Health Risk Assessment of Dietary Cadmium Intake: Do Current Guidelines Indicate How Much is Safe?

1Cadmium (Cd) is a nonessential metal, a food-chain contaminant, and a constituent of cigarette smoke and polluted air. Diet is a major source of Cd exposure for nonsmokers, while cigarette smoke is an additional source for smokers. Cd accumulates in the kidneys. Currently, human exposure to Cd is assumed, primarily, to damage the kidneys, especially the proximal tubular cells where the metal selectively concentrates. Consequently, kidney-based assessment of Cd exposure is often applied, with urinary Cd levels as indicators of Cd exposure. Other means of measuring Cd exposure relate to dietary intake estimates. Cancer risk assessment by the International Agency for Research on Cancer established Cd as a human lung carcinogen. Non-cancer risk assessment by the Food and Agriculture Organization/World Health Organization established a tolerable exposure and urinary threshold level that should protect against kidney damage. However, a wide diversity of Cd toxicity levels is increasingly apparent from recent studies, including the U.S. National Health and Nutrition Examination Survey (NHANES). Challenging kidney-based assessment is the observation that the carcinogenic effects of Cd appear to occur at exposure levels below the levels associated with kidney effects.

2In this article, we highlight the basis of risk assessment for dietary Cd intakes together with dietary Cd intake estimates, derived from dietary and modeling studies. We provide evidence supporting the use of urinary Cd, a measure of cumulative lifetime exposure (body burden), in risk assessment, as opposed to the use of dietary intake estimates. We reviewed cross-sectional and longitudinal studies (published between 2010 and 2016) that link current dietary Cd intake levels to kidney damage, chronic kidney disease (CKD), cancer, and many other adverse health outcomes.

3In 1989, the Joint FAO/WHO Expert Committee on Food Additives (JECFA) established the safe dietary intake guideline, known as the Provisional Tolerable Weekly Intake (PTWI), defined as an estimate of the amount of the chemical with no intended function that can be ingested weekly over a lifetime without appreciable health risk. The original PTWI for Cd was set at 400–500 μg per person per week, based on kidney critical concentration of Cd at 200 μg/g kidney wet weight, attainable after dietary Cd exposure of 140–260 μg/day for over 50 years or 2,000 mg of Cd over a lifetime. It is considered that kidney damage by Cd causes a reduction in tubular re-absorptive function, evident from excess urinary excretion of nutrients (amino acids, glucose, zinc, calcium) and low molecular weight proteins, notably β2-microglobulin (β2-MG), retinol binding protein (RBP). observed a positive correlation between kidney Cd levels and urinary α1-microglobulin (α1-MG) levels, and they suggested that urinary α1-MG could serve as a more sensitive biomarker for kidney toxicity, compared with other injury biomarkers like kidney injury molecule-1 (KIM-1), RBP, and β2-MG, which do not correlate with kidney Cd levels in chronic low-level exposure conditions. The original PTWI for Cd was later revised to 7 μg/kg body weight per week (70 μg/day for a 70-kg person). The current tolerable exposure was set at 25 μg/kg body weight per month (62 μg/day for a 70-kg person), and a urinary threshold of 5.24 μg/g creatinine.

4In the Swedish National Food Consumption Survey, reported a dietary Cd intake of 10.6 μg/day for an average consumer. In this group, 40–50% of the Cd came from staple foods such as potatoes and wheat. For the high-Cd consumer, that is exposure above the 95th percentile, intake was 23 μg/day with additional Cd reportedly coming from seafood and spinach. Data derived from the second French Total Diet Study (TDS) showed the dietary Cd intake of 11.2 μg/day for an average consumer and 18.9 μg/day for the high consumer. For the average consumer, 35% came from bread products and another 26% from potato-based products. The additional Cd came from consumption of mollusks and crustaceans in the high-consumer group. Dietary Cd exposure in the second TDS (2007–2009) was four times higher than that of the first TDS (2000–2004), while the Cd concentrations were reported for the different food groups: Crustaceans and mollusks had the highest Cd content (0.167 mg/kg), followed by offal (0.053 mg/kg), sweet and savory biscuits (0.030 mg/kg) and cereal bars, and chocolate (0.029 mg/kg). However, data on variations in dietary habits were not reported. Likewise, the TDS did not report the body status of essential metals, which governs Cd absorption, or resultant toxicity. A study of 1,764 post-menopausal Danish women indicated leafy vegetables and soy-based products to be dietary Cd sources, but such dietary intake estimates (average 14 μg/day) marginally correlated with urinary Cd levels. These findings suggest such dietary intake estimates to be of limited use in health risk assessment.

