Kazuhiro Nogawa

Reassessment of the threshold of urinary cadmium by using hybrid approach in a cadmium non-polluted area in Japan

BACKGROUND AND OBJECTIVES We applied an updated hybrid approach to estimate the benchmark doses (BMD) and their 95% lower confidence limits (BMDL) for cadmium-induced renal effects as the threshold of urinary cadmium in humans. Using this method, the BMD and BMDL were estimated based on continuous exposure and continuous effect marker, thereby avoiding categorization of subjects, an inevitable outcome of previously used approaches. METHODS The target subjects were 547 men and 723 women, aged 50 years or older, who lived in a cadmium non-polluted area of Japan. We measured urinary cadmium (U-Cd) as a marker of long-term exposure, and urinary protein, β2-microglobulin (β2-MG) and N-acetyl-β-D-glucosaminidase (NAG) as renal effect markers. BMD and BMDL corresponding to an additional risk (BMR) of 5%, were calculated with the background risk at zero exposure set at 5%. RESULTS AND CONCLUSIONS The BMDL of U-Cd for renal effect markers were 2.1 (urinary protein), 2.6 (β2-MG) and 4.1 (NAG) μg/g creatinine in men and 1.5 (urinary protein), 1.4 (β2-MG) and 3.1 (NAG) μg/g creatinine in women. The BMDLs in the present study may contribute to further discussion on health risk assessment of cadmium exposure, when compared to BMDLs obtained by previously reported methods.

ESTIMATION OF THE BENCHMARK DURATION OF SHIFTWORK ASSOCIATED WITH WEIGHT GAIN IN MALE JAPANESE WORKERS

The authors estimated the benchmark durations (BMDs) and their 95% lower confidence limit (BMDL) for the reference duration of shiftwork for weight gain. A 14-yr prospective cohort study was conducted in male workers at a Japanese steel company (n = 7254) who had received annual health check-ups between 1991 and 2005. The endpoints in the study were either a 5%, 7.5%, or 10% increase in body mass index (BMI) during the period of observation, compared to the BMI at entry. The association between the duration of shiftwork and weight gain was investigated using multivariate pooled logistic regression analyses with stepwise selection of covariates, including age, BMI measured during the study, drinking and smoking habits, and habitual exercise. The BMDL/BMD for shiftwork in subjects aged in their 40s or ≥50 yrs was estimated using benchmark responses (BMRs) of 5% or 10% and parameters for the duration of shiftwork and other covariates. For workers aged in their 40s, the BMDL/BMD for shiftwork with a BMR of 5% was 18.6/23.0 yrs (≥7.5%) and 16.9/19.4 yrs (≥10%). For workers aged ≥50 yrs, the BMDL/BMD with a BMR of 5% was 22.9/28.2 yrs (≥7.5%) and 20.6/23.6 yrs (≥10%). The reference duration of shiftwork that associated with weight gain was shown to be at least 17 yrs in middle-aged workers. Special attention should be paid to prevent weight gain at an earlier stage and not when this increase in weight has become apparent. (Author correspondence: suwa@faculty.chiba-u.jp)

Mortality and causes of deaths of inhabitants with renal dysfunction induced by cadmium exposure of the polluted Jinzu River basin, Toyama, Japan; a 26-year follow-up

BackgroundWe aimed to investigate the mortality and causes of deaths of inhabitants with renal dysfunction induced by cadmium (Cd) exposure caused by heavy environmental contamination.MethodsWe 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.ResultsThe 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.ConclusionsThese 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.

Dose-response relationship between tobacco or alcohol consumption and the development of diabetes mellitus in Japanese male workers.

BACKGROUND The aim of this study was to examine the dose-response relationships between tobacco or alcohol consumption and the development of diabetes mellitus. METHODS An 8-year prospective cohort study was conducted in 8423 male workers who received annual health check-ups between 2002 and 2010 at a Japanese steel company. The endpoints were defined as an HbA(lc)≥6.1% or taking any anti-diabetic medication. The dose-response relationships of tobacco or alcohol consumption were investigated using a proportional hazards regression with time-dependent covariates selected from baseline age, body mass index, mean arterial pressure, total serum cholesterol, aspartate aminotransferase, creatinine and uric acid, shift work or day work, and habitual exercise by stepwise selection method. RESULTS A positive dose-response relationship between tobacco consumption and the development of diabetes mellitus was observed, with a significantly higher hazard ratio (HR) seen with higher tobacco consumption (11-20 cigarettes/day, HR 1.26 [95% confidence interval (CI), 1.00-1.59], ≥21 cigarettes/day, HR 1.54 [95%CI, 1.20-1.97]). In contrast, we observed a negative dose-response relationship between alcohol consumption and the development of diabetes mellitus, with a significantly lower HR with higher weekly alcohol consumption (7.0-13.9 gou/week [154-307 g/week], HR 0.73 [95% CI, 0.55-0.97], ≥14.0 gou/week [308 g/week], HR 0.75 [95% CI, 0.57-0.98]). CONCLUSIONS The results indicated that decreasing tobacco consumption will achieve significant prevention of diabetes mellitus. On the other hand, we observed a significant, negative dose-response relationship between alcohol consumption and the development of diabetes mellitus, in contrast to previous studies that reported a positive relationship in the Japanese population.

