Shift work is a risk factor for increased total cholesterol level: a 14-year prospective cohort study in 6886 male workers.

OBJECTIVES: The widespread adoption of 24 h continuous operations in a number of industries has resulted in an increase in shift work, which may influence lipid metabolism because of disturbed circadian rhythms, broken sleep and lifestyle problems. The objective of the present study was to assess the effect of shift work on serum total cholesterol as an index of lipid metabolism. METHODS: A 14-year prospective cohort study was conducted in day workers (n = 4079) and alternating shift workers (n = 2807) who received annual health check-ups between 1991 and 2005 in a Japanese steel company. The end-points were either a 20%, 25%, 30%, 35%, 40% or 45% increase in serum total cholesterol during the period of observation, compared with serum total cholesterol at entry to the study. The association between the job schedule type and increase in serum total cholesterol was investigated using multivariate pooled logistic regression analyses. The odds ratios for the effect of shift work were obtained after adjustment for a number of potential confounders. RESULTS: The significant odds ratios of alternating shift work (and 95% confidence intervals) were: >or=20%, 1.16 (1.07 to 1.26); >or=25%, 1.16 (1.05 to 1.28); >or=35%, 1.23 (1.05 to 1.43); >or=40%, 1.30 (1.07 to 1.58); and >or=45%, 1.28 (1.01 to 1.63) for serum total cholesterol. CONCLUSION: Generally the odds ratios of alternating shift work tended to be higher for stricter cut-points of relative increase in serum total cholesterol level. Our study in male Japanese workers revealed that alternating shift work adversely affected lipid metabolism.

Combination of the C1429T polymorphism in the G-protein beta-3 subunit gene and the A1330V polymorphism in the low-density lipoprotein receptor-related protein 5 gene is a risk factor for hypercholesterolaemia.

The present study examined the relationship between genetic combinations of the C1429T polymorphism in the G-protein beta-3 subunit (GNB3) gene and the A1330V polymorphism in the low-density lipoprotein receptor-related protein 5 (LRP5) gene and the risk of hypercholesterolaemia in Japanese workers. The present study included observations from 1997 to 2002 in 927 males and 662 females who were not hypercholesterolaemic on entry. The endpoint was the development of hypercholesterolaemia, defined as a total cholesterol level > or =240 mg/dl. The odds ratios for the combination of polymorphisms were calculated using pooled logistic regression analyses that incorporated other potential factors into the model. The odds ratios in males and females with GNB3/1429TT and LRP5/1330VV or AV genotypes were 4.17 compared to males with the 1429CT or TT and 1330AA genotypes and 3.53 compared to females with the 1429CC, CT or TT and 1330AA genotypes. Assuming these effects were a mere addition of two independent effects, the odds ratios for both GNB3/1429TT and LRP5/1330VV or AV were estimated to be 3.27 for males and 1.42 for females. Therefore, the synergic effects were shown to be 1.28 times in males (not significant) and 2.49 times in females (P<0.05 by bootstrap method). These results provide clear evidence that the genetic combination has a synergic effect. This study indicates that the combination of GNB3/C1429T and LRP5/A1330V is a very useful marker for predicting the development of hypercholesterolaemia in the general Japanese population.

Skipping breakfast and 5-year changes in body mass index and waist circumference in Japanese men and women.

OBJECTIVE: This study investigated the relationship between frequency of skipping breakfast and annual changes in body mass index (BMI) and waist circumference (WC). METHODS: The participants were 4,430 factory employees. BMI and WC were measured repeatedly at annual medical examinations over a 5-year period. The association between frequency of skipping breakfast at the baseline examination and annual changes in anthropometric indices was evaluated using the generalized estimating equation method. RESULTS: The mean (standard deviation) BMI was 23.3 (3.0) kg m-2 for men and 21.9 (3.6) kg m-2 for women; and the mean WC was 82.6 (8.7) cm for men and 77.8 (9.8) cm for women. During the follow-up period, mean BMI increased by 0.2 kg m-2 for men and women, and mean WC increased by 1.1 cm for men and 1.0 cm for women. The annual change in the BMI of men who skipped breakfast four to six times per week was 0.061 kg m-2 higher, and that of those who skipped breakfast seven times per week was 0.046 kg m-2 higher, compared with those who did not skip breakfast. Annual changes in the WC of male participants who skipped breakfast seven times per week was 0.248 cm higher than that of those who did not skip breakfast. Skipping breakfast was not associated with changes in BMI or WC in women. CONCLUSIONS: Skipping breakfast was closely associated with annual changes in BMI and WC among men, and eating breakfast more than four times per week may prevent the excessive body weight gain associated with skipping breakfast.

