Mammary gland. Gundacker et al. (2007) showed that breast milk samples of Austrian subjects contained, on average, a cadmium content of 0.086 µg/L and that breast milk cadmium content was lower among nonsmok- ers who took vitamins and mineral supple- ments (p < 0.05). In a study by Kippler et al. (2008), the median cadmium level in breast milk from Bangladeshi subjects was 1.6-fold higher than was the level from Austrian sub- jects. The investigators observed a correlation between cadmium and the elemental com- position of milk, including manganese, iron, and calcium levels. Their findings suggest a potential influence of cadmium on mammary gland metal transport and secretion. Cadmium and cancer. Cadmium is clas- sified as a cancer-causing agent in humans based on an elevated incidence of lung cancer and mortality data derived from the occupa- tional groups with evidence of elevated expo- sure to cadmium. Occupational exposures have historically been through inhalation [International Agency for Research on Cancer (IARC) 1993]. A consequence of this initial association of inhaled cadmium with cancer in occupationally exposed workers is that a carcinogenic risk from cadmium of dietary origin has long been ignored by regulatory agencies. However, literature to support a role for dietary cadmium that shows exposure levels associated with increased mortality risk and cancer mortality does exist as summarized in Table 4. In the Kakehashi cohort, a 2.5- fold increase in cancer mortality was observed among women with permanent tubular impairment (Nishijo et al. 2006). This study also noted increased mortality from nephritis, nephrosis, heart failure, and brain infarction among both men and women with severely impaired tubular function. Baseline median urinary cadmium values for men and women in the Kakehashi cohort were 7.0 and 12.1 µg/g creatinine, respectively. This cohort was also used to establish a dose response show- ing the lowest urinary cadmium of 3 µg/g creatinine associated with excess female mor- tality risk (Nakagawa et al. 2006). Similarly, Arisawa et al. (2007a) observed an increased mortality rate among subjects with permanent tubular impairment in the Nagasaki cohort I. They also observed a 2.58-fold concurrent increased risk of cancer mortality among those with tubular impairment. The determi- nants of increased mortality were renal injury, tubular impairment, and renal insufficiency. These effects of cadmium were absent in the Nagasaki cohort II study, most likely because of the selective loss of advanced cases and the reduction in exposure after soil restora- tion that was undertaken between 1980 and 1983 (Arisawa et al. 2007b). Of note, the cadmium exposure levels in the Kakehashi and the Nagasaki cohorts were close to the levels experienced by people in a cadmium pollution area in Thailand (Teeyakasem et al. 2007). In contrast to the above studies, the cad- mium exposure in a Belgian cohort and in a U.S. cohort was below the level that would cause renal injury and yet increased mortality was observed in these studies. In the Belgian cohort, Nawrot et al. (2008) observed a 20% increase in mortality in the low-exposure area. This percentage was increased by 44% in the high-exposure area. Further, mortality risks were increased by 25% and 33% among those with a 2-fold increase in blood cadmium who resided in low- and high-exposure areas, respec- tively. Menke et al. (2009) observed in the U.S. cohort, an increase in cancer mortality by 4.29- fold among men with urinary cadmium lev- els < 0.21 versus > 0.48 µg/g creatinine. They also observed a 1.68-fold increase in all-cause mortality among men after adjusting for cad- mium exposure from cigarette smoking. Mean urinary cadmium for men in the U.S. cohort was 0.28 µg/g creatinine, which was 1.43-fold lower than that for women. Cadmium as a multitissue carcinogen. A substantial number of recent reports have noted a link between cadmium and cancer in non- occupationally exposed populations (Table 5). In the 15-year Belgian cohort, Nawrot et al. (2006) observed a 1.7-, 4.2- and 1.57-fold increase in lung cancer risk