Cadmium Exposure and Clinical Cardiovascular Disease: A Systematic Review Authors
Nutrition (BV Howard, Section Editor)
First Online: 18 August 2013 DOI:
Cite this article as: Tellez-Plaza, M., Jones, M.R., Dominguez-Lucas, A. et al. Curr Atheroscler Rep (2013) 15: 356. doi:10.1007/s11883-013-0356-2 Part of the following topical collections: Topical Collection on Nutrition Abstract
Mounting evidence supports that cadmium, a toxic metal found in tobacco, air and food, is a cardiovascular risk factor. Our objective was to conduct a systematic review of epidemiologic studies evaluating the association between cadmium exposure and cardiovascular disease. Twelve studies were identified. Overall, the pooled relative risks (95 % confidence interval) for cardiovascular disease, coronary heart disease, stroke, and peripheral arterial disease were: 1.36 (95 % CI: 1.11, 1.66), 1.30 (95 % CI: 1.12, 1.52), 1.18 (95 % CI: 0.86, 1.59), and 1.49 (95 % CI: 1.15, 1.92), respectively. The pooled relative risks for cardiovascular disease in men, women and never smokers were 1.29 (1.12, 1.48), 1.20 (0.92, 1.56) and 1.27 (0.97, 1.67), respectively. Together with experimental evidence, our review supports the association between cadmium exposure and cardiovascular disease, especially for coronary heart disease. The number of studies with stroke, heart failure (HF) and peripheral arterial disease (PAD) endpoints was small. More studies, especially studies evaluating incident endpoints, are needed.
Keywords Cadmium Cardiovascular disease Meta-analysis Systematic review Abbreviations CI
Coronary heart disease
Peripheral arterial disease
This article is part of the Topical Collection on
Nutrition Electronic supplementary material
The online version of this article (doi:
) contains supplementary material, which is available to authorized users. 10.1007/s11883-013-0356-2 References Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
Agency for Toxic Substances and Disease Registry (ATSDR). 2012. Toxicological Profile for Cadmium. Available at:
]. Accessed July 2013.
International Agency for Research on Cancer (IARC). 1993. Berillium, cadmium, mercury, and exposures in the glass manfactury industry. Available at:
. Accessed July 2013.
U.S. Geological Survey. 2013. Cadmium statistics and information. Available at:
- myb. Accessed July 2013.
Lalor GC. Review of cadmium transfers from soil to humans and its health effects and Jamaican environment. Sci Total Environ. 2008;400(1–3):162–72.
Staessen JA, Vyncke G, Lauwerys RR, et al. Transfer of cadmium from a sandy acidic soil to man: A population study. Environ Res. 1992;58(1):25–34.
DalCorso G, Farinati S, Maistri S, Furini A. How plants cope with cadmium: Staking all on metabolism and gene expression. J Integr Plant Biol. 2008;50(10):1268–80.
Golia EE, Dimirkou A, Mitsios IK. Heavy-metal concentration in tobacco leaves in relation to their available soil fractions. Commun Soil Sci Plant Anal. 2009;40(1–6):106–20.
Hogervorst J, Plusquin M, Vangronsveld J, et al. House dust as possible route of environmental exposure to cadmium and lead in the adult general population. Environ Res. 2007;103(1):30–7.
Nordberg GF, Nogawa K, Nordberg M, Friberg L. Cadmium. In: Nordberg GF, Fowler BF, Nordberg M, Friberg L, editors. Handbook on the toxicology of metals. Amsterdam: Elsevier; 2007. p. 445–86.
Yassin AS, Martonik JF. Urinary cadmium levels in the U S working population, 1988–1994. J Occup Environ Hyg. 2004;1(5):324–33.
Messner B, Knoflach M, Seubert A, et al. Cadmium is a novel and independent risk factor for early atherosclerosis mechanisms and in vivo relevance. Arterioscler Thromb Vasc Biol. 2009;29(9):1392–8.
Valko M, Morris H, Cronin MT. Metals, toxicity and oxidative stress. Curr Med Chem. 2005;12(10):1161–208.
Jin T, Lu J, Nordberg M. Toxicokinetics and biochemistry of cadmium with special emphasis on the role of metallothionein. Neurotoxicology. 1998;19(4–5):529–35.
