Acute-Duration Inhalation MRL

• An MRL of 3×10⁻⁵ mg Cd/m³ (0.03 µg Cd/m³) has been derived for acute-duration inhalation exposure (<14 days) to cadmium.

The acute toxicity of airborne cadmium, particularly cadmium oxide fumes, was first recognized in the early 1920s and there have been numerous case reports of cadmium workers dying after brief exposures to presumably high concentrations of cadmium fumes (European Chemicals Bureau 2007). The initial symptoms, similar to those observed in metal fume fever, are usually mild but rapidly progress to severe pulmonary edema and chemical pneumonitis. Persistent respiratory effects (often lasting years after the exposure) have been reported in workers surviving these initial effects. There are limited monitoring data for these human reports; however, Elinder (1986b) estimated that an 8-hour exposure to 1–5 mg/m³ would be immediately dangerous.

Animal studies support the findings in humans that acute exposure to cadmium results in lung damage. Single exposures to approximately 1–10 mg Cd/m³ as cadmium chloride or cadmium oxide resulted in interstitial pneumonitis, diffuse alveolitis with hemorrhage, focal interstitial thickening, and edema (Boudreau et al. 1989; Buckley and Bassett 1987b; Bus et al. 1978; Grose et al. 1987; Hart 1986; Henderson et al. 1979; Palmer et al. 1986). Repeated exposure to 6.1 mg Cd/m³ 1 hour/day for 5, 10, or 15 days resulted in emphysema in rats (Snider et al. 1973). Lower concentrations of 0.4–0.5 mg Cd/m³ as cadmium oxide for 2–3 hours (Buckley and Bassett 1987b; Grose et al. 1987) or 0.17 mg Cd/m³ as cadmium chloride 6 hours/day for 10 days (Klimisch 1993) resulted in mild hypercellularity and increases in lung weight. Alveolar histiocytic infiltration and focal inflammation and minimal fibrosis in alveolar septa were observed in rats exposed to 0.088 mg Cd/m³ as cadmium oxide 6.2 hours/day, 5 days/week for 2 weeks (NTP 1995); in similarly exposed mice, histiocytic infiltration was observed at 0.088 mg Cd/m³ (NTP 1995). At similar concentrations (0.19 or 0.88 mg Cd/m³as cadmium chloride), decreases in humoral immune response were observed in mice exposed for 1–2 hours (Graham et al. 1978; Krzystyniak et al. 1987). Other effects that have been reported in animals acutely exposed to cadmium include erosion of the stomach, decreased body weight gain, and tremors in rats exposed to 132 mg Cd/m³ as cadmium carbonate for 2 hours (Rusch et al. 1986) and weight loss and reduced activity in rats exposed to 112 mg Cd/m³ as cadmium oxide for 2 hours (Rusch et al. 1986).

The NTP (1995) study was selected as the basis of an acute duration inhalation MRL. In this study, groups of five male and five female F344 rats were exposed to 0, 0.1, 0.3, 1, 3, or 10 mg cadmium oxide/m³ (0, 0.088, 0.26, 0.88, 2.6, or 8.8 mg Cd/m³) 6.2 hours/day, 5 days/week for 2 weeks. The mean median aerodynamic diameter (MMAD) of the cadmium oxide particles was 1.5 µm with a geometric standard deviation of 1.6–1.8. The animals were observed twice daily and weighed on days 1, 8, and at termination. Other parameters used to assess toxicity included organ weights (heart, kidney, liver, lungs, spleen, testis, and thymus) and histopathological examination (gross lesions, heart, kidney, liver, lungs, tracheobronchial lymph nodes, and nasal cavity and turbinates). All rats in the 8.8 mg Cd/m³ group died by day 6; no other deaths occurred. A slight decrease in terminal body weights was observed at 2.6 mg Cd/m³; however, the body weights were within 10% of control weights. Significant increases in relative and absolute lung weights were observed at 0.26 (males only), 0.88, and 2.6 mg Cd/m³. Histological alterations were limited to the respiratory tract and consisted of alveolar histiocytic infiltrate and focal inflammation and minimal fibrosis in alveolar septa at ≥0.088 mg Cd/m³, necrosis of the epithelium lining alveolar ducts at ≥0.26 mg Cd/m³, tracheobronchial lymph node inflammation at ≥0.88 mg Cd/m³, degeneration of the nasal olfactory epithelium at 0.88 mg Cd/m³, and inflammation and metaplasia of the nasal respiratory epithelium at 2.6 mg Cd/m³.

The lowest-observed-adverse-effect level (LOAEL) of 0.088 mg Cd/m³ was selected as the point of departure for derivation of the MRL; benchmark dose analysis was considered; however, the data were not suitable for benchmark dose analysis because the data do not provide sufficient information about the shape of the dose-response relationship below the 100% response level. The LOAEL_HEC was calculated using the equations below.

The duration-adjusted LOAEL (LOAEL_ADJ) was calculated as follows:

The regional deposited dose ratio (RDDR) for the pulmonary region of 0.617 was calculated with EPA’s RDDR calculator (EPA 1994a) using the final body weight of 0.194 kg for the male rats exposed to 0.088 mg Cd/m³, the reported MMAD of 1.5 µm and the midpoint of the reported range of geometric standard deviations (1.7).

The LOAEL_HEC was divided by an uncertainty factor of 300 (10 for the use of a LOAEL, 3 for extrapolation from animals to humans with dosimetric adjustments, and 10 for human variability) resulting in an acute-duration inhalation MRL of 3×10⁻⁵ mg Cd/m³ (0.03 µg Cd/m³).

Intermediate-Duration Inhalation MRL

There are no studies examining the intermediate-duration toxicity of inhaled cadmium in humans; however, numerous animal studies have identified several targets of cadmium toxicity. Increases in the number of bronchioalveolar macrophages, alveolar histiocytic infiltration, degeneration or metaplasia in the larynx, and proliferations have been observed in rats and mice exposed to 0.022 mg Cd/m³ as cadmium oxide or cadmium chloride (Glaser et al. 1986; NTP 1995; Prigge 1978a). At higher concentrations (>0.88 mg Cd/m³), marked inflammation and fibrosis was observed in lungs of rats (Kutzman et al. 1986; NTP 1995). In general, these studies did not identify no-observed-adverse-effect levels (NOAELs) for lung effects. The NTP (1995) study also found significant increases in the incidence of inflammation of the nasal respiratory epithelium in rats exposed to 0.22 mg Cd/m³ and degeneration of the nasal olfactory epithelium in mice exposed to 0.088 mg Cd/m³. The NTP (1995) study did not find any histological alterations in non-respiratory tract tissues, alterations in urinalysis parameters, or changes in blood pressure (rats only) in rats or mice. Prigge (1978a, 1978b) reported increases in hemoglobin and hematocrit levels in rats continuously exposed to ≥0.052 mg Cd/m³; however, this effect was not observed in the NTP (1995) studies. Reproductive effects (increased duration of estrous cycle and decreased spermatid counts) have also been observed at higher concentrations (0.88–1 mg Cd/m³) (Baranski and Sitarek 1987; NTP 1995).

