Challenges in Toxicological Risk Assessment of Environmental Cadmium Exposure

Dietary exposure to a high-dose cadmium (Cd) ≥ 100 µg/day for at least 50 years or a lifetime intake of Cd ≥ 1 g causes severe damage to kidneys and bones. Alarmingly, however, exposure to a dose of Cd between 10 and 15 µg/day increases worldwide prevalence of non-communicable diseases, including chronic kidney disease (CKD), non-alcoholic fatty liver disease, fragile bones, diabetes, and cancer. Because such a low-dose Cd exposure, results in urinary Cd excretion rates < 1 µg/g creatinine, it has cast considerable doubt on a “tolerable” Cd exposure of 58 µg/day for a 70 kg person, while questioning a threshold level at urinary Cd excretion rate at 5.24 µg/g creatinine. The present review addresses many unmet challenges in a threshold-based risk assessment for Cd. Special emphasis is given to the benchmark dose (BMD) methodology to estimate the Cd exposure limit that aligns with a no-observed adverse effect level (NOAEL). Reported results of BMDL modeling of Cd exposure levels using different nephrotoxicity endpoints are summarized to identify the most sensitive sign on which exposure guidelines should be based. It also aims to demonstrate that a health-protective exposure guideline for Cd should employ the most recent scientific research data, and the dose-response curves, constructed from an unbiased exposure indicator, and clinically relevant adverse effects such as proteinuria and a decrease in estimated glomerular filtration rate. These are signs of developing CKD and its progression to end stage, when dialysis or a kidney transplant is required for survival.