Review of regulatory reference values and background levels for heavy metals in the human diet

Wong, Candace; Roberts, Stephen M.; Saab, Imad Neal

doi:10.1016/j.yrtph.2022.105122

Cited by 68 publications

(50 citation statements)

References 36 publications

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“…This Cd toxicity threshold level was derived from a risk assessment model that assumes β 2 M excretion above ≥300 µg/g creatinine as an endpoint [ 10 . 11 ].…”

Section: Discussionmentioning

confidence: 99%

“…Cd has been shown to cause a reduction in the tubular maximum reabsorption of β 2 M [ 9 ], and increased β 2 M excretion has been used as an indicator of impaired tubular reabsorptive function for many decades. An increase in the excretion of β 2 M above 300 μg/g creatinine is used as an endpoint in health risk assessments of Cd in the human diet, and urinary Cd excretion levels below 5.24 µg Cd/g creatinine have been identified as body burdens that are not associated with such an increase in β 2 M excretion [ 10 , 11 , 12 ]. However, our previous assessment showed that β 2 M excretion of 100–299, 300–999 and ≥ 1000 μg/g creatinine were associated with 4.7-, 6.2- and 10.5-fold increases in the risk of an estimated glomerular filtration rate (eGFR) ≤ 60 mL/min/1.73 m 2 , which is commensurate with chronic kidney disease (CKD) [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

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Dose–Response Analysis of the Tubular and Glomerular Effects of Chronic Exposure to Environmental Cadmium

Satarug

Vesey

Gobé

2022

IJERPH

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We retrospectively analyzed data on the excretion of cadmium (ECd), β2-microglobulin (Eβ2M) and N-acetyl-β-D-glucosaminidase (ENAG), which were recorded for 734 participants in a study conducted in low- and high-exposure areas of Thailand. Increased Eβ2M and ENAG were used to assess tubular integrity, while a reduction in the estimated glomerular filtration rate (eGFR) was a criterion for glomerular dysfunction. ECd, Eβ2M and ENAG were normalized to creatinine clearance (Ccr) as ECd/Ccr, Eβ2M/Ccr and ENAG/Ccr to correct for interindividual variation in the number of surviving nephrons and to eliminate the variation in the excretion of creatinine (Ecr). For a comparison, these parameters were also normalized to Ecr as ECd/Ecr, Eβ2M/Ecr and ENAG/Ecr. According to the covariance analysis, a Cd-dose-dependent reduction in eGFR was statistically significant only when Ecd was normalized to Ccr as ECd/Ccr (F = 11.2, p < 0.001). There was a 23-fold increase in the risk of eGFR ≤ 60 mL/min/1.73 m2 in those with the highest ECd/Ccr range (p = 0.002). In addition, doubling of ECd/Ccr was associated with lower eGFR (β = −0.300, p < 0.001), and higher ENAG/Ccr (β = 0.455, p < 0.001) and Eβ2M/Ccr (β = 0.540, p < 0.001). In contrast, a covariance analysis showed a non-statistically significant relationship between ECd/Ecr and eGFR (F = 1.08, p = 0.165), while the risk of low eGFR was increased by 6.9-fold only among those with the highest ECd/Ecr range. Doubling of ECd/Ecr was associated with lower eGFR and higher ENAG/Ecr and Eβ2M/Ecr, with the β coefficients being smaller than in the Ccr-normalized dataset. Thus, normalization of Cd excretion to Ccr unravels the adverse effect of Cd on GFR and provides a more accurate evaluation of the severity of the tubulo-glomerular effect of Cd.

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“…This Cd toxicity threshold level was derived from a risk assessment model that assumes β 2 M excretion above ≥300 µg/g creatinine as an endpoint [ 10 . 11 ].…”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Dose–Response Analysis of the Tubular and Glomerular Effects of Chronic Exposure to Environmental Cadmium

Satarug

Vesey

Gobé

2022

IJERPH

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“…To safeguard against excessive dietary Cd exposure, health guidance such as a tolerable intake level of Cd was established [ 7 ]. The Joint FAO/WHO Expert Committee on Food Additives and Contaminants (JECFA) considered the kidney to be the critical target of Cd toxicity [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

“…Accordingly, we argue that a reduction in eGFR due to Cd nephropathy could serve as the POD from which health guidance values should be derived. Owing to some shortcomings of the no-observed-adverse-effect level (NOAEL), the benchmark dose (BMD) has been used as the POD [ 7 , 14 , 15 , 16 ]. The BMD is a dose level, derived from an estimated dose–response curve, associated with a specified change in response, termed benchmark response (BMR) which can be set at 1%, 5%, or 10% as required [ 14 , 15 , 16 ].…”

Section: Introductionmentioning

confidence: 99%

The NOAEL Equivalent of Environmental Cadmium Exposure Associated with GFR Reduction and Chronic Kidney Disease

