Selenium and Cadmium Toxicity
An effect of selenium (Se) on Cd toxicity was observed in a study of Bangladeshi preschool children, aged 4.4-5.4years (Skroder et al., 2015). The measured Cd effects were kidney volume, determined by ultrasonography, and eGFR calculated from serum cystatin C levels. Urinary Cd levels were inversely associated with eGFR, especially in girls. Among the girls, an increment of 0.5 pg/L in urinary Cd was associated with a decrease in eGFR of 2.6 mL/min/1.73m2. The association between lower eGFR values and higher urinary Cd levels was stronger in those with urinary Se below 12.6 pg/L. Kidney volume showed also an inverse relationship to urinary Cd excretion
(Skroder et al., 2015). These findings linked Se to Cd toxicity in kidneys in children. As discussed in Section 14.3.2, if uptake of Cd and Se both were mediated by the zinc transporter ZIP8, reduced Cd toxicity in girls with urinary Se levels >12.6 pg/L was probably due to an inhibitory effect of Se on uptake of Cd.
A beneficial effect of Se was suggested in a Chinese case-control study that included 240 invasive breast cancer cases and 246 age-matched non-cancer controls (Wei et al., 2015). There was a 2.83-fold increase in breast cancer risk in women with urinary Cd in the highest tertile and urinary Se in the lowest tertile (Wei et al., 2015). The risk of breast cancer was also reduced in women with urinary Se in the middle tertile (Wei et al., 2015).
Zinc and Cadmium Toxicity in Ocular Tissues
Zinc (Zn) is present in relatively high concentrations in ocular tissues, especially in the retinal pigment epithelium (RPE) cells (Wills et al. 2008a; Ugarte et al., 2013; Ugarte and Osborne, 2014). Zinc transporters, notably ZIP8 and ZIP14, prominently expressed in RPE cells, mediate Zn uptake by RPE cells (Leung et al., 2008). However, these ZIP8 and ZIP14 are known to also mediate Cd uptake (Fujishiro et al., 2012; Schneider et al., 2014; Zhang et al., 2016), thereby accounting for Cd accumulation in RPE (Erie et al. 2005; Wills et al. 2008b).
Evidence that Cd may be involved in the pathogenesis of eye disease, such as MD comes from autopsy and donor studies showing accumulation of Cd in eye tissues. In an autopsy study, Cd was found in RPE and choroids in all eyes examined (Erie et al., 2005). A donor study observed that Cd in eyes from older donors (aged >50years) was higher than those from younger donors (aged <55 years) (Wills et al., 2008b).
Data from NHANES 2005-2008 participants aged >60years showed that blood Cd levels >0.66 pg/L were associated with a 1.56-fold increase in the risk of MD, compared with blood Cd levels <0.25 pg/L (Wu et al., 2014). Urinary Cd, as low as 0.35 pg/L, was associated with 3.31-fold increase in risk of MD in non-Hispanic whites. Thus, a slight elevation of Cd body burden was associated with an increased risk of MD. Non-Hispanic whites may be at increased risk for this complication. The implications of ocular toxicity for Cd health risk assessment are discussed in Section 14.8.
Ocular Cd toxicity was observed also in Koreans, but at blood Cd levels 2.7-fold higher than in U.S. NHANES. Blood Cd levels >1.80 pg/L were associated with an increased risk of MD in Korean men aged >40years (OR 2.11), compared with blood Cd levels <0.79 pg/L (Kim et al., 2014). In another study of Korean subjects aged >40years, the highest quartile of blood Cd levels was associated with an elevated risk of macular generation (OR 1.92) compared with the lowest quartile (Kim et al., 2016).
Work with the human RPE cell line, ARPE-19, showed that co-exposure with either Zn or Mn reduced Cd uptake and accumulation (Satarug et al., 2008). These findings were consistent with the fact that cellualr uptake of Cd, Zn and Mn was mediated by the same set of metals transporters (Fujishiro et al., 2012; Jenkitkasemwong et al., 2012; Schneider et al., 2014; Zhang et al., 2016; Aydemir and Cousins, 2018). The reduction of Cd uptake by Zn co-exposure provide a plausible explanation for the positive outcomes of high-dose zinc supplement in the Age-Related Eye Disease Study in the U.S. (AREDS, 2001; Chew et al., 2013). The AREDS supplement formulations included high-dose antioxidants [vitamin C (500 mg), vitamin E (400IU), (3-carotene (25 mg, equivalent to vitamin A 25,000IU)], high-dose zinc (80mg) with additional 2mg Cu to prevent Cu deficiency anemia from high-dose zinc (AREDS, 2001).
In a 10-year follow-up of participants in AREDS, no adverse effects were associated with the AREDS formulation (Chew et al., 2013). Notably, there was a reduction in the risk of developing advanced MD (OR 0.66) and the development of moderate vision loss (OR 0.71). Reduced mortality from circulatory diseases was seen in participants, assigned to high-dose Zn supplement.
Summary of Dietary, Genetic, and Nutritional Influences of Cadmium Toxicity
Experimental studies indicated that the Zn transporters, notable ZIP8, and ZIP14, mediates cellular uptake of Se as selenite (HSeO,-), Fe2+, Co2+, Zn2+, Mn2+, and Cd2+. In theory, cellular Cd uptake is reduced by any of these metals. Increased Cd levels in retinal pigment epithelial cells from eyes of patients with MD were noted, and epidemiologic studies linked elevated urinary and blood Cd levels to increased risk of MD. High-dose Zn supplementation in studies of age-related eye disease delayed progression of MD while reducing vision loss and mortality.
Adequate dietary Zn intake was associated with reduced risk of Cd-related obstructive lung disease and Cd-related CKD. Increased breast cancer risk was associated with elevated urinary Cd in combination with low urinary Se. A preventive effect of Se was noted in a study showing an inverse association between estimated glomerular filtration and urinary Cd. Indicators of low body iron stores were associated with elevations of urinary and blood Cd levels. Enhanced Cd absorption and low vitamin C intake accounted for high toenail Cd in men who carried the hemochromatosis (HFE) gene H63D variant.
These findings suggest that genetic considerations and the homeostasis of several other metals affect the propensity to Cd toxicity.