5Use of urinary Cd concentration, as a measure of cumulative lifetime exposure and body burden, has its foundation in the Cd-toxicokinetics model, developed by from Swedish autopsy data. In a recent analysis of Cd levels in kidney, blood, and urine samples from 109 living kidney donors (mean age 51 years, mean kidney Cd 12.9 μg/g wet weight), found a urine-to-kidney Cd ratio of 1:60, and urinary Cd of 0.42 μg/g creatinine corresponded to kidney Cd of 25 μg/g kidney. Assuming a urine-to-kidney Cd ratio of 1:20, urinary Cd of 1.25 μg/g creatinine corresponded to 25 μg/g Cd per kidney wet weight, comparable with Cd levels found in kidney cortex samples from Australians, 41–50 years of age. Using the 1:20 ratio, the current WHO urinary Cd threshold of 5.24 μg/g creatinine corresponds to kidney Cd > 100 μg/g kidney weight, the levels seen mostly in workers exposed to high-Cd doses via inhalation. In the general population, blood Cd is considered a good estimate of body burden because population blood Cd levels correlate with urine Cd levels. Blood Cd is a better estimate of exposure for the elderly, people with diabetes, hypertension, and heavy smokers because the high prevalence of kidney dysfunction in these people may bias associations between their urine Cd levels and health outcomes.

6Reverse dosimetry theory dictates that dietary Cd exposure and urinary Cd levels can be derived from a Cd toxicokinetic model, which describes mathematical relationships among the parameters, influencing Cd body burden, such as absorption rate, tissue distribution, half-life, and elimination rate. The original Cd-toxicokinetic model predicts that a Cd level of 50 μg/g kidney cortex wet weight corresponds to urinary Cd excretion of 2–4 μg/day, attainable after 50-year intake of dietary Cd at the tolerable weekly intake rate. A simulation model of Cd-toxicokinetics has been developed as a tool kit for prediction of Cd intake via oral (diet, water) versus inhalation (cigarette smoke, air) routes as a function of age and sex. Such simulation models predict that dietary intake of Cd at current tolerable monthly intake rate for 50 years will result in urinary Cd of 0.70–1.85 μg/g creatinine in men and 0.95–3.07 μg/g creatinine in women. These urinary Cd levels, derived from modeled tolerable intake of dietary Cd, have been associated with kidney damage and CKD, concurrent with death from cancer, liver-related disease, cardiovascular disease (CVD), ischemic heart disease, coronary heart disease, and Alzheimer’s disease. Tables 1 and 2 show details of population-based studies, giving evidence of Cd intake and exposure biomarkers associated with various adverse outcomes.