The studies by Baranski (1984, 1985) provide suggestive evidence that the developing organism is also a sensitive target of cadmium toxicity. Significant alterations in performance on neurobehavioral tests were observed in the offspring of rats exposed to 0.02 mg Cd/m³ as cadmium oxide 5 hours/day, 5 days/week for 5 months prior to mating, during a 3-week mating period, and during gestation days 1–20. No other studies examined neurodevelopmental end points following inhalation exposure. However, the identification of neurodevelopmental effects as a sensitive target of cadmium toxicity is supported by several intermediate-duration animal studies finding neurodevelopmental effects including alterations in motor activity and delays in the development of sensory motor coordination reflexes (Ali et al. 1986; Baranski 1985; Desi et al. 1998; Nagymajtenyi et al. 1997). Other developmental effects observed in the inhalation studies included decreases in fetal body weight in the fetuses of rats exposed to 1.7 or 0.581 mg Cd/m³ (NTP 1995; Prigge 1978b) and mice exposed to 0.4 mg Cd/m³ (NTP 1995).

Based on the available animal data, the LOAEL of 0.022 mg Cd/m³ for lung and larynx effects in mice (NTP 1995) and the LOAEL of 0.02 mg Cd/m³ for neurodevelopmental effects (Baranski 1984, 1985) were evaluated as possible points of departure for the intermediate-duration inhalation MRL for cadmium. The LOAEL of 0.022 mg Cd/m³ identified in the NTP (1995) mouse study was considered as the point of departure for the MRL because the NTP study provided more study details and information on particle size distribution. Because an MRL based on this LOAEL (LOAEL_HEC of 1 µg Cd/m³) would be lower than the chronic-duration inhalation MRL based on human data, an intermediate-duration inhalation MRL was not derived.

Chronic-Duration Inhalation MRL

• An MRL of 0.01 µg Cd/m³ has been derived for chronic-duration inhalation exposure (≥1 year) to cadmium.

Numerous studies examining the toxicity of cadmium in workers have identified the respiratory tract and the kidney as sensitive targets of toxicity. A variety of respiratory tract effects have been observed in cadmium workers including respiratory symptoms (e.g., dyspnea, coughing, wheezing), emphysema, and impaired lung function. However, many of these studies did not control for smoking, and thus, the role of cadmium in the induction of these effects is difficult to determine. Impaired lung function was reported in several studies that controlled for smoking (Chan et al. 1988; Cortona et al. 1992; Davison et al. 1988; Smith et al. 1976); other studies have not found significant alterations (Edling et al. 1986). The observed alterations included an increase in residual volume in workers exposed to air concentrations of cadmium fumes ranging from 0.008 (in 1990) to 1.53 mg/m³ (in 1975) (mean urinary cadmium level in the workers was 4.3 µg/L) (Cortona et al. 1992); alterations in several lung function parameters (e.g., forced expiratory volume, transfer factor, transfer coefficient) in workers exposed to 0.034–0.156 mg/m³ (Davison et al. 1988); and decreased force vital capacity in workers exposed to >0.2 mg/m³ (Smith et al. 1976). Additionally, Chan et al. (1988) found significant improvements in several parameters of lung function of workers following reduction or cessation of cadmium exposure.

The renal toxicity of cadmium in workers chronically exposed to high levels of cadmium is well established. Observed effects include tubular proteinuria (increased excretion of low molecular weight proteins), decreased resorption of other solutes (increased excretion of enzymes such as NAG, amino acids, glucose, calcium, inorganic phosphate), evidence of increased glomerular permeability (increased excretion of albumin), increased kidney stone formation, and decreased glomerular filtration rate (GFR). The earliest sign of cadmium-induced kidney damage is an increase in urinary levels of low molecular weight proteins (particularly, β2-microglobulin, retinol binding protein, and pHC) in cadmium workers, as compared to levels found in a reference group of workers or the general population (Bernard et al. 1990; Chen et al. 2006a, 2006b; Chia et al. 1992; Elinder et al. 1985a; Falck et al. 1983; Jakubowski et al. 1987, 1992; Järup and Elinder 1994; Järup et al. 1988; Shaikh et al. 1987; Toffoletto et al. 1992; Verschoor et al. 1987). Although increases in the excretion of low molecular weight proteins are not diagnostic of renal damage (Bernard et al. 1997; Järup et al. 1998b), tubular proteinuria is considered an adverse effect because it is an early change in a sequence of events which ultimately may result in compromised renal function (Bernard et al. 1997). Most investigators consider a 10% cadmium-associated increase in the prevalence of abnormal levels of renal biomarkers (urinary β2-microglobulin, retinol binding protein, pHC) to be indicative of cadmium-induced renal disease in the population. However, there is less consensus on the low molecular protein level regarded as elevated or abnormal (cut-off point).

Several biomarkers of tubular damage have been used in occupational exposure studies; these include β2-microglobulin, retinol binding protein, NAG, and pHC. Of these biomarkers, which differ in their sensitivities to detect tubular damage, β2-microglobulin is the most widely used in occupational exposure studies. In healthy humans, urinary β2-microglobulin levels are <300 µg/24 hours (approximately 300 µg/g creatinine). Four studies have estimated the prevalence of abnormal urinary β2-microglobulin levels among cadmium workers using cut-off levels of 187–380 µg/g creatinine (Chen et al. 2006a; Elinder et al. 1985a; Jakubowski et al. 1987; Järup and Elinder 1994). The prevalence of abnormal urinary β2-microglobin levels was 10% among workers with urinary cadmium levels of 1.5 (≥60 years of age) or 5 (<60 years of age) µg/g creatinine (β2-microglobulin cut-off level of 220 µg/g creatinine) (Järup and Elinder 1994), 25% among workers with urinary cadmium levels of 2–5 µg/g creatinine (cut-off level of 300 µg/g creatinine) (Elinder et al. 1985a), 40% among workers with urinary cadmium levels of 5–10 µg/g creatinine (cut-off level of 187 µg/g creatinine) (Chen et al. 2006a), and 10% among workers with urinary cadmium levels of 10–15 µg/g creatinine (cut-off level of 380 µg/g creatinine (Jakubowski et al. 1987). A 10% prevalence of abnormal β2-microglobulin levels (cut-off level of 300 µg/g creatinine) was also observed in workers with a cumulative blood cadmium level of 300 µg-years/L (30 years of 10 µg/L) (Jakubowski et al. 1992) or blood cadmium level of 5.6 µg/L (cumulative exposure of 691 µg-years/m³) (Järup et al. 1988).

