Kazuhiro Nogawa

Cadmium (Cd), a widespread pollutant, is primarily absorbed via diet and smoking. Chronic Cd exposure has been associated with various adverse health effects, including renal tubular and skeletal damage. Urinary Cd concentration accurately reflects cumulative Cd exposure owing to its strong correlation with renal cortical Cd levels. This study evaluated the accuracy of estimated lifetime Cd intake by examining its correlation with urinary Cd levels after soil remediation, an aspect unreported even in the Kakehashi River Basin. A total of 565 men and 450 women were included. Lifetime Cd intake (g) was estimated using an established exposure assessment model that incorporated individual residential history, rice Cd concentrations, and dietary assumptions. Urinary Cd concentrations were determined using inductively coupled plasma mass spectrometry. Linear regression analyses were conducted between lifetime cadmium intake and urinary cadmium concentration. The obtained standardized regression coefficients were 0.49 for men and 0.54 for women (both p < 0.001), indicating strong associations. Despite possible exposure misclassification, these findings support the utility of lifetime cadmium intake as a useful surrogate indicator of cumulative cadmium exposure and provide further evidence for its application in risk assessment and the derivation of tolerable cadmium intake values.

This study explored the effects of soil restoration on cadmium (Cd) body burden and renal tubular damage in inhabitants of Cd-polluted areas by estimating the lifetime Cd (LCd) intake and expected LCd intake without soil restoration. In total, 1819 participants (991 men and 828 women) were included in the analysis. Furthermore, 845 participants (503 men and 342 women) who had lived in Cd-polluted areas before soil restoration were selected to estimate LCd intake with and without soil restoration. LCd intake was estimated based on residential history and rice Cd concentrations in each area. First morning urine samples were collected for urinary Cd (U-Cd, as the Cd body burden) and β2-microglobulin (as the renal tubular marker) measurements. The mean LCd intake was 3.0 g for men and 2.6 g for women in Cd-polluted areas with soil restoration. The mean expected LCd intake without soil restoration was 5.1 g for men and 4.6 g for women, indicating that soil restoration reduced LCd intake by approximately 2 g for both sexes. Soil restoration significantly reduces LCd intake, Cd body burden, and renal tubular effects. This information is crucial for developing strategies to reduce Cd exposure worldwide.

The aim of the present study was to apply an updated benchmark dose (BMD) approach to estimate reference urinary cadmium (U-Cd) for renal tubular and glomerular effects. This cross-sectional survey was conducted 30 years ago in 30 men and 44 women living in a Cd-polluted area and in 18 men and 18 women living in a non-polluted area. We applied an updated hybrid approach to estimate the BMDs and 95% lower confidence limits (BMDLs) of U-Cd for creatinine (Cr) clearance (CrCl), estimated glomerular filtration rate (eGFR), β2-microglobulin (β2-MG), and β2-MG tubular reabsorption (%TRβ2-MG). Using a benchmark response (BMR) of 5%, we estimated the BMDLs of U-Cd for adverse renal effect markers to be 2.9 (eGFR), 1.8 (β2-MG), 1.8 (%TRβ2-MG < 95%), and 3.6 μg/g Cr (%TRβ2-MG < 90%) in men, and 3.5 (CrCl), 2.5 (β2-MG), 2.6 (%TRβ2-MG < 95%), and 3.9 μg/g Cr (%TRβ2-MG < 90%) in women. The obtained BMDLs for tubular effects were 1.8–3.6 µg/g Cr and for glomerular effects were 2.9–3.5 µg/g Cr; these are not very high compared to the exposure levels in the general population. The BMDLs calculated in this study provide important information for measures regarding protecting general inhabitants or workers from the adverse health effects of Cd exposure.