Application of the hybrid approach to the benchmark dose of urinary cadmium as the reference level for renal effects in cadmium polluted and non-polluted areas in Japan

OBJECTIVES The aim of this study was to evaluate the reference level of urinary cadmium (Cd) that caused renal effects. An updated hybrid approach was used to estimate the benchmark doses (BMDs) and their 95% lower confidence limits (BMDL) in subjects with a wide range of exposure to Cd. METHODS The total number of subjects was 1509 (650 men and 859 women) in non-polluted areas and 3103 (1397 men and 1706 women) in the environmentally exposed Kakehashi river basin. We measured urinary cadmium (U-Cd) as a marker of long-term exposure, and β2-microglobulin (β2-MG) as a marker of renal effects. The BMD and BMDL that corresponded to an additional risk (BMR) of 5% were calculated with background risk at zero exposure set at 5%. RESULTS The U-Cd BMDL for β2-MG was 3.5μg/g creatinine in men and 3.7 μg/g creatinine in women. CONCLUSIONS The BMDL values for a wide range of U-Cd were generally within the range of values measured in non-polluted areas in Japan. This indicated that the hybrid approach is a robust method for different ranges of cadmium exposure. The present results may contribute further to recent discussions on health risk assessment of Cd exposure.

Application of hybrid approach for estimating the benchmark dose of urinary cadmium for adverse renal effects in the general population of Japan.

We used an updated hybrid approach to estimate the benchmark doses and their 95% lower confidence limits (BMDL) for cadmium‐induced renal effects in humans. Participants were 828 inhabitants (410 men, 418 women), aged 40–59 years who lived in three areas without any known environmental cadmium pollution. We measured urinary cadmium (U‐Cd) as a marker of exposure, and urinary protein, β2‐microglobulin (β2‐MG) and N‐acetyl‐β‐D‐glucosaminidase (NAG) as markers of renal effects. For urinary protein, the BMDL ranged from 0.9 to 1.1 µg g−1 creatinine (cre) and approximately 1.6 µg per 24 h in men, and from 1.9 to 3.4 µg g−1 cre and 2.0 µg per 24 h in women. For the renal tubular markers β2‐MG and NAG, the BMDL for U‐Cd ranged from 0.6 to 1.2 µg g−1 cre and from 0.8 to 1.7 µg per 24 h in men, and from 0.6 to 2.3 µg g−1 cre and from 0.6 to 2.1 µg per 24 h in women. The lowest BMDL for urinary cadmium (0.6 µg g−1 cre) was somewhat lower than average urinary cadmium in Japanese older population. These results suggest the importance of measures to decrease cadmium exposure in the general population of Japan. Copyright

Associations between Rice, Noodle, and Bread Intake and Sleep Quality in Japanese Men and Women

Background Previous studies have shown that a diet with a high-glycemic index is associated with good sleep quality. Therefore, we investigated the association of sleep quality with the intake of 3 common starchy foods with different glycemic indexes–rice, bread, and noodles–as well as the dietary glycemic index in a Japanese population. Methods The participants were 1,848 men and women between 20 and 60 years of age. Rice, bread, and noodle consumption was evaluated using a self-administered diet history questionnaire. Sleep quality was evaluated by using the Japanese version of the Pittsburgh Sleep Quality Index, and a global score >5.5 was considered to indicate poor sleep. Results Multivariate-adjusted odds ratios (95% confidence intervals) for poor sleep across the quintiles of rice consumption were 1.00 (reference), 0.68 (0.49–0.93), 0.61 (0.43–0.85), 0.59 (0.42–0.85), and 0.54 (0.37–0.81) (p for trend = 0.015); those for the quintiles of noodle consumption were 1.00 (reference), 1.25 (0.90–1.74), 1.05 (0.75–1.47), 1.31 (0.94–1.82), and 1.82 (1.31–2.51) (p for trend = 0.002). Bread intake was not associated with sleep quality. A higher dietary glycemic index was significantly associated with a lower risk of poor sleep (p for trend = 0.020). Conclusion A high dietary glycemic index and high rice consumption are significantly associated with good sleep in Japanese men and women, whereas bread intake is not associated with sleep quality and noodle consumption is associated with poor sleep. The different associations of these starchy foods with sleep quality might be attributable to the different glycemic index of each food.

