Confusion about Cadmium Risks: The Unrecognized Limitations of an Extrapolated Paradigm

Abstract

BackgroundCadmium (Cd) risk assessment presently relies on tubular proteinuria as a critical effect and urinary Cd (U-Cd) as an index of the Cd body burden. Based on this paradigm, regulatory bodies have reached contradictory conclusions regarding the safety of Cd in food. Adding to the confusion, epidemiological studies implicate environmental Cd as a risk factor for bone, cardiovascular, and other degenerative diseases at exposure levels that are much lower than points of departure used for setting food standards.ObjectiveThe objective was to examine whether the present confusion over Cd risks is not related to conceptual or methodological problems.DiscussionThe cornerstone of Cd risk assessment is the assumption that U-Cd reflects the lifetime accumulation of the metal in the body. The validity of this assumption as applied to the general population has been questioned by recent studies revealing that low-level U-Cd varies widely within and between individuals depending on urinary flow, urine collection protocol, and recent exposure. There is also evidence that low-level U-Cd increases with proteinuria and essential element deficiencies, two potential confounders that might explain the multiple associations of U-Cd with common degenerative diseases. In essence, the present Cd confusion might arise from the fact that this heavy metal follows the same transport pathways as plasma proteins for its urinary excretion and the same transport pathways as essential elements for its intestinal absorption.ConclusionsThe Cd risk assessment paradigm needs to be rethought taking into consideration that low-level U-Cd is strongly influenced by renal physiology, recent exposure, and factors linked to studied outcomes.CitationBernard A. 2016. Confusion about cadmium risks: the unrecognized limitations of an extrapolated paradigm. Environ Health Perspect 124:1–5; http://dx.doi.org/10.1289/ehp.1509691

Is Urinary Cadmium a Biomarker of Long-term Exposure in Humans? A Review

“…A recent commentary [98•] also highlights two reports of co-excretion of Cd with plasma proteins in urine [80, 99]; factors responsible for excretion of these proteins might therefore also be predictive of U-Cd cr . A possible mechanistic explanation for this observation involves the capacity of the kidneys to filter and reabsorb low molecular weight proteins [80].…”

“…The amount of the protein complex not reabsorbed is excreted in the urine, and as the body’s ability to reabsorb these proteins changes (e.g., due to disease), this can result in increased excretion of Cd along with other proteins. Therefore, because of co-excretion mechanisms, an increase in U-Cd might be observed in people with chronic diseases involving the kidneys and in those who experience an increase of plasma proteins in the urine (proteinuria or albuminuria), which may be a result of bone loss, cardiovascular diseases, or diabetic nephropathy [98•]. The greater risk predicted for certain diseases in cross-sectional epidemiology studies in the presence of elevated U-Cd may in fact be the result of reverse causality, in which higher U-Cd levels were caused by the disease and not vice versa.…”

Cadmium and lead exposure and risk of cataract surgery in U.S. adults

“…Since approximately 50% of the accumulated cadmium is stored in the kidney, urinary cadmium is widely used as a surrogate for cumulative cadmium exposure, which reflects the body cadmium load (Adams and Newcomb, 2014; Faroon et al, 2012; Järup, 2002; Järup and Akesson, 2009; Johri et al, 2010). However, a recent commentary suggests that low-level urinary cadmium is largely affected by factors other than cumulative cadmium exposure, such as recent cadmium intake and kidney function; the assumption that urinary cadmium is an indicator of cumulative cadmium life-burden is now being doubted (Bernard, 2016). To reduce such an impact, we conducted not only a conventional approach that includes urinary creatinine as a covariate in the models but also a CAS+CA(O’Brien et al, 2016), and the results were robust.…”

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“…The ability of kidneys to excrete concentrated or diluted urine depends on the distal reabsorption which is influenced by many regulators of water-electrolyte metabolism. Increased diuresis and excretion of water free from sodium ions could be a result of decreased activity of vasopressin in response to hyponatremia and due to neurotoxicity of cadmium chloride [13]. Cadmium is known to be deposited in those parts of the brain where hematoencephalic barrier is easily penetrated -the pituitary gland and pineal body [14,15].…”