This study aimed to clarify the cause‐effect relationship between renal tubular damage and non‐cancer mortality in the general Japanese population. We conducted a 19‐year cohort study including 1110 men and 1,03 women who lived in three cadmium‐non‐polluted areas in 1993 or 1994. Mortality risk ratios based on urinary β2‐microglobulin (β2MG) and N‐acetyl‐β‐glucosaminidase (NAG) concentrations were estimated for specific non‐cancer diseases using the Fine and Gray competing risks regression model. In men, continuous urinary NAG (+1 μg/g cre) concentrations were significantly correlated with increased mortality caused by diseases of the respiratory system (hazard ratio (HR): 1.09, 95% confidence interval (CI): 1.03–1.15). Urinary β2MG (+100 μg/g cre) concentrations were significantly correlated with increased mortalities caused by kidney and urinary tract diseases (HR: 1.01, 95% CI: 1.00–1.03), renal diseases (HR: 1.01, 95% CI: 1.00–1.03), renal failure (HR: 1.02, 95% CI: 1.00–1.03), and external causes of mortality (HR: 1.01, 95% CI: 1.00–1.02). In women, urinary NAG (+1 μg/g cre) concentrations were significantly associated with increased mortality caused by ischemic heart diseases (HR: 1.02, 95% CI: 1.00–1.04) and kidney and urinary tract diseases (HR: 1.01, 95% CI: 1.00–1.04). Urinary β2MG (+100 μg/g cre) concentrations were significantly correlated with increased mortality caused by cardiovascular diseases (HR: 1.01, 95%CI: 1.00–1.02), ischemic heart diseases (HR: 1.01, 95%CI: 1.00–1.02), and kidney and urinary tract diseases (HR: 1.02, 95% CI: 1.01–1.03). The present study indicates that renal tubular damage was significantly related to several non‐cancer disease causes of mortality in Japan's general population living in cadmium‐non‐polluted areas.

The aim of this paper is to examine the association between physical and cognitive function and stumbling and falling in elderly workers by conducting work-related questionnaire surveys and physical and cognitive function measurements. A total of 611 men and 121 women aged 40–69 years who participated in physical function measurements between June 2017 and June 2021 were included in the study. The general physical function measurements of upper and lower limb muscle strength, dynamic and static balance, and agility and cognitive function included grip strength, Repeated Rise Test, Trail Making test (TMT), and Three-Meter Time Up Go Test (TUG). We also asked the men and women about their experience of falling and stumbling. Logistic regression analysis showed significant odds ratios (OR) for the associations between stumbling in men and age (OR: 1.98), mental burden (OR: 2.44), frequency of field work (OR: 1.74), seated stepping test count (OR: 0.95), and TMTB time (OR: 0.99). Significant ORs were found between falling in men and age (OR: 2.55), mental burden (OR: 2.40), exercise habits (OR: 2.55), and smoking (OR: 2.00). Significant ORs were found between stumbling in women and d_TUG (OR: 1.59) and mental burden (OR: 6.42). The study suggests that there may be an association between cognitive and physical decline and stumbling and falling in elderly workers.

The relationship between cadmium exposure, exposure‐related renal tubular dysfunction, and mortality have been reported, mainly in the residents of Cd‐contaminated areas in Japan. The aim of this study was to establish the cause–effect relationship between renal tubular dysfunction and cancer mortality in the general population in non‐contaminated areas. A 19‐year cohort study was conducted in 1110 men and 1703 women in 1993 or 1994, who lived in three cadmium‐non‐contaminated areas. Mortality risk ratios of urinary β2‐microglobulin (β2MG) and N‐acetyl‐β‐glucosaminidase (NAG) for all malignant neoplasms and specific cancers were estimated using the Fine and Gray competing risks regression model. Significant hazard ratios (HRs) for liver and pancreas cancer were observed for NAG (liver: HR corresponding to an increase of 1 IU/g cr, 1.10, 95%CI, 1.02–1.19, pancreas: HR, 1.10, 95%CI, 1.02–1.19) in men. In women, a negative HR was observed for NAG (lung cancer: HR 0.80, 95% CI, 0.67–0.96) and for β2MG (all malignant neoplasms: HR, 0.97, 95% CI, 0.93–1.00). The present study indicated that renal tubular dysfunction was significantly related to mortality in the general population of cadmium‐non‐contaminated areas in Japan.

Aim: To determine the effects of alcohol consumption and smoking on the onset of hypertension in a long-term longitudinal study. Methods: 7511 non-hypertensive male workers were enrolled. This cohort study was performed over an 8-year period using the results of the annual workers-health screening. The end-point was defined as systolic blood pressure ≥ 140 mmHg, diastolic blood pressure ≥ 90 mmHg, or use of antihypertensive drugs. For alcohol consumption, weekly alcohol intake (g ethanol/week) was estimated (1 “gou” = 22 g ethanol). Annual survey data were analyzed by pooled logistic regression that included alcohol consumption, smoking, age, body mass index, job schedule types, habitual exercise, and blood test measurements into the statistical model. Results: A significant positive dose–response relationship between alcohol consumption and onset of hypertension was observed, with synergistic health effects present. Compared with abstainers and nonsmokers, the adjusted odds ratios (95% confidence interval) for the onset of hypertension were: 1.51 (1.27–1.79) for 154 g ethanol/week and nonsmokers, and 1.81 (1.54–2.11) for 154 g ethanol/week and smokers. An interaction between alcohol and smoking was confirmed. Conclusions: This study provided information useful to the prevention of hypertension. By reducing alcohol consumption and smoking simultaneously, the risk of hypertension may be considerably lowered.