Most of the studies reporting respiratory effects expressed cadmium exposure as air concentrations; however, these air concentrations may not be indicative of cadmium exposure over time. For example, in theCortona et al. (1992) study, cadmium levels of 0.030 mg/m³ were measured in 1990 in one foundry; in 1976, the cadmium levels in this foundry were 1.53 mg/m³.Cortona et al. (1992) also reported cadmium body burden data; the mean urinary cadmium level in the workers was 4.3 µg/L (roughly equivalent to 4 µg/g creatinine). Renal effects have been observed at similar cadmium burdens. Most studies have reported renal effects in workers with urinary cadmium levels of ≥5 µg/g creatinine; Järup and Elinder (1994) found an increased prevalence of low molecular weight proteinuria in workers ≥60 years of age with mean urinary cadmium of 1.5 µg/g creatinine. The air concentration that would result in this urinary cadmium level would be considered a LOAEL. However, cadmium in the workplace air was not the only source of cadmium. The workers were also exposed to other sources of cadmium (e.g., cadmium in the diet); both sources contributed to the renal cadmium burden. Thus, in order to calculate a chronic-duration inhalation MRL from the LOAEL identified in the Järup and Elinder (1994) study, the workers’ other sources of cadmium need to be taken into consideration; this information was not reported in the study.

An alternative approach would be to use environmental exposure studies to establish a point of departure for the urinary cadmium-renal response relationship and pharmacokinetic models (ICRP 1994); Kjellström and Nordberg 1978) to predict cadmium air concentrations. As described in greater detail in the chronic oral MRL section, a meta-analysis of available environmental exposure studies was conducted to estimate an internal dose (urinary cadmium expressed as µg/g creatinine) corresponding to a 10% excess risk of low molecular weight proteinuria (urinary cadmium dose, UCD₁₀). For the inhalation MRL, the meta-analysis also included dose-response data from three occupational exposure studies (Chen et al. 2006a, 2006b; Järup and Elinder 1994; Roels et al. 1993). Analysis of the environmental exposure studies resulted in an estimation of a urinary cadmium level that would result in a 10% increase in the prevalence of β2-microglobulin proteinuria (1.34 µg/g creatinine); the 95% lower confidence limit on this value was 0.5 µg/g creatinine. The UCD₁₀ values from the occupational exposure studies were 7.50 µg/g creatinine for the European cohorts (Järup and Elinder 1994; Roels et al. 1993) and 4.58 µg/g creatinine for the Chinese cohort (Chen et al. 2006a, 2006b). Because the dose-response analysis using the European environmental exposure studies provided the lowest UCD₁₀, it was selected for derivation of the chronic-duration inhalation MRL; the 95% lower confidence limit on this value (UCDL₁₀) of 0.5 µg/g creatinine was used as the point of departure for the MRL.

Deposition and clearance of inhaled cadmium oxide and cadmium sulfide particles were modeled using the ICRP Human Respiratory Tract Model (ICRP 1994). The ICRP model simulates deposition, retention, and absorption of inhaled cadmium particles of specific aerodynamic diameters, when specific parameters for cadmium clearance are used in the model (ICRP 1980). Cadmium-specific parameters represent categories of solubility and dissolution kinetics in the respiratory tract (e.g., slow, S; moderate, M; or fast, F). Cadmium compounds are classified as follows: oxides and hydroxides, S; sulfides, halides and nitrates, M; all other, including chloride salts, F.

Inhalation exposures (µg/m³) to cadmium oxide or cadmium sulfide aerosols having particle diameters of 1, 5, or 10 µg (AMAD) were simulated using the ICRP model. Predicted mass transfers of cadmium from the respiratory tract to the gastrointestinal tract (i.e., mucociliary transport) and to blood (i.e., absorption) were used as inputs to the gastrointestinal and blood compartments of the Nordberg-Kjellström pharmacokinetic model (Kjellström and Nordberg 1978) to simulate the kidney and urinary cadmium levels that correspond to a given inhalation exposure.

As illustrated in Figure 2-1, an airborne cadmium concentration of 1.8–2.4 µg/m³ as cadmium oxide or 1.2–1.4 µg/m³ as cadmium sulfide would result in a urinary cadmium level of 0.5 µg/g creatinine, assuming that there was no dietary source of cadmium. This assumption is not accurate because the diet is a significant contributor to the cadmium body burden. Thus, inhalation exposures were combined with ingestion intakes to estimate an internal dose in terms of urinary cadmium. The age-weighted average intakes of cadmium in non smoking males and females in the United States are 0.35 and 0.30 µg Cd/kg/day, respectively (0.32 µg/kg/day for males and females combined) (estimated from data in Choudhury et al. 2001). Based on the relationship predicted between chronic inhalation exposures to cadmium sulfide (activity median aerodynamic diameter [AMAD]=1 µm) and oral intakes that yield the same urinary cadmium level (Figure 2-1), exposure to an airborne cadmium concentration of 0.1 µg/m³ and a dietary intake of 0.3 µg/kg/day would result in a urinary cadmium level of 0.5 µg/g creatinine. Dividing this cadmium air concentration (0.1 µg Cd/m³) by an uncertainty factor of 3 for human variability and a modifying factor of 3 results in chronic-duration inhalation MRL of 0.01 µg Cd/m³. The uncertainty factor of 3 for human variability was used to account for the possible increased sensitivity of diabetics (Åkesson et al. 2005; Buchet et al. 1990) and the modifying factor of 3 was used to account for the lack of adequate human data, which could be used to compare the relative sensitivities of the respiratory tract and kidneys. Although based on exposure to cadmium sulfide, the MRL would be protective of exposure to cadmium oxide; the pharmacokinetic models predict that exposure to 0.1 µg/m³ as cadmium oxide (AMAD=1 µm) in combination with a dietary intake of 0.3 µg/kg/day would result in a urinary cadmium level of 0.4 µg/g creatinine.

