In 2000, the Codex Committee for Food Additives and Contaminants reached an agreement on the principles for setting maxi- mum levels (MLs) for cumulative food con- taminants (Francesconi 2007). MLs were proposed for lead (Pb2+) and cadmium (Cd2+) in various food categories, including rice, soy- bean, peanuts, and bivalve mollusks. The bio- availability and ML of cadmium became an issue because certain bivalve mollusks were known to be naturally high in cadmium con- tent (Francesconi 2007). A high ML for cad- mium was based on an early study on bluff oysters (McKenzie et al. 1986). Cadmium Sources and Bioavailability Mollusks and crustaceans. Bivalve mollusks and crustaceans are filter feeders that accumulate metals from the aquatic environment indepen- dent of environmental pollution, and contami- nated waters could further increase the content of metals (Whyte et al. 2009). Cadmium con- tent of some Pacific oysters was found to be 13.5 mg/kg dry weight, whereas 2-fold higher cadmium content was reported for some New Zealand bluff oysters (Copes et al. 2008). A bioavailability study was conducted on 57 men and 19 women 20–75 years of age who were associated with the oyster industry (McKenzie et al. 1986). The subjects were divided into groups 1, 2, 3, and 4, according to their aver- age weekly oyster consumption rate at < 6, 6–24, 24 to < 72, and ≥ 72 oysters, respec- tively. The estimated cadmium intake for sub- jects in groups 1, 2, 3, and 4 was 34, 75, 116, and 250 µg/day, respectively. The estimated consumption for all groups, except group 1, Cadmium in food and human health exceeded the FAO/WHO safe guideline. The blood cadmium was higher among smokers than among nonsmokers. For the nonsmokers in group 4 (the highest consumption rate), the increase in blood cadmium attributable to oyster consumption was 1.2 µg/L. Blood selenium was also elevated by oyster consump- tion, but no effect on serum zinc or copper levels was observed. Urinary cadmium, zinc, and β2-microglobulin (β2-MG) levels were not affected, and no relationship was found between cadmium intake and adverse renal effects, defined as glycosuria or proteinuria. In addition, no effect was observed on levels of cadmium, zinc, and copper in hair. McKenzie et al. (1986) concluded that interactions with selenium and other metals in oysters may result in diminished cadmium absorption. This study is extremely important because it has been used as the basis for assigning high cadmium ML values to allow the marketing of oysters and their products that contain naturally high levels of cadmium. It is important to note that no distinction is made between toxicity of natural versus anthropogenic cadmium. In our opin- ion, this study had several flaws. For example, although dietary selenium and zinc were mea- sured in the analysis, other determinants of cadmium absorption were not considered, such as body iron stores and the older age of the sub- jects. Furthermore, evidence (Tables 1–5) now indicates that the blood cadmium 1.2 µg/L attributed to oyster consumption among non- smokers in group 4 can be considered at risk, because blood cadmium levels of < 1 µg/L have been associated with adverse effects. Recently, Copes et al. (2008) and Clark et al. (2007) reexamined the bioavailability of Table 1. Exposure levels associated with kidney and bone effects. Study population, age, reference Sweden, n = 820, 53–64 years of age, Åkesson et al. 2005, 2006 Satarug et al. (2000, 2003) examined the PTWI model by studying cadmium accumu- lation in kidneys and livers of environmentally exposed subjects. Their studies suggested that the safe intake level for an adult should be < 30 µg/day. They also showed that cadmium accumulation in the kidney cortex increased with age, reaching a plateau by 50 years of age (Satarug et al. 2002). An estimated dietary intake at 25–30 µg cadmium/day for persons in the 41- to 50-year-old age group would give rise to a total cadmium body burden of 18 mg. The studies indicated that the estimated intake of 25–30 µg/day may produce adverse kidney effects in about 1% of the adult population when variability in absorption and sensitivity to adverse effects among population members are considered in the analysis. Threshold-based Models for Safe Intake If the relative susceptibility of humans and ani- mals is unknown at the time of derivation of PTWI, the lowest observed adverse effect level (LOAEL) in the most sensitive species is used, which adds an uncertainty factor of 100. Thus, the PTWI value must be substantiated by addi- tional experimental data, and, if warranted, a larger uncertainty factor should be applied to the value. An alternative to LOAEL, the bench- mark dose (BMD), has been used to derive the urinary cadmium threshold. The BMD is defined as the exposure level that produces a change in a response, known as the point of departure (POD). The lower 95% confidence interval (CI) of the BMD corresponding to a 5% (L5) or 10% (L10) level of each index of an adverse effect above the background level may also be calculated as a threshold. Uno et al. (2005) estimated the BMDL10 of uri- nary cadmium to be 0.6–1.2 µg/g creatinine (0.8–1.6 µg/day) in men and 1.2–3.6 µg/g creatinine (0.5–4.7 µg/day) in women. These results were based on data from 828 Japanese subjects (410 men, 418 women), 40–59 years of age, who lived in areas without apparent pollution. In another study, Suwazono et al. (2006) used data from 790 Swedish women, 53–64 years of age, and estimated the BMD of urinary cadmium to be 0.6–1.1 µg/g crea- tinine. Data from selected studies found the POD for early kidney and bone effects to be between 0.5 and 3 µg/g creatinine (Järup and Åkesson 2009). Using the BMD-derived uri- nary cadmium threshold, the tolerable weekly intake for cadmium was 2.5 µg/kg body weight, which corresponds to 25 µg/day for a person who weighs 70 kg (European Food Safety Authority 2009). International Food Legislation In the early 1960s, the Joint FAO/WHO Codex Alimentarius Commission was estab- lished to detail international food legislation. Environmental Health Perspectives • volume 118 | number 2 | February 2010 183 Thailand, n = 200, 16–60 years of age, Satarug et al. 2005 Thailand, n = 224, 30–87 years of age, Teeyakasem et al. 2007 United States, n = 4,258, ≥ 50 years of age, Gallagher et al. 2008 Belgium, n = 294, mean age 49.2 years of age, Schutte et al. 2008b China, n = 148, 3-year observation, Wu et al. 2008 United Kingdom, n = 160, 18–86 years of age, Thomas et al. 2009 United States, n = 14,778, > 20 years of age, Navas-Acien et al. 2009 OR, odds ratio. aEarly renal injury was defined as urinary NAG > 2 IU/g creatinine. Exposure/outcomes Blood and urinary cadmium at 0.38 µg/L and 0.67 µg/g creatinine were associated with tubular impairment. Urinary cadmium at 0.8 µg/g creatinine was associated with glomerular impairment. Increased body burden of cadmium was associated with lowered bone mineral density, decreased serum parathyroid hormone and bone metabolism. A 3-fold increase in body burden associated with 11%, 32%, and 61% increases the probability of having high blood pressure, renal injury, and tubular impairment. OR for tubular impairment was 10.6, comparing urinary cadmium 1–5 versus > 5 µg/g creatinine. A 1.43-fold increase in osteoporosis risk, comparing urinary cadmium 1 versus < 0.5 µg/g creatinine A 2-fold increase in body burden associated with increased bone resorption, urinary calcium loss, decreased proximal forearm bone density, and low serum parathyroid hormone. Progressive tubular and glomerular impairment was observed among those with urinary cadmium > 10 µg/g creatinine. Risk for early renal effectsa was increased by 2.6-fold and 3.6-fold, comparing urinary cadmium 0.3 versus < 0.5 versus ≥ 0.5 µg/g creatinine. Risk for albuminuria was 2.34 and risk for lowered glomerular filtra- tion rate was 1.98, comparing those in the highest versus lowest quartiles of blood cadmium and lead.