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      Cadmium Exposure and Cancer Mortality in a Prospective Cohort: The Strong Heart Study

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          Abstract

          Background: Cadmium (Cd) is a toxic metal classified as a human carcinogen by the International Agency for Research on Cancer.

          Objective: We evaluated the association of long-term Cd exposure, as measured in urine, with cancer mortality in American Indians from Arizona, Oklahoma, and North and South Dakota who participated in the Strong Heart Study during 1989–1991.

          Methods: The Strong Heart Study was a prospective cohort study of 3,792 men and women 45–74 years of age who were followed for up to 20 years. Baseline urinary Cd (U-Cd) was measured using inductively coupled plasma mass spectrometry. We assessed cancer events by annual mortality surveillance.

          Results: The median (interquintile range) U-Cd concentration was 0.93 (0.55, 1.63) μg/g creatinine. After adjusting for sex, age, smoking status, cigarette pack-years, and body mass index, the adjusted hazard ratios (HRs) comparing the 80th versus the 20th percentiles of U-Cd were 1.30 (95% CI: 1.09, 1.55) for total cancer, 2.27 (95% CI: 1.58, 3.27) for lung cancer, and 2.40 (95% CI: 1.39, 4.17) for pancreatic cancer mortality. For all smoking-related cancers combined, the corresponding HR was 1.56 (95% CI: 1.24, 1.96). Cd was not significantly associated with liver, esophagus and stomach, colon and rectum, breast, prostate, kidney, or lymphatic and hematopoietic cancer mortality. On the basis of mediation analysis, we estimated that the percentage of lung cancer deaths due to tobacco smoking that could be attributed to Cd exposure was 9.0% (95% CI: 2.8, 21.8).

          Conclusions: Low-to-moderate Cd exposure was prospectively associated with total cancer mortality and with mortality from cancers of the lung and pancreas. The implementation of population-based preventive measures to decrease Cd exposure could contribute to reducing the burden of cancer.

          Citation: García-Esquinas E, Pollan M, Tellez-Plaza M, Francesconi KA, Goessler W, Guallar E, Umans JG, Yeh J, Best LG, Navas-Acien A. 2014. Cadmium exposure and cancer mortality in a prospective cohort: the Strong Heart Study. Environ Health Perspect 122:363–370;  http://dx.doi.org/10.1289/ehp.1306587

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          Current status of cadmium as an environmental health problem.

          Cadmium is a toxic metal occurring in the environment naturally and as a pollutant emanating from industrial and agricultural sources. Food is the main source of cadmium intake in the non-smoking population. The bioavailability, retention and toxicity are affected by several factors including nutritional status such as low iron status. Cadmium is efficiently retained in the kidney (half-time 10-30 years) and the concentration is proportional to that in urine (U-Cd). Cadmium is nephrotoxic, initially causing kidney tubular damage. Cadmium can also cause bone damage, either via a direct effect on bone tissue or indirectly as a result of renal dysfunction. After prolonged and/or high exposure the tubular injury may progress to glomerular damage with decreased glomerular filtration rate, and eventually to renal failure. Furthermore, recent data also suggest increased cancer risks and increased mortality in environmentally exposed populations. Dose-response assessment using a variety of early markers of kidney damage has identified U-Cd points of departure for early kidney effects between 0.5 and 3 microg Cd/g creatinine, similar to the points of departure for effects on bone. It can be anticipated that a considerable proportion of the non-smoking adult population has urinary cadmium concentrations of 0.5 microg/g creatinine or higher in non-exposed areas. For smokers this proportion is considerably higher. This implies no margin of safety between the point of departure and the exposure levels in the general population. Therefore, measures should be put in place to reduce exposure to a minimum, and the tolerably daily intake should be set in accordance with recent findings.
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            Cadmium carcinogenesis.

