the protein bound to cadmium is digested and ionic cadmium released; thus speciation of cadmium in food would not be a basis for assigning high cadmium MLs for marketing purposes (Francesconi 2007). There has been no indication of decreases in food cadmium content over the past decade or any drastic change in dietary habits. In a British study, Lyon et al. (1999) showed that human kidney cadmium levels were static over a period of 16 years (1978–1993) but were higher than those found in studies conducted in the early 20th century. The distribution of kidney cadmium concentrations was skewed, with about 3.9% of the 2,700 samples > 50 µg/g kidney cortex wet weight, although the population mean was only 19 µg/g wet weight (Lyon et al. 1999). Cadmium Exposure and Effects Observed Kidney and bone: chronic high-dose effects. Long-term exposure to high-dose cadmium causes Itai-itai disease. This disease affects mainly women and is characterized by severely impaired tubular and glomerular function and generalized osteomalacia and osteoporosis that result in multiple bone fractures (Inaba et al. 2005). An estimate of cadmium intake, based on historic rice cadmium content, in the Itai-itai disease endemic area during the 1960s was 600 µg/day, and the threshold lifetime intake was estimated to be between 1,580 and 2,000 mg of cadmium (Kobayashi et al. 2002, 2006). In two reports, investigators showed that the lifetime threshold for early onset of the Itai-itai disease was less than a 3-fold dif- ference from the intake observed in areas with no apparent pollution (Inaba et al. 2005; Uno et al. 2005). This may reflect a small safety margin between population intake levels and the levels that produce overt effects. Kidney and bone: chronic low-dose effects. Long-term exposure to low-dose cadmium has been linked to tubular impairment with a loss of reabsorptive capacity for nutrients, vitamins, and minerals. These losses include zinc and copper bound to the metal binding protein metallothionein (MT), glucose, amino acids, phosphate, calcium, β2-MG, and retinol-bind- ing protein (RBP) [International Programme on Chemical Safety (IPCS) 1992]. The abnor- mal urinary excretion of low-molecular-weight proteins, calcium, amino acid, phosphate and glucose observed in cadmium-exposed indi- viduals share some similarities with Fanconi’s syndrome, a genetic disorder of renal tubular transport. Urinary markers for cadmium effects are cadmium itself, low-molecular-weight sub- stances, and the enzymes of renal tubular ori- gin, such as NAG (Teeyakasem et al. 2007). In general, the urinary cadmium level reflects the body burden over long-term exposure before the development of kidney damage, and blood cadmium is considered an indicator of recent exposure (IPCS 1992). However, for persons > 60 years of age, blood cadmium is consid- ered a better estimate of body burden than is urinary cadmium. Kidney and bone: the Cadmibel project. The Cadmibel study was one of the earliest investigations to examine the effects of low- dose exposure among 2,327 Belgian subjects between 1985 and 1989 (Buchet et al. 1990). The results demonstrated that there was a 10% probability of having tubular impairment when urinary cadmium levels exceeded 2–4 µg/day. The result was derived from a logistic regres- sion of urinary cadmium and various mark- ers, including urinary calcium, amino acids, NAG, RBP, and β2-MG. These markers demonstrated different thresholds for urinary cadmium levels. More than 10% of values for each marker were abnormal when urinary cad- mium (micrograms per day) exceeded 1.92 for calcium, 2.74 for NAG, 2.87 for RBP, 3.05 for β2-MG, and 4.29 for amino acids. The findings showed that urinary calcium excre- tion increased by 10 mg/day for every 2-fold increment in urinary cadmium excretion. An Cadmium in food and human health increased susceptibility to cadmium among subjects with diabetes was noted. Kidney and bone: current exposure levels. Compelling evidence has linked tubu- lar impairment with urinary calcium loss, rapid bone demineralization, and osteopo- rosis (Table 1). For example, Åkesson et al. (2005) showed that tubular impairment among women 53–64 years of age was associ- ated with blood and urinary cadmium lev- els of 0.38 µg/L and 0.67 µg/g creatinine, respectively. Glomerular impairment was associated with urinary cadmium of 0.8 µg/g creatinine. In another study, Åkesson et al. (2006) used the same population and showed the body burden associated with decreased bone mineral density They also showed that participants with diabetes had increased sus- ceptibility to the renal effects of cadmium and that menopausal women were more sus- ceptible to cadmium-induced bone effects than were nonmenopausal women. The risk for osteoporosis among women ≥ 50 years of age increased by 43% when urinary cadmium levels were compared between groups with Table 4. Exposure levels associated with mortality and cancer mortality. Study population, reference Kakehashi (Japan) cohort, n = 3,178, 15-year observation; Nakagawa et al. 2006; Nishijo et al. 2006 Nagasaki (Japan) cohort I, n = 275, 23-year observation; Arisawa et al. 2007a Nagasaki cohort II, n = 329, 13-year observation; Arisawa et al. 2007b Belgian cohort, n = 956, 20.3-year median observation; Nawrot et al. 2008 U.S. cohort, n = 13,958, Menke et al. 2009 Exposure/outcomes Hazard ratio for cancer mortality was 2.5 among women with permanent tubular impairment.a Hazard ratio for all-cause mortality was 2.09 among women with urinary cadmium ≥ 3 µg/g creatinine. OR for cancer mortality was 2.58 among those with tubular impairment.a OR for all-cause mortality was 1.41 among those with permanent tubular impairment.a No effects of body burden of cadmium on mortality were observed. Mortality increased by 20% and 44% in low- and high-exposure areas, respectively, among those with a 2-fold increase in body burden. Mortality increased by 25% and 33% in low- and high-exposure areas, respectively, among those with a 2-fold increase in blood cadmium. Male hazard ratio was 1.7 for all-cause mortality and 4.3 for cancer mortality, comparing urinary cadmium < 0.21 versus > 0.48 µg/g creatinine. OR, odds ratio. aIrreversible tubular impairment was defined as urinary β2-MG ≥ 1,000 µg/g creatinine. Table 5. Exposure levels associated with cancer. Cancer/study population, reference Lung, Belgium, n = 994, 15-year observation; Nawrot et al. 2006 Pancreas, Egypt, n = 31 cases, 52 controls; Kriegel et al. 2006 Breast, United States, n = 246 cases, 254 controls; McElroy et al. 2006 Endometrium, Sweden, n = 30,210, 16-year observation; Åkesson et al. 2008 Prostate, China; n = 297, Zeng et al. 2004 Prostate, Italy, n = 45 cases, 58 controls; Vinceti et al. 2007 Prostate, United States, n = 422; Wijngaarden et al. 2008 Urinary bladder, Belgium, n = 172 cases, 395 controls; Kellen et al. 2007 Exposure/risk estimate Hazard ratios of 1.7, 2.6, and 1.6 were attributed to a 2-fold increase in body burden, living in high-exposure area, and a 2-fold increase in soil cadmium, respectively. ORs of 1.12 and 3.25 were attributed to elevated serum cadmium and farming occupation, respectively. OR of 2.3 when comparing urinary cadmium < 0.26 versus ≥ 0.58 µg/g creatinine OR of 2.9 was attributed to cadmium intake > 15 µg/day. Dose response between body burden and abnormal serum PSA levels OR of 4.7 when comparing nail cadmium content in the lowest versus the highest quartile An increase of urinary cadmium to 1 µg/g creatinine associated with a 35% increase in serum PSA OR of 5.7 when comparing blood cadmium in the lowest versus the highest tertile Abbreviations: OR, odds ratio; PSA, prostate-specific antigen. Environmental Health Perspectives • volume 118 | number 2 | February 2010 185