The U.S. Food and Drug Administration (FDA) has estimated a toxicological reference value (TRV) for cadmium of 0.21–0.36 micrograms per kilogram of bodyweight per day (μg/kg bw/day), based on the results of a systematic literature review and model analyses published in Regulatory Toxicology and Pharmacology. TRVs are useful in the development of action levels for contaminants in foods like toxic heavy metals, which are the focus of FDA’s Closer to Zero initiative.

TRVs are typically derived from levels where adverse effects are observed or a benchmark dose near the low end of the observable range of the data. For the study, researchers from FDA’s Center for Food Safety and Applied Nutrition (CFSAN) conducted a systematic review of studies with data on adverse health effects associated with oral cadmium exposure. Decreased bone mineral density and renal tubular degeneration, which can lead to kidney failure, were identified as the most sensitive health endpoints associated with oral cadmium exposure.

Adverse effects of cadmium on the bone and kidney were associated with levels at approximately 0.50 μg of cadmium (cd) per gram (g) of creatinine for females aged 50–60 based on available epidemiologic data. An upper-bound estimate of 50 μg cd/g was also used based on renal cortical concentration occurring in the U.S. population at 50 years of age. Next, reverse dose-response modeling for the U.S. population was conducted, from which FDA determined a range of 0.21–0.36 μg/kg bw/day to be a TRV that would be protective of public health. A separate TRV (0.63–1.8 μg/kg bw/day) derived from animal studies was compared with the human TRV to support its plausibility.

Although the study used bone demineralization, renal tubular degeneration, and cadmium accumulation in the kidneys as endpoints with the most robust datasets, the authors highlight the lack of data on the cardiovascular effects of cadmium exposure, which animal studies suggest may harm cardiac tissue causing lesions, cell death, and inflammation. Additional research is required to enable dose-response modeling of cadmium effects related to cardiac health data.