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

Background: Cadmium (Cd), a food-chain contaminant, is a significant health hazard. The kidney is one of the primary sites of injury after chronic Cd exposure. Kidney-based risk assessment establishes the urinary Cd threshold at 5.24 μg/g creatinine, and tolerable dietary intake of Cd at 62 μg/day per 70-kg person. However, cohort studies show that dietary Cd intake below a threshold limit and that tolerable levels may increase the risk of death from cancer, cardiovascular disease, and Alzheimer’s disease. Objective: We evaluated if the current tolerable dietary Cd intake guideline and urinary Cd threshold limit provide sufficient health protection. Discussion: Staple foods constitute 40–60% of total dietary Cd intake by average consumers. Diets high in shellfish, crustaceans, mollusks, spinach, and offal add to dietary Cd sources. Modeling studies predict the current tolerable dietary intake corresponding to urinary Cd of 0.70–1.85 μg/g creatinine in men and 0.95–3.07 μg/g creatinine in women. Urinary Cd levels of < 1 μg/g creatinine were associated with progressive kidney dysfunction and peripheral vascular disease. A urinary Cd of 0.37 μg/g creatinine was associated with breast cancer, whereas dietary Cd of 16–31.5 μg/day was associated with 25–94% increase in risk of estrogen receptor–positive breast cancer. Conclusion: Modeling shows that dietary intake levels for Cd exceed the levels associated with kidney damage and many other adverse outcomes. Thus, the threshold level of urinary Cd should be re-evaluated. A more restrictive dietary intake guideline would afford enhanced health protection from this pervasive toxic metal. Citation: Satarug S, Vesey DA, Gobe GC. 2017. Health risk assessment of dietary cadmium intake: do current guidelines indicate how much is safe? Environ Health Perspect 125:284–288; http://dx.doi.org/10.1289/EHP108


Introduction
Cadmium (Cd) is a nonessential metal, a food-chain contaminant, and a constituent of cigarette smoke and polluted air (IPCS 1992). Diet is a major source of Cd exposure for nonsmokers, while cigarette smoke is an additional source for smokers (Satarug et al. 2013). 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 (IARC 1993) established Cd as a human lung carcinogen. Non-cancer risk assessment by the Food and Agriculture Organization/World Health Organization (FAO/WHO 1989, 1993, 2010) 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) (Hyder et al. 2013;Lin et al. 2013Lin et al. , 2014. 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. In 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.

Kidney Threshold Risk Assessment
In 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 (FAO/ WHO 1989). 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 (FAO/WHO 1989). 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). Wallin et al. (2014) 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) (FAO/WHO 1993). 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 (FAO/WHO 2010).

Dietary Cd Intake Estimates for Swedish and French Populations
In the Swedish National Food Consumption Survey, Sand and Becker (2012) 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) (Arnich et al. 2012) 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 potatobased products. The additional Cd came from consumption of mollusks and crustaceans in the high-consumer group. Dietary Cd exposure in the second TDS (2007)(2008)(2009) was four times higher than that of the first TDS (2000)(2001)(2002)(2003)(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 (Vacchi-Suzzi et al. 2015). These findings suggest such dietary intake estimates to be of limited use in health risk assessment.

Urine Cd Concentration as a Measure of Cumulative Lifetime Cd Intake
Use of urinary Cd concentration, as a measure of cumulative lifetime exposure and body burden, has its foundation in the Cd-toxicokinetics model, developed by Kjellström and Nordberg (1978) 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), Akerstrom et al. (2013) 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 (Satarug et al. 2002). Using the 1:20 ratio, the current WHO urinary Cd threshold of 5.24 μg/g creatinine (FAO/WHO 2010) 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 (Tellez-Plaza et al. 2010;Wu et al. 2014). 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.

Model-Based Prediction of Urinary Cd Excretion at Tolerable Intake Guideline
Reverse 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 (Ruiz et al. 2010). 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 (Satarug et al. 2013). These urinary Cd levels, derived from modeled tolerable intake of dietary Cd, have been associated with kidney damage and CKD (Ferraro et al. 2010), concurrent with death from cancer (Lin et al. 2013; Adams  NHANES 1999NHANES -2004, aged ≥ 40 years, male mean urinary Cd levels of 0.31 μg/g creatinine (0.37 μg/L), and female mean urinary Cd levels of 0.44 μg/g creatinine (0.31μg/L).
Three other factors associated with death were low-level physical activity, smoking, and low serum lycopene (a dietary antioxidant). Mortality from Alzheimer's disease, Min and Min (2016), NHANES (1999-2004, followed up until 31 December 2011, n = 4,060, aged ≥ 60 years. Blood Cd levels > 0.6 μg/L were associated with death from Alzheimer's disease (HR 3.83, 95% CI: 1.39, 10.59), compared with blood Cd levels < 0.3 μg/L. Higher-blood Cd levels at baseline were associated with a marginal increase in death from all causes (p = 0.07).
NHANES III follow-up (Lin et al. 2013 (Buser et al. 2016). 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 (Mortensen et al. 2011). 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 (Gallagher et al. 2010), death from heart disease (Tellez-Plaza et al. 2012b), death from cancer (Adams et al. 2012;Lin et al. 2013), and liver-related diseases (Hyder et al. 2013). Further, the prevalence of diminished kidney function among the NHANES 2011-2012 participants of 7.4% exceeds the 5% acceptable disease prevalence (Lin et al. 2014). Thus, restrictive dietary intake guidelines are required to safeguard against a further increase in dietary Cd intake.

Conclusion
Current 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.