Estimation of health risks associated with dietary cadmium exposure.

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 ß2-microglobulin (ß2MG) 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.

Health Risk in a Geographic Area of Thailand with Endemic Cadmium Contamination: Focus on Albuminuria.

An increased level of cadmium (Cd) in food crops, especially rice is concerning because rice is a staple food for over half of the world's population. In some regions, rice contributes to more than 50% of the total Cd intake. Low environmental exposure to Cd has been linked to an increase in albumin excretion to 30 mg/g creatinine, termed albuminuria, and a progressive reduction in the estimated glomerular filtration rate (eGFR) to below 60 mL/min/1.73 m2, termed reduced eGFR. However, research into albuminuria in high exposure conditions is limited. Here, we applied benchmark dose (BMD) analysis to the relevant data recorded for the residents of a Cd contamination area and a low-exposure control area. We normalized the excretion rates of Cd (ECd) and albumin (Ealb) to creatinine clearance (Ccr) as ECd/Ccr and Ealb/Ccr to correct for differences among subjects in the number of surviving nephrons. For the first time, we defined the excretion levels of Cd associated with clinically relevant adverse kidney health outcomes. Ealb/Ccr varied directly with ECd/Ccr (ß = 0.239, p < 0.001), and age (ß = 0.203, p < 0.001), while normotension was associated with lower Ealb/Ccr (ß = −0.106, p = 0.009). ECd/Ccr values between 16.5 and 35.5 ng/L of the filtrate were associated with a 10% prevalence of albuminuria, while the ECd/Ccr value of 59 ng/L of the filtrate was associated with a 10% prevalence of reduced eGFR. Thus, increased albumin excretion and eGFR reduction appeared to occur at low body burdens, and they should form toxicity endpoints suitable for the calculation of health risk due to the Cd contamination of food chains.

Multiple Targets of Toxicity in Environmental Exposure to Low-Dose Cadmium.

Dietary assessment reports and population surveillance programs show that chronic exposure to low levels of environmental cadmium (Cd) is inevitable for most people, and adversely impacts the health of children and adults. Based on a risk assessment model that considers an increase in the excretion of ß2-microglobulin (ß2M) above 300 µg/g creatinine to be the "critical" toxicity endpoint, the tolerable intake level of Cd was set at 0.83 µg/kg body weight/day, and a urinary Cd excretion rate of 5.24 µg/g creatinine was considered to be the toxicity threshold level. The aim of this review is to draw attention to the many other toxicity endpoints that are both clinically relevant and more appropriate to derive Cd exposure limits than a ß2M endpoint. In the present review, we focus on a reduction in the glomerular filtration rate and diminished fecundity because chronic exposure to low-dose Cd, reflected by its excretion levels as low as 0.5 µg/g creatinine, have been associated with dose-dependent increases in risk of these pathological symptoms. Some protective effects of the nutritionally essential elements selenium and zinc are highlighted. Cd-induced mitochondrial dysfunction is discussed as a potential mechanism underlying gonadal toxicities and infertility.

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

We retrospectively analyzed data on the excretion of cadmium (ECd), ß2-microglobulin (Eß2M) and N-acetyl-ß-D-glucosaminidase (ENAG), which were recorded for 734 participants in a study conducted in low- and high-exposure areas of Thailand. Increased Eß2M 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, Eß2M and ENAG were normalized to creatinine clearance (Ccr) as ECd/Ccr, Eß2M/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, Eß2M/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 (ß = -0.300, p < 0.001), and higher ENAG/Ccr (ß = 0.455, p < 0.001) and Eß2M/Ccr (ß = 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 Eß2M/Ecr, with the ß 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.