Bell SG, Vallee BL. The metallothionein/thionein system: An oxidoreductive metabolic zinc link. ChemBioChem. 2009;10(1):55–62.
Gallagher CM, Meliker JR. Blood and urine cadmium, blood pressure, and hypertension: A systematic review and meta-analysis. Environ Health Perspect. 2010;118(12):1676–84.
Caciari T, Sancini A, Fioravanti M,
et al.: Cadmium and hypertension in exposed workers: A meta-analysis. Int J Occup Med Environ Health 2013.
Satarug S, Nishijo M, Lasker JM, Edwards RJ, Moore MR. Kidney dysfunction and hypertension: Role for cadmium, p450 and heme oxygenases? Tohoku J Exp Med. 2006;208(3):179–202.
Navas-Acien A, Tellez-Plaza M, Guallar E, et al. Blood cadmium and lead and chronic kidney disease in US adults: A joint analysis. Am J Epidemiol. 2009;170(9):1156–64.
Hwangbo Y, Weaver VM, Tellez-Plaza M, Guallar E, Lee BK, Navas-Acien A. Blood cadmium and estimated glomerular filtration rate in Korean adults. Environ Health Perspect. 2011;119(12):1800–5.
Stoica A, Katzenellenbogen BS, Martin MB. Activation of estrogen receptor-alpha by the heavy metal cadmium. Mol Endocrinol. 2000;14(4):545–53.
Fechner P, Damdimopoulou P, Gauglitz G. Biosensors paving the way to understanding the interaction between cadmium and the estrogen receptor alpha. PLoS One. 2011;6(8):e23048.
Kluxen FM, Hofer N, Kretzschmar G, Degen GH, Diel P. Cadmium modulates expression of aryl hydrocarbon receptor-associated genes in rat uterus by interaction with the estrogen receptor. Arch Toxicol. 2012;86(4):591–601.
Wang B, Li Y, Shao C, Tan Y, Cai L. Cadmium and its epigenetic effects. Curr Med Chem. 2012;19(16):2611–20.
Jarup L, Rogenfelt A, Elinder CG, Nogawa K, Kjellstrom T. Biological half-time of cadmium in the blood of workers after cessation of exposure. Scand J Work Environ Health. 1983;9(4):327–31.
Nakagawa H, Nishijo M, Morikawa Y, et al. Urinary cadmium and mortality among inhabitants of a cadmium-polluted area in Japan. Environ Res. 2006;100(3):323–9.
Nawrot TS, Van Hecke E, Thijs L, et al. Cadmium-related mortality and long-term secular trends in the cadmium body burden of an environmentally exposed population. Environ Health Perspect. 2008;116(12):1620–8.
Menke A, Muntner P, Silbergeld EK, Platz EA, Guallar E. Cadmium levels in urine and mortality among U.S. adults. Environ Health Perspect. 2009;117(2):190–6.
•• Tellez-Plaza M, Navas-Acien A, Menke A, Crainiceanu CM, Pastor-Barriuso R, Guallar E. Cadmium exposure and all-cause and cardiovascular mortality in the U.S. general population. Environ Health Perspect. 2012;120(7):1017–22.
This is a large prospective study representative of the general US population from 1999–2004 with 8 years of follow-up. After adjusting for sociodemographic and CVD risk factors, including smoking status, recent smoking dose, and cumulative smoking dose increasing cadmium exposure was associated with cardiovascular disease, heart disease and coronary heart disease mortality
•• Tellez-Plaza M, Guallar E, Howard BV, et al. Cadmium exposure and incident cardiovascular disease. Epidemiol. 2013;24(3):421–9.
This is a large prospective study in American Indian communities from the US with 20 years of follow-up. Cadmium exposure was moderately to strongly associated with incident cardiovascular disease, coronary heart disease, stroke and heart failure. The associations were similar in never smokers. The end-points were ascertained by annual mortality and morbidity reviews of hospitalization and death records and at two research clinic visits. This is the first epidemiologic study evaluating incident cardiovascular outcomes
•• Fagerberg B, Bergstrom G, Boren J, Barregard L: Cadmium exposure, intercellular adhesion molecule-1 and peripheral artery disease: a cohort and an experimental study. BMJ Open 2013, 3(3).