            Cadmium is a heavy metal of considerable environmental and occupational concern. Cadmium compounds are classified as human carcinogens by several regulatory agencies. The most convincing data that cadmium is carcinogenic in humans comes from studies indicating occupational cadmium exposure is associated with lung cancer. Cadmium exposure has also been linked to human prostate and renal cancer, although this linkage is weaker than for lung cancer. Other target sites of cadmium carcinogenesis in humans, such as liver, pancreas and stomach, are considered equivocal. In animals, cadmium effectively induces cancers at multiple sites and by various routes. Cadmium inhalation in rats induces pulmonary adenocarcinomas, in accord with its role in human lung cancer. Cadmium can induce tumors and/or preneoplastic lesions within the rat prostate after ingestion or injection. At relatively high doses, cadmium induces benign testicular tumors in rats, but these appear to be due to early toxic lesions and loss of testicular function, rather than from a specific carcinogenic effect of cadmium. Like many other metals, cadmium salts will induce mesenchymal tumors at the site of subcutaneous (s.c.) or intramuscular (i.m.) injections, but the human relevance of these is dubious. Other targets of cadmium in rodents include the liver, adrenal, pancreas, pituitary, and hematopoietic system. With the exception of testicular tumors in rodents, the mechanisms of cadmium carcinogenesis are poorly defined. Cadmium can cause any number of molecular lesions that would be relevant to oncogenesis in various cellular model systems. Most studies indicate cadmium is poorly mutagenic and probably acts through indirect or epigenetic mechanisms, potentially including aberrant activation of oncogenes and suppression of apoptosis.
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              Cadmium: cellular effects, modifications of biomolecules, modulation of DNA repair and genotoxic consequences (a review).

              Cadmium is an important toxic environmental heavy metal. Occupational and environmental pollution with cadmium results mainly from mining, metallurgy industry and manufactures of nickel-cadmium batteries, pigments and plastic stabilizers. Important sources of human intoxication are cigarette smoke as well as food, water and air contaminations. In humans, cadmium exposures have been associated with cancers of the prostate, lungs and testes. Acute exposures are responsible for damage to these organs. Chronic intoxication is associated with obstructive airway disease, emphysema, irreversible renal failure, bone disorders and immuno-suppression. At the cellular level, cadmium affects proliferation, differentiation and causes apoptosis. It has been classified as a carcinogen by the International Agency for Research on Cancer (IARC). However, it is weakly genotoxic. Indirect effects of cadmium provoke generation of reactive oxygen species (ROS) and DNA damage. Cadmium modulates also gene expression and signal transduction, reduces activities of proteins involved in antioxidant defenses. Several studies have shown that it interferes with DNA repair. The present review focuses on the effects of cadmium in mammalian cells with special emphasis on the induction of damage to DNA, membranes and proteins, the inhibition of different types of DNA repair and the induction of apoptosis. Current data and hypotheses on the mechanisms involved in cadmium genotoxicity and carcinogenesis are outlined.
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                Author and article information

                Journal
                Environ Health Perspect
                Environ. Health Perspect
                EHP
                Environmental Health Perspectives
                National Institute of Environmental Health Sciences
                0091-6765
                1552-9924
                14 February 2014
                April 2014
                : 122
                : 4
                : 363-370
                Affiliations
                [1 ]Department of Environmental Health Science, and
                [2 ]Welch Center for Prevention, Epidemiology and Clinical Research, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA
                [3 ]Environmental Epidemiology and Cancer Unit, National Center for Epidemiology, Carlos III Institute of Health, Madrid, Spain
                [4 ]Consortium for Biomedical Research in Epidemiology & Public Health (CIBER en Epidemiología y Salud Pública–CIBERESP), Madrid, Spain
                [5 ]Fundacion de Investigacion del Hospital Clinico de Valencia-INCLIVA, Valencia, Spain
                [6 ]Institute of Chemistry, Analytical Chemistry, Karl-Franzens University, Graz, Austria
                [7 ]Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA
                [8 ]Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA
                [9 ]MedStar Health Research Institute, Hyattsville, Maryland, USA
                [10 ]Georgetown-Howard Universities Center for Clinical and Translational Science, Washington, DC, USA
                [11 ]Center for American Indian Health Research, College of Public Health, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
                [12 ]Missouri Breaks Industries Research Inc., Timber Lake, South Dakota, USA
                [13 ]Department of Oncology, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA
                Author notes
                Address correspondence to E. García-Esquinas, Centro Nacional de Epidemiología, Instituto de Salud Carlos III, C/Sinesio Delgado, 6, 28029, Madrid, Spain. Telephone: 0091-822-26-88. E-mail: esthergge@ 123456gmail.com
                Article
                ehp.1306587
                10.1289/ehp.1306587
                3984227
                24531129
                a850391c-f678-4b8a-aafa-12dfe949c031

                Publication of EHP lies in the public domain and is therefore without copyright. All text from EHP may be reprinted freely. Use of materials published in EHP should be acknowledged (for example, “Reproduced with permission from Environmental Health Perspectives”); pertinent reference information should be provided for the article from which the material was reproduced. Articles from EHP, especially the News section, may contain photographs or illustrations copyrighted by other commercial organizations or individuals that may not be used without obtaining prior approval from the holder of the copyright.

                History
                : 30 January 2013
                : 10 December 2013
                : 14 February 2014
                : 01 April 2014
                Categories
                Research

                Public health
                Public health

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