urinary cadmium (Cd), N-acetyl-beta-D-glucosaminidase (NAG) activity, beta(2)-microglobulin (B2MG) concentration, and for the stiffness index (STIFF) of calcaneal bone using an ultrasound method. The urinary Cd in the subjects, with a mean and range of 2.87 and 0.25-11.4 microg/g creatinine, respectively, showed a significant correlation with NAG but not with B2MG. STIFF was significantly inversely correlated with urinary Cd, and the association remained significant after adjusting for age, body weight, and menstrual status, suggesting a significant effect of Cd on the bone loss in these subjects without signs of Cd-induced kidney damage. A two-fold increase in urinary Cd was accompanied by a decrease in STIFF corresponding to a 1.7-year rise in age. These results emphasize the need for reassessment of the significance of Cd exposure in the general Japanese population.

Alcohol, high blood pressure, and serum gamma-glutamyl transpeptidase level.

The influence of the level of serum gamma-glutamyl transpeptidase, a biological marker of alcohol consumption, on elevations of blood pressure and on the development of hypertension related to increases in alcohol consumption was determined in a cross-sectional study of 1,492 middle-aged male workers and in a subsequent 5-year follow-up study of 1,393 workers. Blood pressure levels, as well as the prevalence and incidence of hypertension, were higher in the subjects with serum gamma-glutamyl transpeptidase levels above 50 units/l than in those with normal levels. These differences were more marked in drinkers who consumed 30 ml or more of alcohol per day. Thus, elevated serum gamma-glutamyl transpeptidase activity may identify drinkers at higher risk for the development of alcohol-related hypertension.

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.

Dose-response relationship between urinary cadmium and β2-microglobulin in a Japanese environmentally cadmium exposed population

This study was carried out to test the dose-response relationship between urinary cadmium (Cd) and beta 2-microglobulin(beta 2-mg) and also to estimate the biological threshold value of urinary Cd concentration in inhabitants exposed to environmental Cd. Urinary Cd and beta 2-mg were measured in 3178 inhabitants over 50 years of age in the Cd-polluted Kakehashi River basin in Japan and 294 inhabitants in non-polluted areas. Urinary Cd and beta 2-mg were significantly higher in the Cd-exposed subjects than in the non-exposed subjects. Prevalence rates of beta 2-microglobulinuria(beta 2-mg-uria) increased proportionally with increasing urinary Cd concentrations and probit linear regression lines could be calculated between them. The urinary Cd concentration corresponding to the prevalence rates of beta 2-mg-uria among non-exposed subjects was calculated using the regression line, and values of 3.8-4.0 micrograms Cd/g creatinine for men and 3.8-4.1 micrograms Cd/g creatinine for women, respectively, were obtained. These values may be of use in establishing the biological threshold of urinary Cd concentration in environmentally Cd-exposed populations.

Contribution of Genetic Polymorphisms in Ethanol- Metabolizing Enzymes to Problem Drinking Behavior in Middle-Aged Japanese Men

Among ethanol-metabolizing enzymes, the ALDH2*2 allele, ADH2*2 allele, and c2 allele of the cytochrome P450-2E1 (CYP2E1) gene are unique to Orientals. This prompted us to analyze their contribution to drinking behavior in 322 middle-aged Japanese men. The ALDH2*2 allele, detected in nearly half of the subjects, showed an overwhelming protective effect against a high level of alcohol consumption and problem drinking behavior, as determined by the Kurihama Alcoholism Screening Test (KAST). The ADH2*2 allele, in 95% of the subjects, exhibited an additive suppressive effect on alcohol consumption, whereas the c2 allele of CYP2E1, in 40% of the subjects, was associated with greater alcohol consumption. Problem drinkers showing a KAST score of 2.0 or higher were frequent among the few subjects with the ADH2*1/1 genotype, but not in the large number of subjects having the c2 allele of CYP2E1. These findings may explain, at least in part, why in Japan the number of alcoholic patients is small relative to the number of heavy drinkers.