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Estimation of health risks associated with dietary cadmium exposure

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A Letter to the Editor, News and Views to this article was published on 02 May 2023

Abstract

In much of the world, currently employed upper limits of tolerable intake and acceptable excretion of cadmium (Cd) (ECd/Ecr) are 0.83 µg/kg body weight/day and 5.24 µg/g creatinine, respectively. These figures were derived from a risk assessment model that interpreted β2-microglobulin (β2MG) excretion > 300 μg/g creatinine as a “critical” endpoint. However, current evidence suggests that Cd accumulation reduces glomerular filtration rate at values of ECd/Ecr much lower than 5.24 µg/g creatinine. Low ECd/Ecr has also been associated with increased risks of kidney disease, type 2 diabetes, osteoporosis, cancer, and other disorders. These associations have cast considerable doubt on conventional guidelines. The goals of this paper are to evaluate whether these guidelines are low enough to minimize associated health risks reliably, and indeed whether permissible intake of a cumulative toxin like Cd is a valid concept. We highlight sources and levels of Cd in the human diet and review absorption, distribution, kidney accumulation, and excretion of the metal. We present evidence for the following propositions: excreted Cd emanates from injured tubular epithelial cells of the kidney; Cd excretion is a manifestation of current tissue injury; reduction of present and future exposure to environmental Cd cannot mitigate injury in progress; and Cd excretion is optimally expressed as a function of creatinine clearance rather than creatinine excretion. We comprehensively review the adverse health effects of Cd and urine and blood Cd levels at which adverse effects have been observed. The cumulative nature of Cd toxicity and the susceptibility of multiple organs to toxicity at low body burdens raise serious doubt that guidelines concerning permissible intake of Cd can be meaningful.

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Data Availability Statement

All data generated or analyzed during this study are included in this published article.

Abbreviations

BMD:

A benchmark dose is a dose level, derived from an estimated dose-response curve, associated with a specified change in response. The benchmark response can be set at 0.1%, 1%, 5%, or 10% incidence

BMDL:

Benchmark dose limit is a lower confidence limit for the BMD, computed to quantify the statistical variation toward the conservative end of health protection. A BMDL5 can be interpreted as a dose for which a response is likely to be smaller than 5%

JECFA:

Joint Food and Agriculture Organization and World Health Organization (FAO/WHO) expert committee on food additives and contaminants

NOAEL:

No-observed-adverse-effect level is the highest experimental dose level for which the response does not significantly differ from the response in the control group

PTWI:

Provisional tolerable weekly intake is an estimate of the amount of a chemical with no known biological function that can be ingested weekly over a lifetime without appreciable health risk

RfD:

Reference dose is an estimate, with uncertainty of an order of magnitude, of a daily exposure over a lifetime that is likely to be without appreciable risk of adverse effects

TMI:

Tolerable monthly intake

TDS:

Total diet study

ALT:

Alanine aminotransferase

AST:

Aspartate aminotransferase

β2MG:

Beta2-microglobulin

Ca:

Calcium

Cd:

Cadmium

CKD-EPI:

Chronic kidney disease epidemiology collaboration

CdMT:

Cadmium–metallothionein complex

CdPC:

Cadmium–phytochelatin complex

Co:

Cobalt

Cu:

Copper

DMT1:

Divalent metal transporter 1

eGFR:

Estimated glomerular filtration rate, units of mL/min/1.73 m2

GSH:

Glutathione

KIM1:

Kidney injury molecule 1

MCU:

Mitochondrial calcium uniporter

mtDNA:

Mitochondrial DNA

Mn:

Manganese

MT:

Metallothionein

NAFLD:

Non-alcoholic fatty liver disease

NAG:

N-acetyl-β-D-glucosaminidase

NASH:

Non-alcoholic steatohepatitis

NGAL:

Neutrophil gelatinase-associated lipocalin

OCTs:

Organic cation transporters

PC:

Phytochelatin

TfR1:

Transferrin receptor protein 1

TRVP5:

Transient receptor potential vanilloid 5

Zn:

Zinc

ZIP8:

Zrt- and Irt-like protein 8

ZIP14:

Zrt- and Irt-like protein 14

Ccr :

Creatinine clearance, units of volume/time

Ex/Ccr :

Excretion rate of x per volume of filtrate, units of mass/volume

[x]u :

Urinary concentration of x

[x]p :

Plasma concentration of x

[x]b :

Blood concentration of x

Vu :

Urine flow rate, units of volume/time

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Acknowledgements

This work was supported with resources of the Kidney Disease Research Collaborative, and the Department of Nephrology, Princess Alexandra Hospital. It was also supported with resources of the Stratton Veterans Affairs Medical Center, Albany, NY, USA. Opinions expressed herein are those of the authors and do not represent the official position of the United States Department of Veterans Affairs.

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Authors and Affiliations

  1. Kidney Disease Research Collaborative, Level 5, Translational Research Institute, Brisbane, QLD, Australia

    Soisungwan Satarug, David A. Vesey & Glenda C. Gobe

  2. Department of Nephrology, Princess Alexandra Hospital, Brisbane, QLD, Australia

    David A. Vesey

  3. School of Biomedical Sciences, The University of Queensland, Brisbane, QLD, Australia

    Glenda C. Gobe

  4. NHMRC Centre of Research Excellence for CKD QLD, UQ Health Sciences, Royal Brisbane and Women’s Hospital, Brisbane, QLD, Australia

    Glenda C. Gobe

  5. Stratton Veterans Affairs Medical Center and Albany Medical College, Albany, NY, USA

    Kenneth R. Phelps

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Correspondence to Soisungwan Satarug.

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This review is dedicated to the late Professor Michael R. Moore, who was Director of the National Research Centre for Environmental Toxicology (EnTox), University of Queensland, between 1994 and 2009. He was instrumental in establishing toxicology research on heavy metals in Australia, and he was an inspiration to all who worked in this field.

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Satarug, S., Vesey, D.A., Gobe, G.C. et al. Estimation of health risks associated with dietary cadmium exposure. Arch Toxicol 97, 329–358 (2023). https://doi.org/10.1007/s00204-022-03432-w

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