7Table 1 is a summary of cross-sectional and case-control studies of Cd exposure outcomes. In NHANES 1999–2006, blood and urinary Cd levels > 1 μg/L were associated with kidney damage [OR 1.41, 95% confidence interval (CI): 1.10, 1.82] and CKD (OR 1.48, 95% CI: 1.01, 2.17). An association of Cd exposure and CKD became obscured when creatinine was used to correct for diluting effects of spot urine samples. This may indicate variability in creatinine secretion by kidney. In NHANES 2011–2012, blood Cd levels > 0.53 μg/L were associated with kidney damage (OR 2.04, 95% CI: 1.13, 3.69) and low GFR (OR 2.21, 95% CI: 1.09, 4.50), and risk of Cd-induced kidney damage was particularly high (OR 3.38, 95% CI: 1.39, 8.28) in the participants who had lower zinc status, compared with those with higher zinc status. In NHANES 1999–2004, urinary Cd levels ≥ 0.69 μg/g creatinine were associated with peripheral arterial disease (PAD) in men (OR 4.90, 95% CI: 1.55, 15.54), and in women (OR 0.56, 95% CI: 0.18, 1.71). Further, PAD risk in male nonsmokers increased with blood Cd levels, but PAD prevalence and blood Cd levels in female nonsmokers showed a U-shape relation, reflecting effects at blood Cd levels below 0.3 μg/L. In NHANES III (1988–1994), found that urinary Cd levels ≥ 0.83 μg/g creatinine were associated with liver inflammation in women (OR 1.26, 95% CI: 1.01, 1.57), while urinary Cd levels ≥ 0.65 μg/g creatinine were associated with liver inflammation (OR 2.21, 95% CI: 1.64, 3.00), non-alcoholic fatty liver (OR 1.30, 95% CI: 1.01, 1.68) and non-alcoholic steatohepatitis (OR 1.95, 95% CI: 1.11, 3.41) in men. found a 1 μg/L increment in urinary Cd was associated with a 1.93% reduction in a neurocognitive test for attention/perception domain among nonsmokers in NHANES III. In NHANES 2007–2010, blood Cd levels ≥ 0.54 μg/L were associated with depressive symptoms in nonsmokers (OR 2.91, 95% CI: 1.12, 7.58), and smokers (OR 2.69, 95% CI: 1.13, 6.42). In NHANES 2005–2008, found blood Cd levels ≥ 0.66 μg/L were associated with age-related macular degeneration (AMD) (OR 1.56, 95% CI: 1.02, 2.40). The Cd and AMD association was particularly strong in non-Hispanic whites with urinary Cd levels ≥ 0.35 μg/L (OR 3.31, 95% CI: 1.37, 8.01). In NHANES 2005–2008, urinary Cd levels > 1.4 μg/g creatinine were associated with risk of prediabetes among nonsmokers. In NHANES 1999–2008, found urinary Cd levels ≥ 0.37 μg/g creatinine were associated with breast cancer among women (OR 2.50, 95% CI: 1.11, 5.63). In another study, found dietary Cd intake levels ≥ 31.5 μg/day were associated with estrogen receptor positive (ER+) breast cancer in Japanese women (OR 1.94, 95% CI: 1.04, 3.63).

8Table 2 is a summary of longitudinal studies of Cd exposure outcomes. In a Swedish cohort, dietary Cd intake levels ≥ 16 μg/day were associated with breast cancer (RR 1.27, 95% CI: 1.07, 1.50), and ER+ breast cancer (RR 1.25, 95% CI: 1.03, 1.52). In NHANES 1999–2004 follow-up, urinary Cd levels ≥ 0.57 μg/g creatinine were associated with death from CVD (HR 1.74, 95% CI: 1.07, 2.83), ischemic heart disease (HR 2.53 95% CI: 1.54, 4.16), and coronary heart disease (HR 2.09, 95% CI: 1.06, 4.13). Population attributed risks suggest that reduction in urinary Cd from 0.57 to 0.14 μg/g creatinine could prevent 8.8% overall deaths and 9.2% CVD deaths. An equivalent analysis using blood Cd data gives parallel results; a reduction of blood Cd from 0.80 to 0.22 μg/L could prevent 7% overall deaths and 7.5% CVD deaths. In NHANES III follow-up, found urinary Cd levels ≥ 0.58 μg/g creatinine were associated with death from lung cancer in men (HR 3.22, 95% CI: 1.26, 8.25), while found female urinary Cd levels ≥ 0.83 μg/g creatinine, and male urinary Cd levels ≥ 0.65 μg/g creatinine were associated with death from liver-related diseases (HR 3.42, 95% CI: 1.12, 10.47). Also in NHANES III follow-up, urinary Cd levels > 0.79 μg/g creatinine were associated with cancer death in men (HR 3.13, 95% CI: 1.88, 5.20), while urinary Cd levels > 1.05 μg/g creatinine were associated with cancer death in women (HR 1.65, 95% CI: 1.13, 2.41). In the NHANES 1999–2004 follow-up, a 1-SD change in logged exposure levels was associated with death from all causes (HR 1.6, 95% CI: 1.3, 2.0 for urinary Cd, and HR 1.4, 95% CI: 1.2, 1.6 for blood Cd). In the NHANES 1999–2004 follow-up, blood Cd levels > 0.6 μg/L were associated with death from Alzheimer’s disease (HR 3.83, 95% CI: 1.39, 10.59).