This is a prospective study of 64-year-old women from Sweden, with 6 years of follow-up. In this study, baseline cadmium exposure was associated with peripheral arterial disease measured at the end of the follow-up. The association appeared to be non-lineal, although the number of cases at the lower range of cadmium levels was limited.
•• Tellez-Plaza M, Guallar E, Fabsitz RR
, et al.: Cadmium Exposure and Incident Peripheral Arterial Disease. Submitted. This is a large prospective study in American Indian communities from the US followed up to 10 years through three examination visits. Cadmium exposure was associated with incident peripheral arterial disease after adjusting for cardiovascular risk factors, including smoking status, and cumulative smoking dose. The associations was also observed in never smokers, although it was not significant.
Afridi HI, Kazi TG, Kazi GH, Jamali MK, Shar GQ. Essential trace and toxic element distribution in the scalp hair of Pakistani myocardial infarction patients and controls. Biol Trace Elem Res. 2006;113(1):19–34.
Afridi HI, Kazi TG, Kazi N, et al. Evaluation of toxic elements in scalp hair samples of myocardial infarction patients at different stages as related to controls. Biol Trace Elem Res. 2010;134(1):1–12.
Afridi HI, Kazi TG, Kazi N, et al. Interactions between cadmium and zinc in the biological samples of Pakistani smokers and nonsmokers cardiovascular disease patients. Biol Trace Elem Res. 2011;139(3):257–68.
Arslan C, Altan H, Akgun OO, et al. Trace elements and toxic heavy metals play a role in Buerger disease and atherosclerotic peripheral arterial occlusive disease. Int Angiol. 2010;29(6):489–95.
Liu JH. Case control study on relationship between serum lead, cadmium and coronary heart disease. Chinese Journal of Industrial Hygiene and Occupational Diseases. 2008;26(11):679. Zhonghua lao dong wei sheng zhi ye bing za zhi = Zhonghua laodong weisheng zhiyebing zazhi.
Tang YR, Zhang SQ, Xiong Y, et al. Studies of five microelement contents in human serum, hair, and fingernails correlated with aged hypertension and coronary heart disease. Biol Trace Elem Res. 2003;92(2):97–104.
Tsai JL, Horng PH, Hwang TJ, Hsu JW, Horng CJ. Determination of urinary trace elements (arsenic, copper, cadmium, manganese, lead, zinc, selenium) in patients with Blackfoot disease. Arch Environ Health. 2004;59(12):686–92.
Wang M, Xu Y, Pan S, et al. Long-term heavy metal pollution and mortality in a chinese population: An ecologic study. Biol Trace Elem Res. 2011;142(3):362–79.
Morgan JM. Tissue cadmium concentration in man. Arch Intern Med. 1969;123(4):405–8.
Adamska-Dyniewska H, Bala T, Florczak H, Trojanowska B. Blood cadmium in healthy subjects and in patients with cardiovascular diseases. Cor et Vasa. 1982;24(6):441–7.
Adamska-Dyniewska H, Kawecka M. Blood cadmium level in the acute phase of myocardial infarction. Polskie Archiwum Medycyny Wewnetrznej. 1983;69(1):9–14.
Ponteva M, Elomaa I, Backman H, Hansson L, Kilpio J. Blood cadmium and plasma zinc measurements in acute myocardial infarction. Eur J Cardiol. 1979;9(5):379–91.
Rong YZ. Clinical significance of blood zinc, copper, cadmium and magnesium determinations in acute myocardial infarction. Zhonghua xin xue guan bing za zhi. 1983;11(4):256–9.
Scott R, Aughey E, Reilly M, Cunningham C, McClelland A, Fell GS. Renal cadmium content in the West of Scotland. Urol Res. 1983;11(6):285–90.
Smetana R, Glogar D, Weidinger F, Meisinger V. Heavy metal and trace element deviations. A comparison of idiopathic dilated cardiomyopathy and coronary heart disease. Wien Med Wochenschr. 1987;137(23):553–7.