Figure 2-1

Combined Chronic Oral Cadmium Intakes (µg/kg/day) and Inhalation Cadmium Exposures (µg/m³) that Achieve a Urinary Excretion of 0.5 µg/g Creatinine at Age 55 Years Predicted by the Cadmium Pharmacokinetic Model International Commission (more...)

Acute-Duration Oral MRL

There are no reliable studies on the acute toxicity of cadmium in humans; animal studies have identified several targets of toxicity. High exposures (>10 mg Cd/kg/day) to cadmium chloride administered via gavage or drinking water resulted in increases in hematological (increased hemoglobin, hematocrit, and erythrocytes, anemia), liver (focal necrosis and degeneration), kidney (focal necrosis of tubular epithelium), intestine (necrosis, hemorrhage, ulcers), stomach (gastritis, necrosis), neurological (decreased motor activity), and testicular (atrophy and necrosis, loss of spermatogenic elements) effects and decreases in body weight in rats and mice (Andersen et al. 1988; Basinger et al. 1988; Bomhard et al. 1987; Borzelleca et al. 1989; Dixon et al. 1976; Kotsonis and Klaassen 1977; Machemer and Lorke 1981; Sakata et al. 1988; Shimizu and Morita 1990). The NOAELs for these effects ranged from 1.12 to 65.6 mg Cd/kg/day.

Developmental effects have been observed at lower cadmium doses. Delayed ossification of the sternum and ribs was observed in the offspring of rats administered 2 mg Cd/kg/day via gavage on gestation days 7–16; at 40 mg Cd/kg/day, fused lower limbs, decreased number of live fetuses, and increased resorptions were observed (Baranski 1985). A significant increase in malformations was observed in the offspring of rats administered 18.39 mg Cd/kg/day on gestation days 6–15 (Machemer and Lorke 1981); no developmental effects were observed in the offspring of rats administered 12.5 mg Cd/kg/day via drinking water on gestation days 6–15 (Machemer and Lorke 1981).

Although the Baranski (1985) study identified the lowest LOAEL (2 mg Cd/kg/day) following acute-duration exposure, this study was not considered suitable for derivation of an MRL. The investigators noted that “a retarded process of ossification of the sternum and ribs was observed after exposure to cadmium at any of the doses used.” However, the data were not shown and the statistical significance of the finding was not reported. Additionally, an intermediate-duration study conducted earlier by this investigator (Baranski et al. 1983) did not find delays in ossification in the offspring of rats administered up to 4 mg Cd/kg/day for 5 weeks prior to mating, during the 3-week mating period, and throughout gestation.

Because of the amount of uncertainty associated with the most sensitive end point, an acute-duration oral MRL was not derived.

Intermediate-Duration Oral MRL

• An MRL of 0.5 µg Cd/kg/day has been derived for intermediate-duration oral exposure (15–364 days) to cadmium.

There are limited data on the toxicity of cadmium in humans following intermediate-duration exposure. Numerous animal studies have examined the systemic, immunological, neurological, reproductive, and developmental toxicity of cadmium. The most sensitive systemic effect following intermediate-duration oral exposure to cadmium appears to be damage to growing bone. Exposure to 0.2 mg Cd/kg/day as cadmium chloride in drinking water for 3–12 months resulted in decreases in bone mineral density, impaired mechanical strength of the lumbar spine, tibia, and femur bones, increased bone turnover, and increased incidence of deformed or fractured lumbar spine bone in young female rats (3 weeks of age at study initiation) (Brzóska and Moniuszko-Jakoniuk 2005d; Brzóska et al. 2004b, 2005a, 2005b, 2005c, 2010); similar findings were observed in young male rats exposed to 0.5 mg Cd/kg/day for up to 12 months (Brzóska and Moniuszko-Jakoniuk 2005a, 2005b). Decreases in bone strength were also observed in young rats exposed to 0.8 mg Cd/kg/day as cadmium chloride in drinking water for 4 weeks (Ogoshi et al. 1989); however, no skeletal effects were observed in adult or elderly female rats exposed to doses >20 mg Cd/kg/day for 4 weeks (Ogoshi et al. 1989). Decreases in bone calcium were observed in mice undergoing repeated pregnancy/lactation periods (Bhattacharyya et al. 1988b) or ovariectomized mice (Bhaattacharyya et al. 1988c); these changes were not observed in groups not under physiological stress.

Renal effects have been observed at higher doses than the skeletal effects. Vesiculation of the proximal tubules was observed in rats exposed to 1.18 mg Cd/kg/day as cadmium chloride in drinking water for 40 weeks (Gatta et al. 1989). At approximately 3–8 mg Cd/kg/day, proteinuria, tubular necrosis, and decreased renal clearance were observed in rats (Cha 1987; Itokawa et al. 1974; Kawamura et al. 1978; Kotsonis and Klaassen 1978; Prigge 1978a). Liver necrosis and anemia (Cha 1987; Groten et al. 1990; Kawamura et al. 1978) were observed at similar cadmium doses.

Immunological effects have been observed in studies of monkeys, rats, and mice. The observed effects include increases in cell-mediated immune response in monkeys exposed to 5 mg Cd/kg/day as cadmium chloride in the diet for 10 weeks (Chopra et al. 1984), decreased humoral immune response in mice exposed to 2.8 mg Cd/kg/day as cadmium chloride in drinking water for 3 weeks (Blakley 1985), and greater susceptibility to lymphocytic leukemia virus in mice exposed to 1.9 mg Cd/kg/day as cadmium chloride in drinking water for 280 days (Blakley 1986).

Neurological effects observed in rats include decreases in motor activity at 3.1 or 9 mg Cd/kg/day (Kotsonis and Klaassen 1978; Nation et al. 1990) and increased passive avoidance at 5 mg Cd/kg/day (Nation et al. 1984). Reproductive effects (necrosis and atrophy of seminiferous tubules, decreased sperm count and motility) were observed in rats exposed to 8–12 mg Cd/kg/day (Cha 1987; Saxena et al. 1989).