9Chronic intake of low-level dietary Cd has long been viewed as a subtle, long term and non-specific impairment. In contrast, such low-level dietary Cd intake has now been implicated in more serious health outcomes than previously perceived. Of concern, NHANES data indicate a significant proportion of the U.S. population is at risk of adverse effects from low-level dietary Cd intakes. Data from the NHANES 1999–2008 participants, aged 20–85 years, indicate Cd exposure prevalence of 94–98% in nonsmokers, and 96–99% in smokers. A decline in Cd exposure in the U.S. over the 20-year (1988–2008) period could only be attributed to a reduction in smoking prevalence with little evidence to suggest a reduction in dietary Cd sources. Overall Cd exposure prevalence among NHANES 2007–2012 participants, aged ≥ 20 years remains as high as 91.9%. These high exposure prevalence rates suggest that even a small increase in disease risk by Cd exposure can result in a large number of people affected by a disease that is preventable. In the NHANES 1999–2006, overall (female) prevalence of urinary Cd > 1, > 0.7 and > 0.5 μg/g creatinine among ≥ 20-year nonsmokers without CKD was 1.7 (2.5)%, 4.8 (7.1)%, and 10.8 (16)%, respectively. These data are a cause for concern because urinary Cd levels ≥ 0.37 to ≥ 0.65 μg/g creatinine have been associated with female breast cancer, death from heart disease, death from cancer, and liver-related diseases. Further, the prevalence of diminished kidney function among the NHANES 2011–2012 participants of 7.4% exceeds the 5% acceptable disease prevalence. Thus, restrictive dietary intake guidelines are required to safeguard against a further increase in dietary Cd intake.

10Current population risk assessment of dietary Cd intake relies on estimates of dietary Cd intake and/or maintenance of threshold levels of urinary Cd that should protect the kidney from Cd-induced damage. Risk assessment using dietary Cd intake estimates has been questioned because they show only a marginal correlation with urinary Cd levels, a well-founded measure of lifetime intakes. Blood Cd levels, however, show a correlation with urinary Cd levels, and they could thus be of value in risk assessment; blood Cd levels ≥ 1 μg/L were associated with CKD, while blood Cd levels above 0.5 μg/L were associated with AMD, depression, and death from Alzheimer’s disease. Using a Cd-toxicokinetic simulation model, we have found that current tolerable dietary intake guidelines do not contain a safety margin, given that the modeled dietary intake levels exceed the levels associated with kidney damage and many other adverse health outcomes seen in cohorts and cross-sectional studies. These data point to the need for a revision of tolerable dietary intake levels for Cd, and public measures to minimize the food-chain contamination by Cd. Risk reduction measures, supported by international food legislation, should not be relaxed. A maximally permissible concentration (MPC) for Cd in foods should be set as low as reasonably achievable. Current MPC for rice is set at 0.4 mg/kg dry grain weight, but global risk assessment suggests 0.1 mg/kg is necessary. Persistence of Cd in the environment, coupled with its high soil-to-plant transfer rates, requires long-term management of Cd in the environment (soil, air, and water), and in agriculture, where consideration should be given to leafy salad vegetables, such as spinach and lettuce, which are known to be hyper accumulators of Cd. In the absence of non-toxic chelating agents to reduce Cd tissue burden, maintenance of the lowest Cd levels in food crops is pivotal.