Review Cadmium, Environmental Exposure, and Health Outcomes Soisungwan Satarug, Scott H. Garrett, Mary Ann Sens, and Donald A. Sens Department of Pathology, University of North Dakota School of Medicine and Health Sciences, Grand Forks, North Dakota, USA : We provide an update of the issues surrounding health risk assessment of exposure to Objectivs Dat Dat cadmium in food. s Ources : We reviewed epidemiologic studies published between 2004 and 2009 concerning the bioavailability of cadmium in food, assessment of exposure, and body burden estimate, along with exposure-related effects in nonoccupationally exposed populations. extraci On an D syntheis : Bioavailability of ingested cadmium has been confirmed in studies of persons with elevated dietary exposure, and the findings have been strengthened by the substantial amounts of cadmium accumulated in kidneys, eyes, and other tissues and organs of envi- ronmentally exposed individuals. We hypothesized that such accumulation results from the efficient absorption and systemic transport of cadmium, employing multiple transporters that are used for the body’s acquisition of calcium, iron, zinc, and manganese. Adverse effects of cadmium on kidney and bone have been observed in environmentally exposed populations at frequencies higher than those predicted from models of exposure. Increasing evidence implicates cadmium in the risk of dis- eases that involve other tissues and organ systems at cadmium concentrations that do not produce effects on bone or renal function. c Onclusi Ons : Population data raise concerns about the validity of the current safe intake level that uses the kidney as the sole target in assessing the health risk from ingested cadmium. The data also question the validity of incorporating the default 5% absorption rate in the threshold-type risk assessment model, known as the provisional tolerable weekly intake (PTWI), to derive a safe intake level for cadmium. Key w Or Ds : cadmium, calcium, cancer, diet, disease burden, environmental exposure, iron, manganese, zinc. Environ Health Perspect 118:182–190 (2010). doi:10.1289/ehp.0901234 avail- able via http://dx.doi.org/ [Online 5 October 2009] Because of its high rates of soil-to-plant transfer, cadmium is a contaminant found in most human foodstuffs, which renders diet a primary source of exposure among non- smoking, nonoccupationally exposed popu- lations (Clemens 2006; Franz et al. 2008; McLaughlin et al. 2006). A safe intake limit of 7 µg cadmium/week/kg body weight was set based on the critical renal cadmium con- centration of between 100 and 200 µg/g wet weight that corresponds to a urinary threshold limit of 5–10 µg/g creatinine [World Health Organization (WHO) 1989, 1993]. However, numerous studies have revealed adverse kidney effects at urinary cadmium levels < 0.5 µg/g creatinine (Satarug and Moore 2004). Further, accumulating evidence links environmental exposure to cadmium with increased cancer incidence. For example, in prospective studies in Japan and the United States, excess can- cer mortality was found to be associated with environmental exposure to cadmium (Arisawa et al. 2007b; Menke et al. 2009; Nishijo et al. 2006). Åkesson et al. (2008) observed increased endometrial cancer risk in a Swedish cohort among participants who consumed > 15 µg/day of cadmium, mainly from cereals and vegetables. These findings suggest a very large health burden associated with exposure to cadmium at levels experienced by many populations worldwide. This review provides an update on cad- mium exposure levels and the potential adverse 182 health effects they may elicit in adult popu- lations. We focus first on key issues under- pinning health risk assessment of low-level cadmium in the diet, including bioavailability of dietary origin, the 5% default absorption rate, thresholds and safe intake levels, and the kidney as a specific target for cadmium accu- mulation. Second, we review epidemiologic studies from 2004 to 2009 that link exposure levels to observed effects in classic targets (kid- ney and bone) along with newly identified potential target organs. We also summarize evidence that links cadmium with diabetes, diabetic nephropathy, hypertension, periph- eral artery disease (PAD), myocardial infarc- tion, diminished lung function, periodontal disease, and age-related macular degeneration (AMD). Evidence from prospective studies reveal potential causal relationships of cad- mium exposure with life prognosis (all-cause mortality) and excess cancer mortality and suggest that cadmium is at least a comorbid- ity factor if not a causative factor. Specifically, we summarize cadmium-cancer associations for the lung, pancreas, breast, endometrium, prostate, and urinary bladder. FAO/WHO Guidelines for Safe Intake The major issue addressed in this article is whether the guidelines established for the safe intake of cadmium adequately protect indi- viduals from increased health risk. The Food and Agriculture Organization/World Health Organization (FAO/WHO) Joint Expert Committee on Food Additives has defined the provisional tolerable weekly intake (PTWI) for a chemical with no intended function as an estimate of the amount of the chemical that can be ingested weekly over a lifetime without appreciable health risk (WHO 1989). The PTWI value initially set for cadmium was 400–500 µg/person/week (WHO 1989). These levels were based on a critical renal con- centration of 100–200 µg cadmium/g wet kid- ney cortex weight, attained after a cadmium intake of 140–260 µg/day for > 50 years or 2,000 mg over a lifetime (WHO 1989). The PTWI model incorporates an oral absorp- tion rate of 5% and a daily excretion rate of 0.005% of total body burden. In 1992, the PTWI for cadmium was refined and subse- quently expressed in terms of cadmium intake per kilogram of body weight (WHO 1993). This refinement also recognized that the model PTWI for cadmium did not include a safety factor and that only a very modest mar- gin existed between the level of exposure in a normal diet and a level predicted to produce a potential effect on the kidney. Despite this narrow safety factor, the PTWI for cadmium was retained at 7 µg/kg body weight, which translates to 70 µg/day for a person who weighs 70 kg. A toxicokinetic model predicts, based on similar assumptions, that the renal cortical cadmium level of 50 µg/g wet weight could be attained at the cadmium intake of 1 µg/kg body weight/day over 50 years (Buchet et al. 1990). The renal cortical cad- mium 50 µg/g wet weight corresponds to uri- nary cadmium 2 µg/g creatinine, but kidney effects have been observed at urinary cadmium levels < 0.5 µg/g creatinine (Table 1). These findings argue that the current safe intake level does not provide sufficient health protection and that it should be lowered. Address correspondence to S. Satarug, Department of Pathology, School of Medicine and Health Sciences, University of North Dakota, 501 North Columbia Rd., Grand Forks, ND 58202 USA. Telephone: (701) 777-0389. Fax: (701) 777-3108. E-mail: ssatarug@medicine.nodak.edu This review was made possible by grant R01 E S 0 1 5 1 0 0 f r o m t h e N a t i o n a l I n s t i t u t e o f Environmental Health Sciences (NIEHS), National Institutes of Health (NIH). Contents of this review are solely the responsibility of the authors and do not necessarily represent the official views of the NIEHS, NIH. The authors declare they have no competing financial interests. Received 29 June 2009; accepted 5 October 2009. ovlume 118 | number 2 | February 2010 • Environmental Health Perspectives