Causes of death and renal tubular dysfunction in residents exposed to cadmium in the environment.

OBJECTIVES: To clarify the causes of death of residents with renal tubular dysfunction induced by cadmium (Cd) in the environment. METHODS: A 15 year follow up study was performed with the inhabitants living in the Cd polluted Kakehashi River basin in Japan. Standardised mortality ratios (SMRs) for causes of death, classified by ICD-9, were computed using the person-years method to investigate the excess mortality of subjects with urinary beta2-MG (microglobulin) > or =1000 microg/gCr. Mortality risk analysis was performed using Cox's proportional model to compare mortality between subjects with urinary beta2-MG > or =1000 and <1000 microg/gCr, and to investigate the relationship between the degree of urinary beta2-MG and mortality. RESULTS: Excess mortality due to heart failure and cerebral infarction in both sexes, and nephritis and nephrosis in men, was observed among subjects with urinary beta2-MG > or =1000 microg/gCr. Significant increases in mortality risk for cerebral infarction in men and for malignant neoplasms in women with urinary beta2-MG > or =1000 microg/gCr were observed during the first five year observation period. For nephritis and nephrosis, the mortality risks for men and women with urinary beta2-MG > or =1000 microg/gCr significantly increased over the 15 year observation period. The mortality risks for heart failure and cerebral infarction increased in proportion to the increased urinary beta2-MG in both sexes. Increased mortality risks for nephritis and nephrosis were identified in the subjects with urinary beta2-MG > or =10000 microg/gCr in both sexes. CONCLUSION: Renal tubular dysfunction induced by Cd affected the causes of death, and mortality for heart failure, cerebral infarction, and nephritis and nephrosis was increased among inhabitants living in a Cd polluted area in Japan. In women, cancer mortality may have been increased while Cd pollution was ongoing.

Biologic indicators of cadmium nephrotoxicity in persons with low-level cadmium exposure.

The relationship between abnormal urinary findings and renal function was investigated for 33 Itai-Itai patients, 17 suspected patients, 235 subjects exposed to Cd and 41 subjects not exposed to Cd pollution. High correlation coefficients were observed between urinary findings and renal function in advanced cases of chronic cadmium poisoning, and multiple correlation coefficients between them are as high as 0.73 to 0.86. beta 2-microglobulin in urine also correlated closely with renal function and age in slight to moderate cases of cadmium poisoning. It is concluded that urinary findings such as proteinuria, glucosuria and low molecular weight proteinuria are good indicators of renal dysfunction in moderate to severe cases of chronic cadmium poisoning. In slight to moderate cases beta 2-microglobulin in urine has a close relation with renal dysfunction.

Pulmonary and gastrointestinal exposure to cadmium oxide dust in a battery factory.

The elimination of cadmium in feces was studied in a group of 15 male workers exposed to cadmium oxide dust in a nickel-cadmium battery factory. The elimination of cadmium in feces was on the average 619 and 268 microgram/day in seven smokers and eight nonsmokers, respectively. The corresponding ranges were 97-2577 and 31-1102 microgram/day. The cadmium concentrations in blood were significantly higher in smokers than in nonsmokers, both before and after one month of vacation. Among the smokers there was a significant decrease in the cadmium concentrations during the vacation period, but not among the nonsmokers. It was estimated that cadmium naturally occurring in food and cigarettes, cadmium excreted from the gastrointestinal tract, and cadmium transported from the lungs by mucocillary clearance to the gastrointestinal tract only could explain up to 100 microgram of the cadmium in the feces. Since even among some nonsmokers much higher values for fecal cadmium were recorded, this was interpreted as being the result of ingestion of cadmium from contaminated hands and other body surfaces. Among the smokers, direct oral contact with contaminated cigarettes or pipes is an additional factor; the smokers also inhale cadmium in the tobacco smoke from contaminated cigarettes. Part of that cadmium is transferred to the gastrointestinal tract by mucociliary clearance and also adds to the fecal cadmium.