A number of developmental effects have been observed in the offspring of rats exposed to cadmium during gestation and lactation. Decreases in glomerular filtration rates and increases in urinary fractional excretion of phosphate, magnesium, potassium, sodium, and calcium were observed in 60-day-old offspring of rats administered via gavage 0.5 mg Cd/kg/day on gestation days 1–21 (Jacquillet et al. 2007). Neurodevelopmental alterations have also been observed at the low maternal doses. Delays in the development of sensory motor coordination reflexes and increased motor activity were observed at 0.706 mg Cd/kg/day (gestation days 1–21) (Ali et al. 1986), decreased motor activity at 0.04 mg Cd/kg/day (5–8 weeks of pre-gestation exposure, gestation days 1–21) (Baranski et al. 1983), decreased ambulation and rearing activity and altered ECG at 14 mg Cd/kg/day (gestation days 5–15, lactation days 2–28, postnatal days 1–56) (Desi et al. 1998) or 7 mg Cd/kg/day (F₂ and F₃ generations) (Nagymajtenyi et al. 1997) have been observed. Decreases in pup body weight were observed at ≥5 mg Cd/kg/day (Baranski 1987; Gupta et al. 1993; Kostial et al. 1993; Pond and Walker 1975) and decreases in fetal body weight or birth weight were observed at ≥2.4 mg Cd/kg/day (Petering et al. 1979; Sorell and Graziano 1990; Webster 1978; Sutou et al. 1980). Another commonly reported developmental effect was alterations in hematocrit levels or anemia in the offspring of animals exposed to ≥1.5 mg Cd/kg/day (Baranski 1987; Kelman et al. 1978; Webster 1978). Increases in the occurrence of malformations or anomalies is limited to a study by Sutou et al. (1980), which reported a significant delay in ossification in rats exposed to 10 mg Cd/kg/day.

The animal studies identify several sensitive targets of toxicity following intermediate-duration exposure to cadmium; these include skeletal mineralization in young female rats exposed for at least 3 months to 0.2 mg Cd/kg/day (Brzóska and Moniuszko-Jakoniuk 2005d; Brzóska et al. 2004b, 2005a, 2005b, 2005c), decreased glomerular filtration in young rats exposed during gestation to maternal doses of 0.5 mg Cd/kg/day (Jacquillet et al. 2007), and neurodevelopmental effects following gestational exposure to 0.04 mg Cd/kg/day (Baranski et al. 1983). Although theBaranski et al. (1983) study reported the lowest LOAEL, it was not selected as the principal study for derivation of an intermediate-duration MRL. For locomotor activity, a significant decrease in activity was observed in female offspring exposed to 0.04, 0.4, and 4 mg Cd/kg/day, as compared to controls; however, no significant differences were found between the cadmium groups despite the 100-fold difference in doses. Locomotor activity was also decreased in males exposed to 0.4 or 4 mg Cd/kg/day. For the rotorod test, a significant decrease in the length of time the rat stayed on the rotorod was observed in males exposed to 0.04 and 0.4 mg Cd/kg/day, but not to 4 mg Cd/kg/day and in females exposed to 0.4 and 4 mg Cd/kg/day; no differences between the cadmium groups were observed in the males and females. The results were not well described and the investigators did not explain the lack of dose-response of the effects or the discrepancy between genders.

The skeletal effects observed in young rats exposed to cadmium during the period of rapid skeletal growth and mineralization was selected as the critical effect. The Brzóska and associate study (Brzóska and Moniuszko-Jakoniuk 2005d; Brzóska et al. 2005a, 2005c) was selected as the principal study. In this study, groups of 40 3-week-old female Wistar rats were exposed to 0, 1, 5, or 50 mg Cd/L as cadmium chloride in drinking water for 12 months. The investigators noted that cadmium intakes were 0.059–0.219, 0.236–1.005, and 2.247–9.649 mg Cd/kg/day in the 1, 5, and 50 mg/L groups, respectively. Using cadmium intake data presented in a figure, cadmium intakes of 0.2, 0.5, and 4 mg Cd/kg/day were estimated. Bone mineral density, bone mineral concentration, and mineralization area of the lumbar spine, femur, and total skeleton (bone mineral density only) were assessed after 3, 6, 9, or 12 months of exposure. The mechanical properties of the femur and tibia were evaluated after 12 months of exposure. Markers for bone resorption (urinary and serum levels of C-terminal cross-linking telopeptide of type I collagen [CTX]) and bone formation (serum osteocalcin, total alkaline phosphatase, and cortical bone and trabecular bone alkaline phosphatase), and serum and urinary levels of calcium were also measured at 3, 6, 9, and 12 months.

No significant alterations in body weight gain or food and water consumption were observed. Significant decreases in total skeletal bone mineral density was observed at ≥0.2 mg Cd/kg/day; the decrease was significant after 3 months in the 4 mg Cd/kg/day group, after 6 months in the 0.5 mg Cd/kg/day group, and after 9 months in the 0.2 mg Cd/kg/day group. Significant decreases in whole tibia and diaphysis bone mineral density were observed at ≥0.2 mg Cd/kg/day after 12 months of exposure. At 0.2 mg Cd/kg/day, bone mineral density was decreased at the proximal and distal ends of the femur after 6 months of exposure; diaphysis bone mineral density was not affected. At 0.5 mg Cd/kg/day, bone mineral density was decreased at the femur proximal and distal ends after 3 months of exposure and diaphysis bone mineral density after 6 months of exposure. At 4 mg Cd/kg/day decreases in femoral proximal, distal, and diaphysis bone mineral density were decreased after 3 months of exposure. Similarly, bone mineral density was significantly decreased in the lumbar spine in the 0.2 and 0.5 mg Cd/kg/day groups beginning at 6 months and at 3 months in the 4 mg Cd/kg/day group. Significant decreases in the mineralization area were observed in the femur and lumbar spine of rats exposed to 4 mg Cd/kg/day; lumbar spine bone mineral area was also affected at 0.5 mg Cd/kg/day. Significant decreases in tibia weight and length were observed at 4 mg Cd/kg/day. In tests of the mechanical properties of the tibia diaphysis, significant alterations in ultimate load, yield load, and displacement at load were observed at ≥0.2 mg Cd/kg/day; work to fracture was also significantly altered at 4 mg Cd/kg/day. In the mechanical properties compression tests of the tibia, significant alterations were observed in ultimate load, ultimate load, and stiffness at 0.2 mg Cd/kg/day; displacement at yield and work to fracture at ≥0.5 mg Cd/kg/day; and displacement at ultimate at 4 mg Cd/kg/day. Multiple regression analysis showed that the cadmium-induced weakness in bone mechanical properties of the tibia was primarily due to its effects on bone composition, particularly the non-organic components, organic components, and the ratio of ash weight to organic weight. The mechanical properties of the femur were strongly influenced by the bone mineral density (at the whole bone and diaphysis). A significant decrease in femur length was observed at 6 months of exposure to ≥0.2 mg Cd/kg/day; however, decreases in length were not observed at other time points in the 0.2 or 0.5 mg Cd/kg/day groups. Femur weight was significantly decreased at 4 mg Cd/kg/day. In tests of mechanical properties of the femur (neck and distal portions), decreases in yield load, ultimate load, displacement at ultimate, work to fracture (neck only), and stiffness (distal only) were observed at ≥0.2 mg Cd/kg/day. For the femoral diaphysis, significant alterations were observed for yield load, displacement at yield, and stiffness at ≥0.2 mg Cd/kg/day. Significant decreases in osteocalcin concentrations were observed in all cadmium groups during the first 6 months of exposure, but not during the last 6 months. Decreases in total alkaline phosphatase levels at 4 mg Cd/kg/day, trabecular bone alkaline phosphatase at 0.2 mg Cd/kg/day, and cortical bone alkaline phosphatase at 4 mg Cd/kg/day were observed. CTX was decreased at ≥0.2 mg Cd/kg/day. Total urinary calcium and fractional excretion of calcium were increased at ≥0.2 mg Cd/kg/day.

