Satarug et al. urinary cadmium < 0.5 and > 1.0 µg/g crea- tinine (Gallagher et al. 2008). In a prospec- tive study of Flemish women, Schutte et al. (2008b) found bone effects among those with a 2-fold increase in body cadmium burden, but no tubular effects were documented in the population. In Thailand, Satarug et al. (2005) found that tubular impairment and renal injury were associated with increased risk of high blood pressure among subjects 16–60 years of age who had mean urinary cadmium of 0.39 µg/L and mean serum cadmium of 0.47 µg/L. They demonstrated that a 3-fold increase in uri- nary cadmium (0.39 to 1.12 µg/L) was asso- ciated with an 11%, 32% and 61% increase in the probability of having high blood pres- sure, renal injury, and tubular impairment, respectively. The probability of having high blood pressure was increased by 20% among those with evidence of renal injury. The odds of tubular impairment were found to be 10.6 times higher when comparisons were made between urinary cadmium levels of 1–5 versus > 5 µg/g creatinine (Teeyakasem et al. 2007). Thomas et al. (2009) reported a dose–response relationship between urinary cadmium and early renal injury, whereas Wu et al. (2008) found progressive tubular and glomerular impairment among those with uri- nary cadmium > 10 µg/g creatinine. In a study of 14,778 U.S. adults > 20 years of age with mean blood cadmium and lead of 0.41 µg/L and 1.58 µg/L, respectively, Navas-Acien et al. (2009) found that the risk for albuminuria was 2.34; it was 1.98 for lowered glomerular filtra- tion rate among those in the highest quartiles of blood cadmium and lead than among those in the lowest. These findings suggest that envi- ronmental exposure to cadmium and lead may constitute the risk factors for chronic kidney disease in the United States. Diabetes. Schwartz et al. (2003) dem- onstrated a dose response between urinary cadmium level and an increased risk of pre- diabetes and diabetes. The risk estimates for abnormal fasting glucose and diabetes were 1.48 and 1.24 when comparisons were made for urinary cadmium levels of < 1 with those between 1.00 and 1.99 µg/g creatinine. These values increased to 2.05 and 1.45 when they compared urinary cadmium < 1 µg/g with ≥ 2 µg/g creatinine, respectively. As noted by Edwards and Prozialeck (2009), the incidence of diabetes is rising globally and has reached epidemic levels in some nations. Thus, the potential role played by low-dose cadmium in prediabetes and diabetes warrants further research. In a study involving Chinese subjects between 44 and 78 years of age (mean, 66 years) with type 2 diabetes, Chen et al. (2006) found tubular impairment among those who had had diabetes for 8.6 years. They also noted that the risk for tubular impairment was 186 increased by 3.34 when they compared urinary cadmium of < 1 versus ≥ 1 µg/g creatinine and by 5.56 when they compared low versus high levels of circulating MT antibody. These data suggested increased susceptibility to cadmium tubular effects among diabetic subjects with high MT antibody in plasma. The authors considered that mean urinary cadmium 0.38 µg/g creatinine and mean blood cadmium 0.61 µg/L were below threshold for glomeru- lar effects. Afridi et al. (2008) reported higher blood and urinary cadmium among Pakistani men 31–60 years of age who had had type 2 diabetes, on average, for 16 years. Diabetic nephropathy. A dose–response relationship has been observed between uri- nary cadmium and albuminuria among Torres Strait subjects with type 2 diabetes (Haswell- Elkins et al. 2008). For persons with diabetes, the geometric mean for urinary cadmium with albuminuria was 61% higher than for those without albuminuria. For those without albu- minuria, the average urinary cadmium level was 0.74 µg/g creatinine. The higher urinary cadmium levels among diabetic subjects could be the result of extensive kidney damage that leads to the release of cadmium in the kidney into the urine. One way to interpret these data is to suggest that the threshold urinary cad- mium for people with diabetes should be no greater than 0.74 µg/g creatinine to prevent or delay the onset of renal complications. Such an interpretation considers albuminuria to