The NOAEL equivalent for the cumulative body burden of cadmium: focus on proteinuria as an endpoint

The risk of developing chronic kidney disease (CKD), signified by a decrease in the estimated glomerular filtration rate (eGFR), has been linked to long-term exposure to low levels of the metal pollutant cadmium (Cd). Proteinuria is a hallmark of CKD and predicts continued progressive functional decline of the kidney. The aim of this study was to use the extent of proteinuria for Cd health risk assessment. Data were from 405 apparently healthy Thai nationals, of whom 12.6% had an eGFR below 60 mL/min/1.73 m2 (low eGFR), and 16.3% and 13.5% had moderate and severe proteinuria. Urinary excretion of Cd (ECd) and urinary total protein (Epro) were measured and normalized to both creatinine clearance (Ccr) and creatinine excretion (Ecr). We found that the risk of having a low eGFR prevalence odds ratio (POR) = 12.2, P < 0.001 and severe proteinuria [POR = 10.4, P = 0.001) were increased markedly for every ten-fold increase in ECd/Ccr. However, when ECd was normalized to Ecr, the association between eGFR and ECd was found to be insignificant due to non-differential errors introduced by the Ecr-normalization. Respective benchmark dose limit (BMDL) values of ECd/Ecr that increased protein excretion by 5% and 10% were 0.0536 and 0.1140 µg/g creatinine. The ECd/Ecr at which 5% of the population had Cd-related proteinuria was 1.86 µg/g creatinine, respectively. For the first time, a urinary Cd excretion rate of 0.0536 µg/g creatinine has been derived as a Cd exposure level that produces negligible kidney damage.