At the lowest dose tested, 0.2 mg Cd/kg/day, a number of skeletal alterations were observed including decreases in bone mineral density in the lumbar spine, femur, and tibia, alterations in the mechanical properties of the femur and tibia, decreases in osteocalcin levels, decreases in trabecular bone alkaline phosphatase, and decreases in CTX. Of these skeletal end points, the decrease in bone mineral density was selected as the critical effect because Brzóska et al. (2005a, 2005c) demonstrated that the bone mineral density was a stronger predictor of femur and tibia strength and the risk of fractures. As discussed in greater detail in Appendix A, available continuous models in the EPA Benchmark Dose Software (version 1.4.1c) were fit to data for changes in bone mineral density of the femur and lumbar spine in female rats resulting from exposure to cadmium in the drinking water for 6, 9, or 12 months (Brzóska and Moniuszko-Jakoniuk 2005d). The benchmark dose (BMD) and the 95% lower confidence limit (BMDL) is an estimate of the doses associated with a change of 1 standard deviation from the control. The BMDL_sd1 derived from the best fitting models for each dataset ranged from 0.05 to 0.17 mg Cd/kg/day. The BMDL_sd1 of 0.05 mg Cd/kg/day estimated from the 9-month lumbar spine data set was selected as the point of departure for the MRL. In young female rats, the process of intense bone formation occurs during the first 7 months of life (the first 6 months of exposure in this study); thereafter, the increase in bone mineral density slows. In the lumbar spine of the control group, the changes in bone mineral density at 3–6 months, 6–9 months, and 9–12 months were 15, 4, and 1%, respectively. Thus, the 9-month data may best reflect the effect of cadmium on bone mineral density during the period of rapid skeletal growth. The lumbar spine data was selected over the femur data set because trabecular bone, which is abundant in the spine, appears to be more susceptible to cadmium toxicity than cortical bone. The BMDL_sd1 was divided by an uncertainty factor of 100 (10 for extrapolation from animals to humans and 10 for human variability) resulting in an intermediate-duration oral MRL of 0.5 µg Cd/kg/day.

Chronic-Duration Oral MRL

• An MRL of 0.1 µg/kg/day has been derived for chronic-duration oral exposure (≥1 year) to cadmium.

The database examining the chronic toxicity of cadmium following oral exposure is extensive. Although there are some chronic studies in animals, the majority of the studies in the chronic database examine the relationship between urinary cadmium levels (or cumulative cadmium intake) and adverse health effects in the general population or in populations living in cadmium polluted areas. A variety of health effects have been observed including skeletal defects (osteoporosis, increased bone fractures, decreased bone mineral density), kidney dysfunction, and alterations in reproductive hormone levels. These environmental exposure studies strongly support the identification of bone and kidney as the most sensitive targets of chronic cadmium toxicity.

Bone effects, particularly osteomalacia and/or osteoporosis and increased bone fractures, were first reported in Japanese women living in areas with heavy cadmium contamination. Chronic cadmium exposure has been shown to play a role in this disorder, referred to as Itai-Itai disease; however, other factors such as multiple pregnancies, poor nutrition (low calories, calcium, protein, vitamin D, and iron intakes), and low zinc levels in food also play important roles in the etiology. Although a conclusive role of cadmium in Itai-Itai has not been established, several other studies have found bone defects. Observed bone effects include increased risk of bone fractures in postmenopausal women with urinary cadmium levels of >1 µg/day (approximately >0.7 µg Cd/g creatinine; Staessen et al. 1999), individuals (>50 years of age) with urinary cadmium levels of >2 µg/g creatinine (Alfvén et al. 2004), and men and women (>40 years of age) with urinary cadmium levels of 9.20 and 12.86 µg/g creatinine, respectively (Wang et al. 2003); increased risk of osteoporosis in men (>60 years of age) with urinary cadmium levels of ≥1.5 µg/g creatinine (Alfvén et al. 2000), in males and females with urinary cadmium levels of ≥10 µg/g creatinine (Jin et al. 2004b), in males and females (>40 years of age) with urinary cadmium levels of 9.20 and 12.86 µg/g creatinine, respectively (Wang et al. 2003), and women with renal tubular damage (urinary NAG ≥12 IU/g creatinine) (Chen et al. 2011); and decreased bone mineral density in women with urinary cadmium levels of >0.6 µg/g creatinine (Schutte et al. 2008), postmenopausal women with urinary cadmium levels of >20 µg/g creatinine (Nordberg et al. 2002), postmenopausal women with median urinary cadmium levels of 1.1 µg/g creatinine (Engström et al. 2009), and men with urinary cadmium levels of ≥2 µg/g creatinine (Trzcinka-Ochocka et al. 2010).

