Satarug et al. Uetani et al. (2006) documented differences in cadmium accumulation in a range of tis- sues and organs between 72 men and women who lived in areas with no apparent cad- mium pollution. In addition, several studies on human eyes have shown that the retinal pigment epithelium and choroids contained more cadmium than did the retina (Erie et al. 2005; Wills et al. 2008). These studies also found that women, men and women of older age, and smokers of both sexes had elevated levels of cadmium accumulation in eye tis- sues. Additional studies have demonstrated sex differences in ocular metal content in non- diseased eyes and those afflicted with AMD (Wills et al. 2008, 2009). Intestinal absorption of metals, body burden variability, and metal transporters. Highly efficient absorption, transport, and cellular uptake mechanisms have evolved in living organisms to ensure an optimal sup- ply of essential metals. Such mechanisms are crucial for metals, because they cannot be synthesized or destroyed by the cells and must be mined from the external environ- ment (Clemens 2006). As predicted from the U-shaped dose–response curve characteristics of essential metals, mechanisms designed to prevent deficiency or overdose toxicity have likely evolved for maintenance of homeo- stasis (Slikker et al. 2004). Cadmium has no known physiologic function, and no mecha- nism would have been expected to be evolved for its selective transport and homeostasis. In all likelihood, cadmium is acquired by trans- port mechanisms developed for essential met- als. From physical and chemical properties, those metals are most likely to be zinc (Zn2+), iron (Fe2+), manganese (Mn2+), and calcium (Ca2+). In the literature, a considerable range defines the possible intestinal absorption rate for cadmium. For instance, it was estimated to be between 3 and 7% in humans and between 0.3 and 3.5% in rats. These values were used to assign an average 5% absorption rate in deriving a safe exposure level for cad- mium (IPCS 1992; WHO 1989). However, higher cadmium absorption rates (20–40%) were shown in balanced studies (Horiguchi et al. 2004; Kikuchi et al. 2003). These stud- ies also observed enhanced rates among young subjects and considered the possible biliary excretion and reuptake via enterohepatic cir- culation. Many investigators have shown the influence of body iron stores on absorption rate and body burden of cadmium. Satarug et al. (2004) found a 3- to 4-fold increase in cadmium body burden among Thai women who had low iron stores when compared with those of the same age and of normal iron stores. Kippler et al. (2007) found increased cadmium burden among Bangladeshi women associated with low iron stores only among those with adequate zinc status. An inverse 188 correlation between serum iron and blood cadmium was observed among Canadian subjects: men had higher serum iron, blood lead, and serum selenium values than did women, and women had higher serum cop- per and blood manganese than did men (Clark et al. 2007; Copes et al. 2008). The higher blood manganese in women might be expected because low iron stores have been associated with enhanced manganese absorp- tion (Finley 1999; Kippler et al. 2009). Some studies have shown no influence on body iron stores, but these were conducted in chronic high-exposure situations where metal trans- porters would likely be saturated with metal. Current data thus suggest metal transporters could be one of the determinants of cadmium body burden—a factor that may explain the variability in blood cadmium levels observed by Björkman et al. (2000) in a cohort of 61 monozygotic and 103 dizygotic twin pairs. Conclusions and Perspectives Recent epidemiologic studies involving an exposure–effect assessment have linked low- level cadmium exposure of current popula- tions with some adverse effects that are not restricted to kidney and bone, but include almost every organ and tissue where cad- mium accumulates, including eye tissues. These data argue strongly for public health measures aimed at reducing exposure. In the past, the wide variation in cadmium body burden among people has been attributed to cigarette smoking and the high pulmo- nary absorption rates of cadmium in cigarette smoke. However, as revealed in the present review, the difference in body burden of cad- mium between smokers and nonsmokers is less than 3-fold. We suggest that the signs of early renal injury and mild tubular impair- ment observed in chronic low-dose exposure situations viewed previously as benign could indeed be an early warning sign of subclini- cal or clinical morbidity and mortality. This assertion is substantiated by the dose response observed between cadmium body burden and all-cause mortality and cancer mortality in the Belgian and the U.S. cohorts. We also believe that cadmium is secreted in breast milk and that calcium and zinc supplements could be considered to lower the cadmium content in breast milk to minimize potential effects of early-life exposure to cadmium. Many issues require further research. A precise risk estimate is needed to quantify the carcinogenic risk because the high preva- lence of cadmium exposure means that even a small increase in risk could yield a large number of preventable cancer cases. To be valid, the threshold-based PTWI model, although appearing to be a reasonable method for deriving a safe exposure level, will require appropriate input from current scientific knowledge. Thus, revising the current safe intake level for cadmium is much needed. A strong consideration should be given to a safety factor issue, which is necessary to pro- tect subpopulations with increased suscep- tibility, such as those with diabetes. Animal studies have shown that the symptoms of dia- betic nephropathy and cadmium renal toxic- ity are enhanced when both the metal and the disease are present. The enhanced cadmium absorption noted for young age groups indi- cates that new intake guidelines may need to be established for pediatric populations. The application of the BMD method should be expanded and applied to other toxicity end points to identify the organs, other than the kidney, that should be considered as critical for deriving safe exposure levels. The poten- tial genetically determined rates of cadmium absorption, uptake, accumulation, and toxic- ity remain largely unexplored and should be subjects of future research. With the looming cancer and chronic disease epidemics world- wide, we encourage research in the following areas: cadmium exposure assessment, iden- tification of potential exposure sources, and the determination of cadmium body burden in future epidemiologic investigations. Such research would provide an estimate of total disease burden (cost) of population exposure. In addition, therapeutically effective chelat- ing agents to enhance excretion of cadmium are lacking, and this factor makes preven- tion of cadmium accumulation pivotal. The persistence of cadmium in the environment requires a long-term approach to minimize human exposure through environmental man- agement and maintenance of lower cadmium levels wherever possible. Ref Rencs Afridi HI, Kazi TG, Kazi N, Jamali MK, Arain MB, Jalbani N, et al. 2008. Evaluation of status of toxic metals in biological samples of diabetes mellitus patients. Diabetes Res Clin Pract 80(2):280–288. 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Cadmium-induced renal dysfunction and mortality in two cohorts: disappearance of the association in a gen- eration born later. Toxicol Lett 169(3):214–221. Arnold SM, Zarnke RL, Lynn TV, Chimonas MA, Frank A. 2006. Public health evaluation of cadmium concentrations in liver and kidney of moose (Alces alces) from four areas of Alaska. Sci Total Environ 357(1-3):103–111. ovlume 118 | number 2 | February 2010 • Environmental Health Perspectives