Relation of tubular dysfunction marker levels with cadmium in urine in non-polluted areas In Japan

Introduction
Previous findings suggest that the dose (in terms of cadmium in urine) -response (tubular dysfunction markers in urine) relationship after environmental exposure to cadmium (Cd) is bi-phasic in a shape of a hockey stick with a very steep slope when Cd exposure exceeds a critical level. The present study was initiated to examine if the dose-response is linear below the critical level of Cd among non-exposed populations.

Methods
Data were cited from previous publications on Cd (as an exposure marker), α1-MG, β2-MG, NAG (as three tubular dysfunction markers), creatinine (CR) and specific gravity (SG) in urine obtained from more than 17000 adult Japanese women. The cases were selected for age (50-59 years), CR (0.3-3.0 g/l), and SG (1.010-1.030) so that 5306 cases were available after selection. In ananlyses, observed (non-corrected) values were employed.

Results
The relationship of the effect markers with Cd was not linear. In case of β2-MG, the slope of the regression line between Cd (µg/l) (as X) and β2-MG (µg/l) (as Y), 17.6, when Cd was less than 2.5 µg/l, was significantly (p<0.01) steeper than the slope, 6.06 when Cd was >2.5 µg/l. The two regression line crossed at Cd=2.4 µg/l. A steeper slope at lower Cd and shallower one at higher Cd was also the case for α1-MG and NAG, with crossing points at Cd=2.3 and 1.3 µg/l, respectively.

Discussion
The relationship between Cd exposure and tubular dysfunction is not bi-phasic but tri-phasic. The dysfunction markers were elevated rather steeply at a low Cd range (<2-3 µg/), rather shallowly in the middle range (up to 5-10 µg/), whereas very steeply when Cd exposure is high (e.g., >10 µg/l) as observed in Cd-polluted areas. Bio-toxicological significance of the tri-phasic relationship deserves further study.