Evidence of renal dysfunction in environmentally exposed populations include increases in deaths from renal dysfunction in residents living in cadmium polluted areas of Japan (Arisawa et al. 2001, 2007b; Iwata et al. 1991a, 1991b; Matsuda et al. 2002; Nakagawa et al. 1993; Nishijo et al. 1995, 2004a, 2006), increases in renal replacement therapy which is indicative of severe renal dysfunction (Hellström et al. 2001), and increases in the excretion of biomarkers of renal dysfunction in association with increased cadmium intake, increased renal cadmium concentrations, increased blood cadmium levels, and/or increased urinary cadmium concentrations (Bandara et al. 2010; Buchet et al. 1990; Cai et al. 1990, 1992, 1998, 2001; Ferraro et al. 2010; Hayano et al. 1996; Honda et al. 2010; Horiguchi et al. 2004, 2010; Hwangbo et al. 2011; Ishizaki et al. 1989; Izuno et al. 2000; Järup et al. 2000; Jin et al. 2002, 2004a, 2004c; Kawada et al. 1992; Kido and Nogawa 1993; Kobayashi et al. 2002a, 2009b; Monzawa et al. 1998; Nakadaira and Nishi 2003; Nakashima et al. 1997; Nogawa et al. 1989; Noonan et al. 2002; Nordberg et al. 1997; Olsson et al. 2002; Oo et al. 2000; Osawa et al. 2001; Roels et al. 1981b; Suwazono et al. 2006; Teeyakasem et al. 2007; Trzcinka-Ochocka et al. 2004; Uno et al. 2005; Yamanaka et al. 1998; Wu et al. 2001). The urinary excretion of several biomarkers have been shown to increase due to cadmium-related alterations in kidney function; these biomarkers include low molecular weight proteins (e.g., β2-microglobulin, pHC, retinol binding protein), intracellular tubular enzymes (e.g., NAG), amino acids, high molecular weight proteins (e.g., albumin), metallothionein, and electrolytes (e.g., potassium, sodium, calcium). Although the more severe renal effects have been observed in populations living in highly contaminated areas (e.g., decreased glomerular filtration rate), alterations in the above biomarkers have been observed in areas not considered to be cadmium polluted. Alterations in these biomarker levels appear to be the most sensitive indicator of cadmium toxicity. Many of the studies examining biomarkers have reported significant correlations between urinary cadmium levels and biomarker levels. However, these correlations do not provide insight into exposure levels associated with renal dysfunction. In this MRL analysis, attention was given to dose-response studies examining the derived quantitative relationships between cadmium exposure and the prevalence of abnormal biomarker levels. As discussed in the inhalation MRL section, a 10% increase in the prevalence of abnormal biomarker levels (particularly β2-microglobulin, pHC, or retinol binding protein) in association with increasing cadmium exposure is generally considered to be indicative of cadmium-associated renal dysfunction in populations. However, when examining the prevalence of abnormal levels, careful consideration should be given to the response criterion (cut-off level) used in the study. A wide range of cut-off levels have been used in the environmental exposure studies. For β2-microglobulin, the most commonly used biomarker, the cut-off values ranged from 283 to 1,129 µg/g creatinine. A summary of environmental studies finding significant dose-response associations between urinary cadmium (or cumulative cadmium intake) and the prevalence of abnormal levels of urinary biomarkers of renal dysfunction is presented in Table 2-1. The adverse effect levels range from urinary cadmium levels of 1 µg/g creatinine (Järup et al. 2000) to 9.51 µg/g creatinine (Jin et al. 2004a).

Table 2-1

Summary of Human Studies Finding Dose-Response Relationships Between Biomarkers of Renal Dysfunction and Cadmium Exposure.

The adverse effect levels for renal effects were similar to those observed for skeletal effects. Because the renal effects database is stronger, it was used for derivation of a chronic-duration oral MRL for cadmium. Several approaches were considered for derivation of the MRL: (1) NOAEL/LOAEL approach using a single environmental exposure study finding an increased prevalence of abnormal renal effect biomarker levels, (2) selection of a point of departure from a published benchmark dose. analysis, or (3) selection of a point of departure based on an analysis of the dose-response functions from a number of environmental exposure studies.

In the first approach, all studies in which individual internal doses for subjects were estimated based on urinary cadmium were considered. TheJärup et al. (2000) study is selected as the principal study because it identified the lowest adverse effect level (Table 2-1). In this study, 1,021 individuals living near a nickel-cadmium battery factory (n=799) or employed at the factory (n=222) were examined. The mean urinary cadmium concentrations were 0.81 µg/g creatinine in men and 0.65 µg/g creatinine in women. A significant association was found between urinary cadmium concentrations and urinary pHC levels, after adjustment for age; the association remained statistically significant after removal of the cadmium workers from the analysis. The investigators estimated that a urinary cadmium level of 1 µg/g creatinine would be associated with a 10% increase in the prevalence of abnormal pHC levels above background prevalence (approximately a 10% added risk). However, the European Chemicals Bureau (2007) recalculated the probability of HC proteinuria because the reference population and the study population were not matched for age (40 versus 53 years, respectively). They estimated that the probability of HC proteinuria (13%) would be twice as high as the reference population at a urinary cadmium concentration of 0.5 µg/g creatinine.

The second approach involves the evaluation of eight published benchmark dose analyses. The benchmark doses and the lower 95% confidence interval of the benchmark dose (BMDL) for low molecular weight proteinuria are presented in Table 2-2 (benchmark doses and BMDLs for all effect parameters are presented in Table 3-8 in the toxicological profile). The BMDL values corresponding to a 10% increase in the prevalence of low molecular weight proteinuria above background (excess risk) ranged from 0.7 µg/g creatinine (Uno et al. 2005) to 9.9 µg/g creatinine (Kobayashi et al. 2006). Both studies examined populations living in non-cadmium polluted areas of Japan and used β2-microglobulin as the effect biomarker. The large difference in cut-off values (233 versus 784 µg/g creatinine) likely contributed to the order of magnitude difference in BMDLs. The BMDL₁₀ of 0.7 µg/g creatinine is supported by the Suwazono et al. (2006) benchmark dose analysis, which found a similar BMDL₁₀ (0.81 µg/g creatinine) using pHC as the effect biomarker. The Uno et al. (2005) study examined 410 men and 418 women (aged 40–59 years) living in three areas of Japan without any known environmental cadmium pollution. Mean urinary cadmium concentrations were 1.3 and 1.6 µg/g creatinine in men and women, respectively. Cut-off levels for β2-microglobulin were 233 and 274 µg/g creatinine in males and females; these values represent the 84% upper limit values calculated from the target population assuming a log normal distribution.

Table 2-2

Selected Benchmark Dose Estimations of Urinary Cadmium Levels Associated with Increases in the Prevalence of Low Molecular Weight Proteinuria.