A study of the relationship between cadmium concentrations in urine and renal effects of cadmium.

The relationship between urinary cadmium concentration expressed as microgram/g creatinine and renal effects of cadmium exposure was studied in 542 inhabitants over 20 years of age who lived in the Jinzu River basin which is polluted by cadmium. Cadmium concentration in urine was employed as the index of cadmium exposure. Total protein with glucose, beta 2-microglobulin, retinol binding protein, and proline served as indices of renal effects. The prevalent rate of high beta 2-microglobulin excretion was the highest among these indices both in men and women. Prevalence rates of indices of renal effects increased proportionally with increasing cadmium concentrations in urine and probit linear regression lines could be calculated between them. The urinary cadmium concentrations corresponding to 1% prevalence rates of indices of the renal effects were calculated by the regression line. For beta 2-microglobulin, 3.2 microgram Cd/g creatinine and 5.2 microgram Cd/g creatinine were obtained in men and women, respectively. This method may be useful for evaluating the risk of renal damage of exposed inhabitants.

Alcohol consumption and blood pressure change: 5-year follow-up study of the association in normotensive workers.

This study endeavours to clarify the effect of alcohol consumption on changes in the blood pressure of Japanese men. The subjects, who were followed from 1990 to 1995, were 2189 male normotensive steelworkers aged from 40 to 54 years in 1990. Drinking habits were represented by two variables: average daily baseline alcohol consumption, and change in alcohol consumption during the observation period, both derived from self-report questionnaires and interviews. Nine other items were analysed as covariates: systolic and diastolic blood pressure, age, body mass index (BMI), salt intake, physical activity, and levels of gamma glutamyl transpeptidase (GTP), uric acid and plasma glucose in 1990. The association between drinking habits and blood pressure was evaluated using ANCOVA. Subjects who had initiated antihypertensive therapy by 1995 were excluded from this dataset. The results of analysis disclosed that both daily alcohol consumption and its change were significantly associated with changes in systolic and diastolic blood pressure during the observation period. J-shaped associations of daily alcohol consumption with adjusted changes in systolic and diastolic blood pressure were found. Positive associations were observed between changes in alcohol consumption and adjusted changes in systolic and diastolic blood pressure. In conclusion, daily alcohol consumption was associated non-linearly with changes in blood pressure and with a threshold effect at 18 ml of ethanol per day in these middle-aged Japanese workers. In addition, increasing alcohol consumption was associated with blood pressure elevation, and decreasing consumption was associated with suppression of blood pressure elevation.

An association between smoking habits and blood pressure in normotensive Japanese men.

We conducted a cross-sectional study to clarify the dose-effect relationship of smoking habits with blood pressure in Japanese men. The subjects were 2781 normotensive male steelworkers ranging in age from 40 to 54 years. They were classified into five categories according to their smoking habits: non-smokers, ex-smokers, light smokers, moderate smokers and heavy smokers. Age, body mass index, salt intake, physical activity, drinking habits, and levels of gamma-glutamyl transpeptidase, total serum cholesterol, uric acid, creatinine and plasma glucose were analysed as covariates. The association between smoking habits and blood pressure was evaluated using analysis of covariance. Our results showed that there was no significant difference in the adjusted systolic and diastolic blood pressure between non-smokers and ex-smokers. The adjusted systolic and diastolic blood pressures in light, moderate and heavy smokers were significantly lower than in non- and ex-smokers. However, among smokers, no significant difference was observed in correlation with smoking amount. In conclusion, blood pressure of smokers was lower than that of non- and ex-smokers. However, there were no significant dose-effect relationships between smoking amount and blood pressure when lifestyle and other confounding factors were considered.

Relationship between serum gamma-glutamyl transpeptidase activity, blood pressure and alcohol consumption.