Sun RX, Su YX, Sun JH. Determination of trace elements in cerebrospinal fluid (CSF) of patients suffering cerebrovascular disease by atomic absorption spectrometry. Guang pu xue yu guang pu fen xi = Guang pu. 2006;26(4):720–2.
Voors AW, Shuman MS, Johnson WD. Additive statistical effects of cadmium and lead on heart-related disease in a North Carolina autopsy series. Arch Environ Health. 1982;37(2):98–102.
Adamska-Dyniewska H, Bala T, Florczak H, Trojanowska B, Trzcinka M. Blood cadmium level in coronary disease depending on the risk factors. Kardiologia polska. 1980;23(6):467–73.
Adamska-Dyniewska H, Bala T, Trojanowska B, Trzcinka M. Blood cadmium level in chronic circulatory insufficiency. Pol Tyg Lek. 1980;35(31):1173–5.
Voors AW, Shuman MS, Gallagher PN. Atherosclerosis and hypertension in relation to some trace elements in tissues-1. World Rev Nutr Diet. 1975;20:299–326.
•• Li Q, Nishijo M, Nakagawa H, et al. Relationship between urinary cadmium and mortality in habitants of a cadmium-polluted area: A 22-year follow-up study in Japan. Chin Med J. 2011;124(21):3504–9.
This is a large prospective study of Japanese inhabitants of a cadmium-polluted area, with 22-year follow-up. In this study, cadmium exposure as measured in urine was associated with cardiovascular disease mortality in both men and women, and with stroke mortality only in women. A limitation of this study is the lack of adjustment for smoking and other relevant cardiovascular risk factors. An additional limitation is that the number of cardiovascular deaths is limited, specially for women
Ferraro PM, Sturniolo A, Naticchia A, D'Alonzo S, Gambaro G. Temporal trend of cadmium exposure in the United States population suggests gender specificities. Intern Med J. 2012;42(6):691–7.
Guallar E, Silbergeld EK, Navas-Acien A, et al. Confounding of the relation between homocysteine and peripheral arterial disease by lead, cadmium, and renal function. Am J Epidemiol. 2006;163(8):700–8.
Navas-Acien A, Selvin E, Sharrett AR, Calderon-Aranda E, Silbergeld E, Guallar E. Lead, cadmium, smoking, and increased risk of peripheral arterial disease. Circulation. 2004;109(25):3196–201.
Ju YR, Chen WY, Liao CM. Assessing human exposure risk to cadmium through inhalation and seafood consumption. J Hazard Mater. 2012;227–228:353–61.
Longnecker MP, Berlin JA, Orza MJ, Chalmers TC. A meta-analysis of alcohol consumption in relation to risk of breast cancer. JAMA. 1988;260(5):652–6.
Everett CJ, Frithsen IL. Association of urinary cadmium and myocardial infarction. Environ Res. 2008;106(2):284–6.
Agarwal S, Zaman T, Tuzcu EM, Kapadia SR. Heavy metals and cardiovascular disease: Results from the national health and nutrition examination survey (NHANES) 1999–2006. Angiology. 2011;62(5):422–9.
• Peters JL, Perlstein TS, Perry MJ, McNeely E, Weuve J. Cadmium exposure in association with history of stroke and heart failure. Environ Res. 2010;110(2):199–206.
This is a large crossectional study conducted in a representative sample of the US general population in 1999–2006. In this study cadmium exposure was associated with the prevalence of self-reported myocardial infarction, stroke and heart failure, after adjustment for cardiovascular risk factors including smoking status but not cumulative smoking dose and recent smoking dose . The associations were similar for men and women
Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002;21(11):1539–58.
• Tellez-Plaza M, Navas-Acien A, Crainiceanu CM, Sharrett AR, Guallar E. Cadmium and peripheral arterial disease: Gender differences in the 1999–2004 US national health and nutrition examination survey. Am J Epidemiol. 2010;172(6):671–81.