The third approach involved a meta-analysis of selected environmental exposure dose-response studies. Studies were selected for inclusion in this analysis based on the following qualitative criteria: (1) the study measured urinary cadmium as indicator of internal dose; (2) the study measured reliable indicators of low molecular weight (LMW) proteinuria; (3) a dose-response relationship was reported in sufficient detail so that the dose-response function could be reproduced independently; (4) the study was of reasonable size to have provided statistical strength to the estimates of dose-response model parameters (i.e., most studies selected included several hundred to several thousand subjects); and (5) major co-variables that might affect the dose-response relationship (e.g., age, gender) were measured or constrained by design and included in the dose-response analysis. No attempt was made to weight selected studies for quality, statistical power, or statistical uncertainty in dose-response parameters. Studies using a cut-off value for β2-microglobulin of ≥1,000 µg/g creatinine were eliminated from the analysis based on the conclusions of Bernard et al. (1997) that urinary β2-microglobulin levels of 1,000–10,000 µg/g creatinine were indicative of irreversible tubular proteinuria, which may lead to an age-related decline in GFR. Additionally, an attempt was made to avoid using multiple analyses of the same study population.

The individual dose-response functions from each study were implemented to arrive at estimates of the internal dose (urinary cadmium expressed as µg/g creatinine) corresponding to probabilities of 10% excess risk of low molecular weight proteinuria (urinary cadmium dose, UCD₁₀). Estimates were derived from the seven environmental exposure studies listed in Table 2-3. When available, male and female data were treated separately; thus, 11 dose-response relationships were analyzed. For studies that did not report the UCD₁₀, the value was estimated by iteration of the reported dose response relationship for varying values of urinary cadmium, until an excess risk of 10% was achieved:

Table 2-3

Selected Studies of Dose-Response Relationship for Cadmium-Induced Low Molecular Weight Proteinuria.

Aggregate UCD₁₀ estimates and the estimates stratified by location (i.e., Europe, Japan, China) are presented in Figure 2-2. The lowest UCD₁₀ (1.34 µg/g creatinine) was estimated from the European database and the 95% lower confidence limit on this UCD₁₀ (UCDL₁₀) of 0.5 µg/g creatinine was considered as a potential point of departure for the MRL.

Figure 2-2

Estimates of the UCD₁₀ from Environmental Exposure Dose-Response Studies*. *Estimates of urinary cadmium concentrations (μg/g creatinine) associated with a 10% excess risk of urinary β2-microglobulin (UCD₁₀) using data from European, Japanese, (more...)

Points of departure selected using the three different approaches are similar: 0.5 µg/g creatinine from the Järup et al. (2000) study (using the European Chemicals Bureau 2007 recalculation), 0.7 µg/g creatinine from theUno et al. (2005) benchmark dose analysis, and 0.5 µg/g creatinine from the dose-response analysis. The third approach (meta-analysis of environmental exposure studies) was selected for the derivation of the MRL because it uses the whole dose-response curves from several studies rather than data from a single study.

The UCDL₁₀ of 0.5 µg/g creatinine was transformed into estimates of chronic cadmium intake (expressed as µg Cd/kg/day) that would result in the UCDL₁₀ at age 55 (approximate age of peak cadmium concentration in the renal cortex associated with a constant chronic intake; Figure 2-3). The dose transformations were achieved by simulation using a modification of the Nordberg-Kjellström model (Kjellström and Nordberg 1978). The following modifications (Choudhury et al. 2001; Diamond et al. 2003) were made to the model: (1) the equations describing intercompartmental transfers of cadmium were implemented as differential equations in Advanced Computer Simulation Language (acslXtreme, version 2.4.0.9); (2) growth algorithms for males and females and corresponding organ weights (O’Flaherty 1993) were used to calculate age-specific cadmium concentrations from tissue cadmium masses; (3) the cadmium concentration in renal cortex (RC, µg/g) was calculated as follows:

Figure 2-3

Urinary Cadmium (µg/g creatinine) and Renal Cortex Cadmium Concentration (µg/g wet tissue) Predicted by the Cadmium Pharmacokinetic Model*. *Shown is a simulation of peak renal cadmium concentration (at age 55) in females based on a chronic (more...)

(4) the rate of creatinine excretion (e.g., Cr_ur, g creatinine/day) was calculated from the relationship between lean body mass (LBM) and Cr_ur; and (5) absorption of ingested cadmium was assumed to be 5% in males and 10% in females. The rate of creatinine excretion (e.g., Cr_ur, g creatinine/day) was estimated from the relationship between LBM (kg) and Cr_ur:

Dose units expressed as cadmium intake (µg/kg/day), urinary cadmium excretion (µg/g creatinine), or kidney tissue cadmium (µg/g cortex) were interconverted by iterative pharmacokinetic model simulations of constant intakes for the life-time to age 55 years, the age at which renal cortex cadmium concentrations are predicted to reach their peak when the rate of intake (µg/kg/day) is constant.

The dietary cadmium intakes which would result in urinary cadmium levels of 1.34 and 0.5 µg/g creatinine (UCD₁₀ and UCDL₁₀) are 0.97 and 0.33 µg/kg/day in females and 2.24 and 0.70 µg/kg/day in males. The dietary concentration associated with the UCDL₁₀ in females (0.33 µg/kg/day) was divided by an uncertainty factor of 3 for human variability resulting in a chronic-duration oral MRL of 0.1 µg/kg/day (1×10⁻⁴ mg Cd/kg/day). The UCD is based on several large-scale environmental exposure studies that likely included sensitive subpopulations; however, there is concern that individuals with diabetes may be especially sensitive to the renal toxicity of cadmium (Åkesson et al. 2005; Buchet et al. 1990) and diabetics were excluded from a number of the human studies, and thus, an uncertainty factor of 3 was used.

The urinary cadmium point of departure used as the basis of the MRL (0.5 µg/g creatinine) is approximately 2-fold higher than the geometric mean urinary cadmium concentrations in the United States, which is 0.247 µg/g creatinine for adults 20 years and older (CDC 2011). The MRL of 0.1 µg/kg/day is lower than the estimated age-weighted cadmium intake of 0.3 µg/kg/day (estimated from data in Choudhury et al. 2001). Because this intake is derived from the cadmium dietary exposure model which estimates food cadmium concentrations from national survey data and food consumption patterns, it should not be considered a precise value. A better comparison would be between the mean urinary cadmium concentration in adults living in the United States (0.247 µg/g creatinine) and the MRL expressed as a urinary cadmium concentration (0.2 µg/g creatinine).