The associations among alcohol consumption, gamma-glutamyl transpeptidase (gamma-GTP) activity in serum and blood pressure (BP) were analysed in a cross-sectional study of 1,156 healthy male workers 35 to 59 years of age, consisting of 349 non-drinkers, 682 light-daily drinkers (consuming less than 58 ml of alcohol per day) and 125 heavy-daily drinkers consuming more. No marked elevation of BP with high alcohol consumption was seen in the present subjects. On the other hand, a linear elevation of BP together with an increase in serum gamma-GTP activity was found in subjects above 40 years of age. The BP levels corresponding to the three different drinking habits, non-drinkers, light drinkers and heavy drinkers, were similar to each other regarding gamma-GTP levels. The relationship between gamma-GTP and BP was shown, by multiple regression analysis, to be independent of age, obesity and the dose of alcohol consumed. The contribution to the rise in BP of the dose of alcohol consumed, in comparison with that of gamma-GTP, was negligible. Serum gamma-GTP activity is a useful indicator of the susceptibility to the pressor effect of alcohol.

Dose-response relationship between total cadmium intake and metallothioneinuria using logistic regression analysis.

The dose-response relationship for environmental cadmium exposure was assessed using logistic regression analysis. The prevalence of metallothioneinuria was employed as a response variable, while age and total cadmium intake, calculated from the average cadmium concentration in rice and duration of residence in the cadmium-polluted area, were used as explanatory variables. The target population comprised of 1843 cadmium-exposed and 240 non-exposed inhabitants of Ishikawa, Japan. The individuals were divided into 96 subgroups by sex, age (4 categories), cadmium concentrations in rice (3 categories) and length of residence in the polluted area (4 categories). Only total cadmium intake had a significant association with the prevalence of metallothioneinuria. In the non-exposed subjects total cadmium intakes corresponding to 2.5% prevalence of metallothioneinuria were calculated. Based on metallothionein levels expressed as either microgram/l urine or microgram/g creatinine, the total intakes were: 2.221 or 2.207 g in men and 2.365 or 0.319 g in women, respectively. Most of these values were similar to those reported by us previously, employing simple regression analysis. It is concluded, therefore, that a maximum allowable intake of about 2 g cadmium is a reasonable estimate for preventing the cadmium-induced renal dysfunction.

Dose-response relationship between urinary cadmium and metallothionein in a Japanese population environmentally exposed to cadmium.

The dose-response relationship between cadmium (Cd) exposure and renal dysfunction, as measured by urinary Cd and metallothoinein (MT), was evaluated in a population living in the Kakehashi River basin, a Cd-polluted area in Japan. Morning urine specimens were collected from 1397 men and 1713 women who were 50 years or older. In addition, urine specimens were collected from a control population consisting of 110 men and 130 women. The 97.5% upper limits for MT in the control population were used to determine the prevalence rates for MT-uria at various urinary Cd concentrations. Probit linear regression analysis showed significant dose-response relationships between MT and Cd. In the control population, prevalence rates of MT-uria for men and women were 1.8 and 3.1%, respectively. Based on the prevalence rates of MT-uria in the control population, the upper limits for the urinary Cd concentrations were calculated from the slopes of the regression lines to be 4.2 and 4.8 micrograms/g creatinine for men and women, respectively. These values, which are similar to those reported previously using urinary beta 2-microglobulin as the indicator, may be of use in establishing the biological threshold, i.e. maximum allowable concentration, for urinary Cd in the environmentally exposed Japanese population.

Dose-response relationship between dietary cadmium intake and metallothioneinuria in a population from a cadmium-polluted area of Japan.

An epidemiological study to examine the dose-response relationship for environmental cadmium exposure was performed in 1843 cadmium-exposed and 240 non-exposed inhabitants of the Kakehashi River basin in Ishikawa, Japan. The average cadmium concentration in rice from each village was employed as an indicator of cadmium exposure and the individuals were grouped according to the length of residence in the polluted area. Metallothioneinuria was used as an index of renal tubular dysfunction produced by the chronic exposure to cadmium. A dose-related increase in metallothioneinuria was observed. The chronic total cadmium intake resulting in metallothioneinuria in this population was calculated to be approximately 2 g for both men and women. The cumulative lifetime dose of 2 g cadmium over a 50-year period, means an average daily intake of 110 micrograms. Thus, these values may be regarded as the maximum allowable lifetime and daily intake limits, respectively for chronic dietary exposure to cadmium.

Elevated urinary excretion of metallothionein due to environmental cadmium exposure.

