Cadmium-induced nephrotoxicity assessed by benchmark dose calculations in two exposure-effect datasets

Cadmium (Cd), a ubiquitous metal contaminant, accumulates preferentially in the proximal tubular cells (PTCs) of the kidneys, which can lead to tubular injury and a decline in the estimated glomerular filtration rate (eGFR). To define exposure limits for Cd, the excretion of β ₂ -microglobulin (β ₂ M) at a rate above 300 µg/g creatinine, termed β ₂ -microglobulinuria (β ₂ M-uria) was most frequently used. Here, we used changes in the eGFR and β ₂ M excretion rate to define the critical exposure levels of Cd, known as benchmark dose limit (BMDL). The BMD analysis was applied to two exposure-effect datasets from 799 non-diabetic Thai Nationals, mean age 49.2 (18–87) years. Their excretion of Cd (E _Cd ) and β ₂ M (E _β2M ) were normalized to creatinine excretion (E _cr ) as E _Cd /E _cr and E _β2M /E _cr and to creatinine clearance (C _cr ), as E _Cd /C _cr and E _β2M /C _cr . For E _cr -normalized dataset, the BMDL value of E _Cd /E _cr based on the eGFR endpoint was 0.17 µg/g creatinine, but the BMDL value of E _Cd /E _cr could not be reliably estimated from the β ₂ M endpoint. For the C _cr -normalized dataset, the BMDL values of E _Cd /C _cr were obtained from both endpoints. The 5% prevalences of β ₂ M-uria and eGFR ≤ 60 mL/min/1.73 m ² were linked with Cd excretion rate of 2.35 and 2.23 µg/g creatinine, respectively. Thus, β ₂ M-nuria could signify nephron loss even though E _β2M /E _cr could not reliably reflect tubular dysfunction induced by Cd. In comparison, eGFR was sensitive to Cd because a 5% decrease in eGFR was associated with a Cd excretion rate as little as 0.17 µg/g creatinine, making it suitable for calculating exposure limits.