Effects of Environmental Cadmium Exposure Sufficient to Induce Renal Tubular Dysfunction on Bone Mineral Density Among Female Farmers in Cadmium-Polluted Areas in Northern Japan

In the Japanese Multi-Centered Environmental Toxicant Study (JMETS) conducted in five areas across Japan, we demonstrated that bone mineral density (BMD) in female farmers without renal tubular dysfunction was not adversely affected by exposure to low to moderate levels of cadmium (Cd). We then expanded JMETS to the most Cd-polluted area in northern Japan, Akita prefecture, with area A as the control and areas B and C as Cd-polluted areas (Cd exposure levels: B < C), which also covered more female farmers with a wider age range (20-82 years) and Cd exposure sufficient to induce renal tubular dysfunction. We selected 1267 eligible subjects in the three areas and classified them by age and menstrual status. The distribution of blood and urinary Cd levels over the areas was A < B < C (blood Cd: 2.10, 3.78, and 3.39 µg/L, and urinary Cd: 3.02, 4.29, and 6.15 µg/g cr., respectively; <i>p</i> < 0.05), with the steepest age-dependent increase in area C, particularly in older postmenopausal subjects with a urinary Cd level around the threshold for renal tubular dysfunction. Urinary α1-microglobulin (α1MG) and ß2-microglobulin (ß2MG) levels in the three areas also showed age-dependent increases, with higher levels being observed in areas B and C than in area A. Furthermore, ß2MG levels in older postmenopausal subjects were significantly higher in area C than in area A (273 and 157 μg/g cr., respectively, <i>p</i> < 0.05). Age-dependent decreases in BMD were noted in all areas, with rapid reductions from peri- to postmenopausal subjects; however, marked differences in each age class were not observed among the three areas. In multiple regression models of BMD in all subjects using age, body weight, grip, urinary creatinine, urinary α1MG or ß2MG, and blood or urinary Cd as independent variables, urinary α1MG and ß2MG levels correlated with BMD, whereas blood and urinary Cd levels did not. Moreover, age and body weight correlated more strongly with BMD than blood and urinary Cd levels. Therefore, Cd, not only at a low level but also at a level that was sufficient to deteriorate renal tubular function, did not affect bones. These results provide further support for Cd exposure itself not directly affecting bones.