Cadmium, Environmental Exposure, and Health Outcomes

Soisungwan Satarug; Scott H. Garrett; Mary Ann Sens; Donald A. Sens

Disclosures

Environ Health Perspect. 2010;118(2):182-90. 

In This Article

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 difference 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-binding protein (RBP) [International Programme on Chemical Safety (IPCS) 1992]. The abnormal urinary excretion of low-molecular-weight proteins, calcium, amino acid, phosphate and glucose observed in cadmium-exposed individuals 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 substances, and the enzymes of renal tubular origin, 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 considered 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 24 µg/day. The result was derived from a logistic regression of urinary cadmium and various markers, 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 cadmium (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 excretion increased by 10 mg/day for every 2-fold increment in urinary cadmium excretion. An increased susceptibility to cadmium among subjects with diabetes was noted.

Kidney and Bone: Current Exposure Levels

Compelling evidence has linked tubular impairment with urinary calcium loss, rapid bone demineralization, and osteoporosis (Table 1). For example, Åkesson et al. (2005) showed that tubular impairment among women 5364 years of age was associated with blood and urinary cadmium levels 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 susceptibility to the renal effects of cadmium and that menopausal women were more susceptible 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 urinary cadmium < 0.5 and > 1.0 µg/g creatinine (Gallagher et al. 2008). In a prospective 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 1660 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 urinary cadmium (0.39 to 1.12 µg/L) was associated with an 11%, 32% and 61% increase in the probability of having high blood pressure, 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 15 versus > 5 µg/g creatinine (Teeyakasem et al. 2007). Thomas et al. (2009) reported a doseresponse relationship between urinary cadmium and early renal injury, whereas Wu et al. (2008) found progressive tubular and glomerular impairment among those with urinary 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 filtration rate among those in the highest quartiles of blood cadmium and lead than among those in the lowest. These findings suggest that environmental exposure to cadmium and lead may constitute the risk factors for chronic kidney disease in the United States.

Diabetes

Schwartz et al. (2003) demonstrated a dose response between urinary cadmium level and an increased risk of prediabetes 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 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 glomerular effects. Afridi et al. (2008) reported higher blood and urinary cadmium among Pakistani men 3160 years of age who had had type 2 diabetes, on average, for 16 years.

Diabetic Nephropathy

A doseresponse relationship has been observed between urinary 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 albuminuria, 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 cadmium 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 impairment associated with the urinary cadmium 0.8 µg/g creatinine (Åkesson et al. 2005).

Hypertension

Eum et al. (2008) observed a doseresponse relationship between urinary cadmium and hypertension. Of the Korean subjects in their study, 26.2% were hypertensive. For this population, the mean blood cadmium was 1.67µg/L, and the risk estimate for hypertension was 1.51 when blood cadmium levels in the lowest tertile were compared with those in the highest. An association was also found between blood cadmium and blood pressure levels in a U.S. sample population, 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 findings 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. Navas-Acien et al. (2005) showed that subjects with PAD had 36% higher urinary 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 compared 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. 2008a). Everett and Frithsen (2008) found the risk of myocardial 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 urinary cadmium (0.18 versus 0.63 µg/g creatinine) has been reported to be associated with a 54% higher prevalence odds ratio (OR) for periodontal 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 urinary 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).

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 nonsmokers who took vitamins and mineral supplements (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 subjects. The investigators observed a correlation between cadmium and the elemental composition 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 classified as a cancer-causing agent in humans based on an elevated incidence of lung cancer and mortality data derived from the occupational groups with evidence of elevated exposure 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 showing the lowest urinary cadmium of 3 µg/g creatinine associated with excess female mortality 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 determinants 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 restoration 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 cadmium 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, respectively. Menke et al. (2009) observed in the U.S. cohort, an increase in cancer mortality by 4.29-fold among men with urinary cadmium levels < 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 cadmium 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 nonoccupationally 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 pancreatic 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 individuals with urinary cadmium of ≤ 0.26 were compared with those with ≥ 0.58 µg/g creatinine, 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 doseresponse relationship was shown between urinary cadmium and abnormal serum levels of prostate specific antigen (PSA) (Zeng et al. 2004). It has also been shown that an increase in urinary cadmium to 1 µg/g creatinine 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 compared between individuals with < 0.007 and among those with > 0.03 µg cadmium/g toenail (Vinceti et al. 2007). In a study of bladder 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.

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