This is a large crossectional study conducted in a representative sample of the US general population in 1999–2004. In this study higher blood and urine cadmium levels were associated with increased prevalence of PAD, but women never smokers showed a U-shaped relation with increased prevalence of PAD at very low cadmium levels. The models adjusted for sociodemographic and CVD risk factors, including smoking status, recent smoking dose, and cumulative smoking dose
• Lee MS, Park SK, Hu H, Lee S. Cadmium exposure and cardiovascular disease in the 2005 Korea national health and nutrition examination survey. Environ Res. 2011;111(1):171–6.
This is a crossectional study conducted in a representative sample of the Korean general population in 2005. Blood cadmium was associated with the prevalence of self-reported ischemic heart disease among men and women, and with the prevalence of self-reported stroke only in men. The models were adjusted for sociodemographic and CVD risk factors, including smoking status. The number of prevalent cardiovascular cases, however, was relatively low
National Center for Health Statistics. 2013. National Health and Nutrition Examination Survey. Available at:
. Accessed July 2013.
Korean Centers for Disease Control and Prevention. 2013. Korean National Health and Nutrition Examination Survey (KHANES). Available at:
. Accessed July 2013.
Himeno S, Yanagiya T, Fujishiro H. The role of zinc transporters in cadmium and manganese transport in mammalian cells. Biochimie. 2009;91(10):1218–22.
Akerstrom M, Barregard L, Lundh T, Sallsten G. The relationship between cadmium in kidney and cadmium in urine and blood in an environmentally exposed population. Toxicol Appl Pharmacol. 2013;268(3):286–93.
Akerstrom M, Sallsten G, Lundh T, Barregard L. Associations between urinary excretion of cadmium and proteins in a nonsmoking population: Renal toxicity or normal physiology? Environ Health Perspect. 2013;121(2):187–91.
Akerstrom M, Lundh T, Barregard L, Sallsten G. Sampling of urinary cadmium: Differences between 24-h urine and overnight spot urine sampling, and impact of adjustment for dilution. Int Arch Occup Environ Health. 2012;85(2):189–96.
Plusquin M, Nawrot TS, Staessen JA. Peripheral arterial disease and metals in urine and blood. Environ Health Perspect. 2005;113(8):A510–1. author reply A511.
Elliott P, Arnold R, Cockings S, et al. Risk of mortality, cancer incidence, and stroke in a population potentially exposed to cadmium. Occup Environ Med. 2000;57(2):94–7.
Sorahan T, Waterhouse JA. Mortality study of nickel-cadmium battery workers by the method of regression models in life tables. Br J Ind Med. 1983;40(3):293–300.
Elinder CG, Kjellstrom T, Hogstedt C, Andersson K, Spang G. Cancer mortality of cadmium workers. Br J Ind Med. 1985;42(10):651–5.
Kazantzis G, Lam TH, Sullivan KR. Mortality of cadmium-exposed workers. A five-year update. Scand J Work Environ Health. 1988;14(4):220–3.
Ishihara T, Kobayashi E, Okubo Y, et al. Association between cadmium concentration in rice and mortality in the Jinzu River basin. Japan Toxicology. 2001;163(1):23–8.
Nishijo M, Satarug S, Honda R, Tsuritani I, Aoshima K. The gender differences in health effects of environmental cadmium exposure and potential mechanisms. Mol Cell Biochem. 2004;255(1–2):87–92.
Vahter M, Akesson A, Liden C, Ceccatelli S, Berglund M. Gender differences in the disposition and toxicity of metals. Environ Res. 2007;104(1):85–95.
Tellez-Plaza M, Navas-Acien A, Crainiceanu CM, Guallar E. Cadmium exposure and hypertension in the 1999–2004 national health and nutrition examination survey (NHANES). Environ Health Perspect. 2008;116(1):51–6.
Hellstrom L, Elinder CG, Dahlberg B, et al. Cadmium exposure and end-stage renal disease. American journal of kidney diseases : the official journal of the National Kidney Foundation. 2001;38(5):1001–8.
Kasuya M. Recent epidemiologial studies on Itai-itai disease as a chronic cadmium poisoning in Japan. Water Sci Tech. 2000;42:147–55.
Staessen JA, Roels HA, Emelianov D, et al. Environmental exposure to cadmium, forearm bone density, and risk of fractures: prospective population study. Public Health and Environmental Exposure to Cadmium (PheeCad) Study Group. Lancet. 1999;353(9159):1140–4.