among those with a 2-fold increase in cadmium body burden, those living in a high exposure area, and those with a 2-fold increase in soil-cadmium content, respectively. Serum cadmium and a farming occupation have been associated with pancrea- tic cancer with the risk attributed to increased serum cadmium of 1.12 µg/L and of 3.25 µg/L for farming occupation (Kriegel et al. 2006). A dose response between breast cancer risk and cadmium exposure could be seen when indi- viduals with urinary cadmium of ≤ 0.26 were compared with those with ≥ 0.58 µg/g crea- tinine, suggesting a 2.29-fold increase in risk (McElroy et al. 2006). In a prospective study, Åkesson et al. (2008) found a 2.9-fold increase in endometrial cancer risk among women with cadmium intake greater than an average value of 15 µg/day; 80% of cadmium intake was derived from cereals and vegetables. Several studies have examined prostate disease. A dose–response relationship was shown between urinary cadmium and abnormal serum lev- els of prostate specific antigen (PSA) (Zeng et al. 2004). It has also been shown that an increase in urinary cadmium to 1 µg/g creati- nine is associated with a 35% increase in serum PSA level among men whose zinc intakes were < 12.7 mg/day (van Wijngaarden et al. 2008). Safe and adequate zinc intake for an adult is 15 mg/day (Slikker et al. 2004). A 4.7-fold increase in prostate cancer risk was found among subjects where toenail cadmium was Environmental Health Perspectives • volume 118 | number 2 | February 2010 Cadmium in food and human health compared between individuals with < 0.007 and among those with > 0.03 µg cadmium/g toenail (Vinceti et al. 2007). In a study of blad- der cancer, Kellen et al. (2007) demonstrated a 5.7-fold increase in risk between subjects with blood cadmium at the lowest tertile versus the highest. The risk estimate was corrected for sex, age, smoking habits, and workplace exposure. Mean blood cadmium for bladder cancer cases was 1.1 µg/L and this level was 1.6-fold higher than that of the controls. Cadmium Body Burden Sex and tissue differential cadmium accu- mulation. Tissue collected from postmor- tem examinations has been used to define cadmium accumulation levels in tissues and organs of human subjects (Table 6). In an analysis of 61 environmentally exposed sub- jects between 2 and 89 years of age (mean 38.5 years), Satarug et al. (2002) revealed that renal cadmium accumulation was greater in younger age groups with little increase, or even a reduction, in the older age groups. Some investigators have suggested that younger individuals have high rates of renal cadmium accumulation because of a very high rate of dietary cadmium absorption (Horiguchi et al. 2004; Kikuchi et al. 2003). Conversely, a lack of renal cadmium accumu- lation in older individuals may be caused by a fall in dietary absorption rate plus a reduc- tion in tubular reabsorptive capacity, which is associated with the aging of the kidney. A few studies have examined sex differences and cadmium accumulation. For example, Satarug et al. (2002) showed that Australian women had twice the level of cadmium in their livers than did their male counterparts; they also noted a trend for higher cadmium content in the kidneys of the female subjects. Table 6. Cadmium accumulation in the body of environmentally exposed subjects. Study population, reference Cadmium content (µg/g wet tissue weight) Men Women Australia, Satarug et al. 2002a Lung 0.11 ± 0.19 0.17 ± 0.35 Liver 0.78 ± 0.71 1.36 ± 0.96b Kidney cortex 14.6 ± 12.4 18.1 ± 18.0 Japan, Uetani et al. 2006c Liver 7.9 (2.1) 13.1 (2.1) Kidney cortex 72.1 (1.7) 83.9 (2.2) Kidney medulla 18.3 (2.2) 24.5 (2.1) Pancreas 7.4 (2.0) 10.5 (2.1) Thyroid 10.6 (2.2) 11.9 (2.0) Heart 0.3 (1.5) 0.4 (2.0) Muscle 1.2 (2.1) 2.2 (2.4) Aorta 1.0 (2.1) 1.1 (1.9) Bone 0.4 (1.6) 0.6 (1.8) aAn Australian study comprising 43 men and 18 women, 2–89 years of age (mean age, 38.5 years). Values are arithmetic mean ± SD. bHigher in women than in men. cA Japanese study comprising 36 men and 36 women, 60–91 years of age (mean age, 74 years). Values are geo- metric mean (SD). 187