Threshold limit values of the cadmium concentration in rice in the development of itai-itai disease using benchmark dose analysis

The aim of this study was to estimate the benchmark dose (BMD) as the threshold limit level of the cadmium (Cd) concentration in rice for itai‐itai disease and/or suspected disease; it was based on the data that previously evaluated the association for such diseases with the Cd concentration in rice by using a logistic regression model. From 1971 to 1976, a total of 2446 rice samples were analyzed across the 88 hamlets in the Jinzu river basin. The mean Cd concentration in rice in each hamlet was used as the index of external Cd exposure of the entire population of the hamlet. We employed the incidence of itai‐itai disease and/or suspected disease obtained from the available 55 hamlets. As the threshold, the lower limit of the BMD (BMDL) of the Cd concentration in rice for itai‐itai disease and/or suspected disease was estimated using a logistic model, setting the benchmark response at 1% or 2%. The estimated BMDLs of the Cd concentration in rice for itai‐itai disease and/or suspected disease were 0.62–0.76 and 0.27–0.56 mg kg−1 in men and women, respectively. The lowest BMDL was 0.27 mg kg−1 in women. In the present study, the threshold limit level of the Cd concentration in rice for itai‐itai disease, which is the most severe form of chronic Cd poisoning, was estimated for the first time. This result provides important information about the worldwide standard for the Cd concentration in rice. Copyright

Impact of urinary cadmium on mortality in the Japanese general population in cadmium non-polluted areas.

PURPOSE The aim of the present study was to evaluate the dose-effect relationship between urinary cadmium (U-Cd as an index of internal Cd exposure) and mortality in a cohort of the Japanese general population. METHODS A 19-year cohort study was conducted in 897 men and 1307 women who lived in two non-polluted areas in Japan. The subjects were categorized into four quartiles based on creatinine adjusted U-Cd (μg/g cre). Hazard ratio (HR) and 95% confidence interval (95%CI) of the quartiles of U-Cd for mortality was calculated using a proportional hazards regression. Forward stepwise model selection was applied to the potential covariates such as age, body mass index, mean arterial pressure, various lifestyle factors and present illness. RESULTS The mortality rates per 1000 person years were 27.8 and 12.5 in men and women, respectively. In men, the fourth quartile of U-Cd (≥ 2.919 μg/g cre) showed a significant, positive HR (1.50, 95%CI: 1.11-2.02) for mortality compared to the first quartile (< 1.014). In women, the fourth quartile of U-Cd (≥ 3.943 μg/g cre) also showed a significant HR (1.50, 95%CI: 1.08-2.09) for mortality compared to the first quartile (< 1.140). CONCLUSION The present study clarified that U-Cd was significantly associated with increased mortality, indicating the worsened life prognosis of the general population in Cd non-polluted areas in Japan. These results highlight the importance of further discussion of the health risk assessment of Cd exposure in the general population.

HOMA-IR and the risk of hyperuricemia: a prospective study in non-diabetic Japanese men.

AIMS To examine the relation of insulin resistant status determined by homeostasis model assessment of insulin resistance (HOMA-IR) with the risk of incident hyperuricemia. METHODS The study participants included 2071 Japanese men without hyperuricemia and diabetes, aged 35-54 years. The participants had undergone annual heath examinations for 6 years to compare incident hyperuricemia (serum uric acid >416.4μmol/L (7.0mg/dL) and/or taking medication for hyperuricemia) in four groups based on quartiles of baseline HOMA-IR. RESULTS During follow-up there were 331 incident cases of hyperuricemia. The hazard ratios for hyperuricemia, compared with HOMA-IR ≤0.66, were 1.42 (95% confidence interval 1.02-1.98) for HOMA-IR 0.67-0.98, 1.20 (0.86-1.68) for HOMA-IR 0.99-1.49 and 1.44 (1.04-1.98) for HOMA-IR ≥1.50 after adjustment for baseline serum uric acid, creatinine, hypercholesterolemia and hypertension status, age, alcohol intake, and smoking and exercise habits. The hazard ratio associated with an increase of one standard deviation in lnHOMA-IR (1.85 as one geometric standard deviation of HOMA-IR) was 1.14 (1.03-1.28) (p for trend=0.02). CONCLUSIONS Increased HOMA-IR independently predicted the subsequent development of hyperuricemia. Insulin resistance itself or compensatory hyperinsulinemia may contribute to the development of hyperuricemia.