We evaluated the association between urinary cadmium concentration (uCd, μg/g Cr) and risk of cause-specific mortality according to urinary β2-microglobulin (MG) concentration. Participants were 1383 male and 1700 female inhabitants of the Cd-polluted Kakehashi River basin. The uCd and β2-MG were evaluated in a survey in 1981–1982, where those participants were followed-up over 35 years later. Among the participants with a urinary β2-MG < 1000, the hazard ratios (HRs) (95% confidence interval) for mortality were significantly higher in those with a uCd of ≥10.0 compared with <5.0 for cardiovascular disease [HR 1.92 (1.08–3.40) for men, 1.71 (1.07–2.71) for women], pneumonia or influenza [2.10 (1.10–4.00) for men, 2.22 (1.17–4.19) for women], and digestive diseases [for men; 3.81 (1.49–9.74)]. The uCd was significantly associated with mortality from heart failure in women and digestive diseases in men, after adjustment for other causes of death using the Fine and Gray competing risk regression model. For participants with a urinary β2-MG of ≥1000, no significant association was observed between uCd and any major cause of death. In the absence of kidney damage, Cd may increase the risk of death from cardiovascular disease, pneumonia, and digestive diseases.

Objectives: The aim of this study was to determine the no observed adverse effect level (NOAEL), the lowest observed adverse effect level (LOAEL) and the benchmark dose low (BMDL) of cadmium exposure by re-evaluation of the dose–response relationship between cumulative cadmium exposure and renal tubular damage reported previously. Methods: The participants were workers (326 men and 114 women) employed for at least three months between 1931 and 1982. Blood cadmium (Cd-B) and air cadmium (Cd-A) were collected at regular intervals with urinary β2-microglobulin as the tubular effect marker. Cumulative Cd-A and Cd-B were estimated by multiplying concentration and working period. The BMDL was calculated using Benchmark Dose Software (version 3.1.2). The benchmark response (BMR) was set at 5% or 10%. Results: By logistic regression, the NOAEL of mean cumulative Cd-B was 7122 months nmol/L. The LOAEL of cumulative Cd-A and least-squares cumulative Cd-B was 691 yrs μg/m³ and 8586 months nmol/L, respectively. Among various models for dose–response relationships, a probit model was adopted as the best fitting model. The obtained BMDLs of cumulative Cd-A were 272.3 yrs µg/m³ (BMR5%) and 707.5 yrs µg/m³ (BMR10%). The BMDLs of mean cumulative Cd-B were 3967.2 months nmol/L (BMR5%) and 7798.1 months nmol/L (BMR10%). The BMDLs of least-squares cumulative Cd-B were 3588.6 months nmol/L (BMR5%) and 8616.3 months nmol/L (BMR10%). Assuming a working period of 40 years, the BMDLs for BMR10% corresponded to 17.7 µg/m³ (Cd-A) and 1.8~2.0 µg/L (Cd-B). Discussion: This study provides new valuable information to enhance the reliability of limit values and thereby make a significant contribution to preventing the health effects of Cd in exposed workers.

Background: The aim of this study was to determine whether a causative relationship exists between the development of liver damage and increased high-sensitivity C-reactive protein (HsCRP) levels by long-term follow-up in Japanese workers. Methods: The target participants comprised 7830 male workers in a Japanese steel company. The prospective cohort study was performed over a 6-year period, and annual health screening information was analyzed by pooled logistic regression. The endpoint, regarded as the development of liver damage, was defined as aspartate aminotransferase (AST) ≥ 40 IU/L. Results: A significant relationship between the development of liver damage and increased HsCRP levels was observed after adjusting for confounding factors such as various physiological and blood chemistry parameters and lifestyle factors. The odds ratio of a 1.5-fold increase in HsCRP was 1.07 (95% confidence interval: 1.03–1.10, p < 0.001). Conclusions: The results suggested that an increase of HsCRP is associated with the development of liver damage.