Variation in benchmark dose (BMD) and the 95% lower confidence limit of benchmark dose (BMDL) among general Japanese populations with no anthropogenic exposure to cadmium

The use of benchmark dose (BMD) and the 95% lower confidence limit of benchmark dose (BMDL) have been gaining popularity not only in experimental studies but also in epidemiological studies including those on toxicology of cadmium (Cd), a ubiquitous hazardous element in the environment. However, the reproducibility of BMD and BMDL values has seldom been examined. This study was initiated to determine whether consistent BMD and BMDL values are obtained for similar non-exposed populations, i.e., the populations with no anthropogenic exposure to Cd in a single nation of Japan. Cd (an exposure marker), alpha(1)-microglobulin (alpha(1)-MG), beta(2)-microglobulin (beta(2)-MG) and N-acetyl-beta-D-glucosaminidase (NAG) (three effect markers of tubular dysfunction) levels in the urine of adult Japanese women from five previous publications of this study group were examined. Overall, data were available for 17,375 cases (in 16 prefectures) regarding Cd, alpha(1)-MG and beta(2)-MG, and 6,409 cases (in ten prefectures) regarding NAG. The data were used to calculate BMD and BMDL values taking advantage of the hybrid approach (Budtz-JCrgensen et al. in Biometrics 57:698-706, 2001). It was possible to calculate BMD and BMDL values for alpha(1)-MG and beta(2)-MG for all of the 16 prefectures with 17,375 cases, whereas the values for NAG were successfully calculated for nine prefectures with 5,843 cases. The application gave BMD values of 1.92, 2.46 and 2.32 mu g Cd/g cr for alpha(1)-MG, beta(2)-MG and NAG, respectively, and BMDL values of 1.83, 2.32 and 2.09 mu g Cd/g cr. Large inter-prefectural variations were observed in the BMD and BMDL; there was about fourfold difference both in BMD and in BMDL calculated for alpha(1)-MG and beta(2)-MG in 16 prefectures, and the variation was greater (i.e., by about sevenfold) in BMD and BMDL for NAG in nine prefectures. A survey of relevant literature revealed variation in BMD and BMDL values of similar folds as observed in the present analyses in five studies of Japanese populations. Multiple regression analyses taking BMD or BMDL as a dependent variable and age, CR concentration and Cd concentration as independent variables showed both BMD and BMDL were significantly influenced by Cd concentration in cases of alpha(1)-MG and beta(2)-MG, whereas BMD and BMDL for NAG was by CR. Even when the analysis was conducted in a single nation, both BMD and BMDL for the Cd effect markers varied by ca. fourfold when examining alpha(1)-MG or beta(2)-MG and the values varied by ca. sevenfold for NAG among Cd-non-exposed populations. The most influential factors in the study population may include urine density and Cd levels in the urine.