Satarug

Djordjevic

Yimthiang

et al. 2022

Toxics

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Cadmium (Cd) is a highly toxic metal pollutant present in virtually all food types. Health guidance values were established to safeguard against excessive dietary Cd exposure. The derivation of such health guidance figures has been shifted from the no-observed-adverse-effect level (NOAEL) to the lower 95% confidence bound of the benchmark dose (BMD), termed BMDL. Here, we used the PROAST software to calculate the BMDL figures for Cd excretion (ECd) associated with a reduction in the estimated glomerular filtration rate (eGFR), and an increased prevalence of chronic kidney disease (CKD), defined as eGFR ≤ 60 mL/min/1.73m2. Data were from 1189 Thai subjects (493 males and 696 females) mean age of 43.2 years. The overall percentages of smokers, hypertension and CKD were 33.6%, 29.4% and 6.2%, respectively. The overall mean ECd normalized to the excretion of creatinine (Ecr) as ECd/Ecr was 0.64 µg/g creatinine. ECd/Ecr, age and body mass index (BMI) were independently associated with increased prevalence odds ratios (POR) for CKD. BMI figures ≥ 24 kg/m2 were associated with an increase in POR for CKD by 2.81-fold (p = 0.028). ECd/Ecr values of 0.38−2.49 µg/g creatinine were associated with an increase in POR for CKD risk by 6.2-fold (p = 0.001). The NOAEL equivalent figures of ECd/Ecr based on eGFR reduction in males, females and all subjects were 0.839, 0.849 and 0.828 µg/g creatinine, respectively. The BMDL/BMDU values of ECd/Ecr associated with a 10% increase in CKD prevalence were 2.77/5.06 µg/g creatinine. These data indicate that Cd-induced eGFR reduction occurs at relatively low body burdens and that the population health risk associated with ECd/Ecr of 2.77−5.06 µg/g creatinine was not negligible.

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“…In 2010, the Joint Food and Agriculture Organisation (FAO) and World Health Organisation (WHO) Expert Committee on Food Additives and Contaminants (JECFA) deemed the kidneys to be a suitable target for evaluating cadmium toxicity, as measurements of ß 2 -microglobulin could be used as a surrogate biomarker for the effects of dietary cadmium intake [ 148 ]. The JECFA established a tolerable monthly intake of 25 µg/kg/bodyweight per month, with a urinary cadmium excretion rate of 5.24 µg/g creatinine or 0.8 µg/kg/day as a nephrotoxicity threshold [ 148 , 149 , 150 ]. While the EFSA and JECFA share the same critical ß 2 -microglobulin endpoint of 300 µg/g creatinine, the EFSA adopted a different cadmium excretion rate of 1 µg/g creatinine as the nephrotoxicity threshold, along with an uncertainty factor of 0.36 µg/kg bodyweight per day for 50 years as a benchmark dose [ 151 ].…”

Section: Cadmium and Human Healthmentioning

confidence: 99%

Cadmium: A Focus on the Brown Crab (Cancer pagurus) Industry and Potential Human Health Risks

Lordan

Zabetakis

2022

Toxics

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Cadmium is a major health risk globally and is usually associated with pollution and anthropogenic activity. The presence of cadmium in food is monitored to ensure that the health and safety of consumers are maintained. Cadmium is ubiquitous in the Asian and Western diets, with the highest levels present in grains, leafy greens, and shellfish. As part of their natural lifecycle of moulting and shell renewal, all crustaceans—including the brown crab (Cancer pagurus)—bioaccumulate cadmium from their environment in their hepatopancreas. The brown crab is an important species to the crab-fishing industries of many European countries, including Ireland. However, the industry has come under scrutiny in Europe due to the presence of cadmium in the brown crab meat intended for live export to Asia. This review explores evidence regarding the effects of cadmium consumption on human health, with a focus on the brown crab. Differences in cadmium surveillance have given rise to issues in the crab industry, with economic consequences for multiple countries. Currently, evidence suggests that brown crab consumption is safe for humans in moderation, but individuals who consume diets characterised by high levels of cadmium from multiple food groups should be mindful of their dietary choices.

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Review of regulatory reference values and background levels for heavy metals in the human diet

Cited by 68 publications

References 36 publications

Dose–Response Analysis of the Tubular and Glomerular Effects of Chronic Exposure to Environmental Cadmium

Dose–Response Analysis of the Tubular and Glomerular Effects of Chronic Exposure to Environmental Cadmium

The NOAEL Equivalent of Environmental Cadmium Exposure Associated with GFR Reduction and Chronic Kidney Disease

Cadmium: A Focus on the Brown Crab (Cancer pagurus) Industry and Potential Human Health Risks

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