be a predictor of glomerular impairment, end- stage renal failure, and adverse cardiovascular outcomes. A similar threshold was suggested in another study that found glomerular impair- ment associated with the urinary cadmium 0.8 µg/g creatinine (Åkesson et al. 2005). Hypertension. Eum et al. (2008) observed a dose–response relationship between urinary cadmium and hypertension. Of the Korean subjects in their study, 26.2% were hyper- tensive. For this population, the mean blood cadmium was 1.67µg/L, and the risk estimate for hypertension was 1.51 when blood cad- mium levels in the lowest tertile were com- pared with those in the highest. An association was also found between blood cadmium and blood pressure levels in a U.S. sample popu- lation, where the mean blood cadmium was 3.98-fold lower than the mean level found in the Korean study (Tellez-Plaza et al. 2008). The strength of the cadmium blood pressure association was greatest among nonsmokers, intermediate among former smokers, and small or absent among current smokers. These find- ings support “pressor” effects, which have been shown to be characteristic of chronic exposure to low-dose cadmium (Satarug et al. 2005). Blood vessels and the heart. A set of studies has found evidence linking an increased risk of PAD with low-dose cadmium exposure (Navas- Acien et al. 2004, 2005). The risk for PAD was 1.07, 1.30, and 2.82 when blood cadmium quartiles 2, 3, and 4 were compared with the lowest quartile (p for trend = 0.01). Evidence that cadmium might be a key contributor to the high PAD risk was the finding that the risk of PAD for current smokers was 4.13-fold higher than for those who never smoked; for never smokers, the risk of PAD diminished to 1.84 after controlling for cadmium. In this study, subjects with PAD had 36% higher uri- nary cadmium than did those without disease where average urinary cadmium of the sample group was 0.36 µg/L and where the 25th and 90th percentile urinary cadmium level was 0.19 and 1.16 µg/L, respectively. Furthermore, the PAD risk was found to be 3.05 when the 75th percentile urinary cadmium was com- pared with that of the 25th percentile (Navas- Acien et al. 2005). It has also been shown that increased cadmium body burden is associated with lower aortic pulse wave velocity, lower pulse pressure, and higher femoral distensibility among subjects from low and high cadmium exposure areas (Schutte et al. 2008b). Everett and Frithsen (2008) found the risk of myocar- dial infarction among female subjects to be 1.8 when urinary cadmium > 0.88 µg/g creatinine was compared with < 0.43 µg/g creatinine. The risk remained when the analysis was restricted to nonsmokers. Lung. Lampe et al. (2008) examined the potential effects of exposure to cadmium on lung function using a sample group of 96 men who underwent one to three lung function tests between 1994 and 2002. They found a reduction in forced expiratory volume in 1 sec (a reflection of lung function) associated with increased urinary cadmium among those who smoked. These data suggest that lung disease among smokers may be mediated in part by cadmium, because urinary cadmium is also a marker of cumulative smoking, an established risk factor in lung disease. Periodontal tissues. A 3-fold increase in uri- nary cadmium (0.18 versus 0.63 µg/g creati- nine) has been reported to be associated with a 54% higher prevalence odds ratio (OR) for peri- odontal disease. For example, Arora et al. (2009) found that among a sample of adults, 15.4% had periodontal disease. The age-adjusted mean urinary cadmium for subjects with periodontal disease was 0.50 µg/g creatinine and 0.30 µg/g creatinine for unaffected individuals. Ocular tissues. Higher urinary cadmium was found to be associated with AMD among smokers (Erie et al. (2007). The median uri- nary cadmium level of current and former smokers with AMD was 1.18 µg/g creatinine. This level was 1.97-, 2.03-, and 2.07-fold higher than that of smokers without AMD, nonsmokers with AMD, and nonsmokers without disease, respectively. Increased retinal cadmium content has also been found in male subjects with AMD (Wills et al. 2008, 2009). ovlume 118 | number 2 | February 2010 • Environmental Health Perspectives