Metallothionein, a low molecular weight cadmium-binding protein, has been determined for the first time in urine of "itai-itai" disease patients and other Japanese women environmentally exposed to cadmium. On a group basis, the urinary metallothionein levels of "itai-itai" disease patients and suspected patients were significantly higher than that of women living in a cadmium-polluted area. Women living in a non-polluted area excreted significantly less metallothionein than women living in a cadmium-polluted area. A similar trend was observed for urinary beta 2-microglobulin, a nonspecific index of renal tubular dysfunction. However, mean levels of urinary cadmium in the "itai-itai" disease patients, suspected patients and women living in the cadmium-polluted area were similar. It is suggested that if, in addition to beta 2-microglobulin and cadmium, metallothionein is used as another index of cadmium exposure, monitoring of renal tubular dysfunction caused by cadmium may be more effectively carried out.

Urinary excretion levels of sodium and potassium in environmental cadmium-exposed subjects.

The urinary excretion levels of sodium (Na) and potassium (K) in cadmium (Cd)-exposed subjects as related with urinary beta2-microglobulin (beta2-MG) and Cd concentrations were investigated. The target population comprised of 3164 inhabitants of Japan who were more than 50 years of age and who lived in cadmium-polluted areas and 294 inhabitants who lived in non-polluted areas of Japan. A significant increase in urinary excretion of K was shown in Cd-exposed subjects although there was no significant difference in urinary excretion of Na between the Cd-exposed and non-exposed subjects. Urinary K concentrations in both sexes were significantly correlated with age, urinary beta2-MG and Cd concentrations by multiple regression analysis. Urinary Na concentration was significantly correlated with age, beta2-MG and Cd in men, but in women it was significantly associated with only the urinary beta2-MG concentration. The present study demonstrated that increased K excretion was a more sensitive effect of cadmium exposure than increased Na excretion.

Prevalence of metallothioneinuria among the population living in the Kakehashi River basin in Japan--an epidemiological study.

An epidemiological study to evaluate cadmium-induced renal dysfunction by urinary metallothionein levels was carried out in an environmentally-exposed Japanese population. The study population consisted of 3168 men and women from a cadmium-polluted area who were 50 years and older and 291 individuals from a non-polluted area. The mean metallothionein levels in urine of the control population were 138.2 +/- 2.1 and 198.6 +/- 1.9 microgram/g creatinine for men and women, respectively. The corresponding values for the cadmium-exposed population were 157.8 +/- 2.2 and 248.0 +/- 2.2. The 97.5% upper limits for men in the control population was determined to be 638 and for women 693 microgram MT/g creatinine. Based on these values as the cut-off levels, the prevalence of metallothioneinuria was calculated to be 4.6% in men and 8.4% in women from the cadmium-polluted area. Further selection of the population, based on life-time residence in the polluted area accompanied with the consumption of cadmium-containing rice, showed an even greater prevalence of metallothioneinuria: 5.4% in men and 10.9% in women of all ages. The prevalence of metallothioneinuria increased with age and duration of residence in the polluted area. These results suggest that metallothioneinuria can be used as an indicator of renal dysfunction due to environmental cadmium exposure.

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.

Dose-response relationship between urinary cadmium and beta 2-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.

Dose-response relationship between total cadmium intake and beta 2-microglobulinuria using logistic regression analysis.

The dose-response relationship between total cadmium intake and beta 2-microglobulinuria was investigated using logistic regression analysis in order to consider the effect of age on this association. The target population consisted of 1850 inhabitants of the cadmium-polluted Kakehashi River basin in Ishikawa prefecture, Japan. They were divided into 58 subgroups (27 in the men and 31 in the women) by four factors of sex, age, rice cadmium concentration and length of residence in cadmium-polluted areas. Logistic regression analysis was performed for this dose-response relationship, and both age and total cadmium intake were significantly associated with beta 2-microglobulinuria. It was confirmed that total cadmium intake had a significant association with beta 2-microglobulinuria, independent of the aging effect.

Urinary N-acetyl-beta-D-glucosaminidase and beta 2-microglobulin in 'itai-itai' disease.

N-acetyl-beta-D-glucosaminidase (NAG) activity in urine was measured in patients with 'itai-itai' disease, from chronically advanced cadmium poisoning. Elevation of NAG activity, however, was not so marked as that of beta 2-microglobulin (beta 2-MG) in the urine of patients and suspected patients. We conclude that the beta 2-MG test is more valuable than the NAG test for evaluating the severity of the renal tubular damage in chronically advanced cadmium (Cd) poisoning.