Benchmark dose modeling to define permissible exposure levels for environmental cadmium

Kidney and bone destruction in patients with itai-itai disease is caused by consuming rice contaminated with the heavy metal cadmium (Cd). Based on a lifetime intake of 2 g of Cd, and an elevation of β2-microglobulin (β2M) excretion rate, a tolerable Cd intake level was 0.83 µg/kg body weight per day (58 µg/day for a 70 kg person), with a threshold of 5.24 µg/g creatinine. However, current evidence suggests that these guidelines are inadequate to protect public health. Using experimental dosing and human population data, this review highlights the imprecision in determining exposure, internal doses, and adverse effects, leading to erroneous conclusions that Cd exposure did not diminish the estimated glomerular filtration rate (eGFR) nor did it accelerate progressive eGFR decline toward kidney failure among Cd-exposed people. It discusses the principles and application of the benchmark dose (BMD) modeling to human exposure-effect relationships from which the critical Cd exposure levels can be identified reliably, with kidney effect indicators other than the β2M excretion. It offers insights into the utility of multiple mathematical dose-response models to define the benchmark dose limit (BMDL) value for Cd exposure, which carries discernible health risk. From BMD modeling studies, Cd excretion benchmarks for early kidney effects, reflected by excretion of total proteins, N-acetyl-β-D-glucosaminidase, and eGFR decline, were 0.95, 1.34, and 3.24% of the current threshold, respectively. These Cd excretion levels are ideal for the derivation of safe Cd exposure guidelines because they are equivalent to no-observed-adverse-effect levels (NOAELs).