Chen X, Zhu G, Jin T, et al. Changes in bone mineral density 10 years after marked reduction of cadmium exposure in a Chinese population. Environ Res. 2009;109(7):874–9.
US Department of Health and Human Services. 2010. A report of the surgeon general: how tobacco smoke causes disease. The biology and behavioral basis for smoking-attributable disease. Available at:
. Accessed July 2013.
Tellez-Plaza M, Navas-Acien A, Caldwell KL, Menke A, Muntner P, Guallar E. Reduction in cadmium exposure in the United States population, 1988–2008: the contribution of declining smoking rates. Environ Health Perspect. 2012;120(2):204–9.
Swaddiwudhipong W, Mahasakpan P, Limpatanachote P, Krintratun S. Correlations of urinary cadmium with hypertension and diabetes in persons living in cadmium-contaminated villages in northwestern Thailand: A population study. Environ Res. 2010;110(6):612–6.
Swaddiwudhipong W, Limpatanachote P, Mahasakpan P, Krintratun S, Punta B, Funkhiew T. Progress in cadmium-related health effects in persons with high environmental exposure in northwestern Thailand: a five-year follow-up. Environ Res. 2012;112:194–8.
Schwartz GG, Il'yasova D, Ivanova A. Urinary cadmium, impaired fasting glucose, and diabetes in the NHANES III. Diabetes Care. 2003;26(2):468–70.
Barregard L, Bergstrom G, Fagerberg B. Cadmium exposure in relation to insulin production, insulin sensitivity and type 2 diabetes: A cross-sectional and prospective study in women. Environ Res. 2013;121:104–9.
•• Fagerberg B, Bergstrom G, Boren J, Barregard L. Cadmium exposure is accompanied by increased prevalence and future growth of atherosclerotic plaques in 64-year-old women. J Intern Med. 2012;272(6):601–10.
In this study of 64-year-old women from Sweden, with over 6 years of follow-up, cadmium exposure was cross-sectionally and prospectively associated with the presence of carotide plaque, after adjusting for cardiovascular risk factors including cumulative smoking dose. Cadmium exposure at baseline was also positively associated with the change in carotid plaque area at the end of the follow-up. Cadmium-related subclinical atherosclerosis is especially relevant for clinical cardiovascular disease prevention
Bjorkman L, Vahter M, Pedersen NL. Both the environment and genes are important for concentrations of cadmium and lead in blood. Environ Health Perspect. 2000;108(8):719–22.
Whitfield JB, Dy V, McQuilty R, et al. Genetic effects on toxic and essential elements in humans: Arsenic, cadmium, copper, lead, mercury, selenium, and zinc in erythrocytes. Environ Health Perspect. 2010;118(6):776–82.
Rentschler G, Kippler M, Axmon A, et al. Polymorphisms in iron homeostasis genes and urinary cadmium concentrations among nonsmoking women in Argentina and Bangladesh. Environ Health Perspect. 2013;121(4):467–72. 472e461-467.
Khansakorn N, Wongwit W, Tharnpoophasiam P, et al. Genetic variations of glutathione s-transferase influence on blood cadmium concentration. J Toxicol. 2012;2012:356126.
Kayaalti Z, Aliyev V, Soylemezoglu T. The potential effect of metallothionein 2A–5A/G single nucleotide polymorphism on blood cadmium, lead, zinc and copper levels. Toxicol Appl Pharmacol. 2011;256(1):1–7.
Kayaalti Z, Mergen G, Soylemezoglu T. Effect of metallothionein core promoter region polymorphism on cadmium, zinc and copper levels in autopsy kidney tissues from a Turkish population. Toxicol Appl Pharmacol. 2010;245(2):252–5.
Lei L, Chang X, Rentschler G, et al. A polymorphism in metallothionein 1A (MT1A) is associated with cadmium-related excretion of urinary beta 2-microglobulin. Toxicol Appl Pharmacol. 2012;265(3):373–9.
Feinberg AP. Genome-scale approaches to the epigenetics of common human disease. Virchows Archiv: An international journal of pathology. 2010;456(1):13–21.
CrossRef Copyright information
© Springer Science+Business Media New York 2013