University of Pittsburgh
right1057275CADMIUM AND LIVER DISEASEbyYi ChenBS in Biotechnology National Talent Base Class, Lanzhou University, China, 2004-2008MS in Cell Biology, Lanzhou University, China, 2008-2011Submitted to the Graduate Faculty ofEnvironmental and Occupational HealthGraduate School of Public Health in partial fulfillment of the requirements for the degree ofMaster of Public Health University of Pittsburgh201400CADMIUM AND LIVER DISEASEbyYi ChenBS in Biotechnology National Talent Base Class, Lanzhou University, China, 2004-2008MS in Cell Biology, Lanzhou University, China, 2008-2011Submitted to the Graduate Faculty ofEnvironmental and Occupational HealthGraduate School of Public Health in partial fulfillment of the requirements for the degree ofMaster of Public Health University of Pittsburgh2014left104775UNIVERSITY OF PITTSBURGHGRADUATE SCHOOL OF PUBLIC HEALTHThis essay is submittedbyYi ChenonApril 25th, 2014and approved byEssay Advisor: James Peterson, Ph.D______________________________________Associate ProfessorDepartment of Environmental and Occupational HealthGraduate School of Public HealthUniversity of PittsburghEssay Reader:Fernando Holguin, MD.______________________________________Assistant ProfessorDepartment of Pulmonary, Allergy and Critical Care MedicineUniversity of Pittsburgh Medical CenterUniversity of Pittsburgh00UNIVERSITY OF PITTSBURGHGRADUATE SCHOOL OF PUBLIC HEALTHThis essay is submittedbyYi ChenonApril 25th, 2014and approved byEssay Advisor: James Peterson, Ph.D______________________________________Associate ProfessorDepartment of Environmental and Occupational HealthGraduate School of Public HealthUniversity of PittsburghEssay Reader:Fernando Holguin, MD.______________________________________Assistant ProfessorDepartment of Pulmonary, Allergy and Critical Care MedicineUniversity of Pittsburgh Medical CenterUniversity of Pittsburghright4619625Copyright ? by Yi Chen201400Copyright ? by Yi Chen2014right-635James Peterson, PhDCADMIUM AND LIVER DISEASEYi Chen, MPH University of Pittsburgh, 201400James Peterson, PhDCADMIUM AND LIVER DISEASEYi Chen, MPH University of Pittsburgh, 2014ABSTRACTCadmium, which released into the environment, has increased in past 100 years. Exposure to cadmium induced harmful environmental effects in the atomsphere and biosphere, contributes to adverse health effects in humans, including liver damages. Liver disease is one of top 10 causes of death around all the world, which mostly reduces the quality of life and longevity for humans. It is important to understand the relationship between liver disease and cadmium exposure in order to improve public health. This literature review consults research articles, peer reviews, government reports and regulations to determine the public health importance regarding cadmium-related liver disease. It is clear that chronic cadmium exposure is related with some kinds of liver diseases, both in animals and humans. Although cadmium is classified as a carcinogenic agent, there is insufficient evidence to support that liver cancer is associated with cadmium exposure. Further studies are required to investigate whether chronic low-doses of cadmium exposure could induce liver cancer and other liver diseases. If environmental exposure to cadmium is ultimately found to cause liver diseases, further efforts should be made to reduce it. For example, the government could consider developing regulations for cadmium in agriculture products and tobacco products. Additionally, clinical trial could be initiated to evaluate therapeutic agents to mitigate toxic exposure to cadmium.TABLE OF CONTENTSINTRODUCTION……………………………………………………………............................. 1ENVIRONMENTAL BURDEN OF CADMIUM……………………………………………... 3Cadmium Properties……………………………………………………………………… 3Production and Consumption…………………………………………………………….. 3Environmental Exposure and Effects…………………………………………………….. 4Human Exposure…………………………………………………………………………...7ADVERSE HEALTH EFFECTS OF CADMIUM EXPOSURE…………………………...... 9Adverse Health Effects (Noncancer....……………………………………………………. 9Carcinogenicity…………………………………………………………………………....10CADMIUM EXPOSURE AND LIVER DISEASE…………………………….………….…..11Burden of Liver disease…………………………………………………………………….11Hepatotoxicity of Cadmium……………………………………………………………….12Animal Studies of Cadmium-induced Liver Disease……………………………………..14Epidemiological Studies of Cadmium-dependent Liver-related Disease………………..15Potential Mitigating Agents……………………………………………………………......17CONCLUSIONS……………………………………………………………………………......19BIBLIOGRAPHY……………………………………………………………………………... 22INTRODUCTIONCadmium is a toxic heavy metal found widely in the environment. Cadmium release into the environment is a burden we need to consider ADDIN EN.CITE <EndNote><Cite><Year>2003</Year><RecNum>30</RecNum><DisplayText><style face="superscript">1</style></DisplayText><record><rec-number>30</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1395951507">30</key></foreign-keys><ref-type name="Government Document">46</ref-type><contributors><secondary-authors><author>Nordic Council of MInisters</author></secondary-authors></contributors><titles><title>Cadmium Review</title></titles><number>4</number><dates><year>2003</year></dates><isbn>1</isbn><urls></urls><access-date>January 2003</access-date></record></Cite></EndNote>1. Due to the fact that cadmium is not degraded in nature, new release adds to the already existing deposit of cadmium in the environment and cadmium stays in circulation and enters into the food chain. ADDIN EN.CITE <EndNote><Cite><Year>2003</Year><RecNum>30</RecNum><DisplayText><style face="superscript">1</style></DisplayText><record><rec-number>30</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1395951507">30</key></foreign-keys><ref-type name="Government Document">46</ref-type><contributors><secondary-authors><author>Nordic Council of MInisters</author></secondary-authors></contributors><titles><title>Cadmium Review</title></titles><number>4</number><dates><year>2003</year></dates><isbn>1</isbn><urls></urls><access-date>January 2003</access-date></record></Cite></EndNote>1 Everyone is exposed to cadmium since cadmium exists in the earth’s crust and is released into the air, water and soil ADDIN EN.CITE <EndNote><Cite><Year>2003</Year><RecNum>30</RecNum><DisplayText><style face="superscript">1</style></DisplayText><record><rec-number>30</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1395951507">30</key></foreign-keys><ref-type name="Government Document">46</ref-type><contributors><secondary-authors><author>Nordic Council of MInisters</author></secondary-authors></contributors><titles><title>Cadmium Review</title></titles><number>4</number><dates><year>2003</year></dates><isbn>1</isbn><urls></urls><access-date>January 2003</access-date></record></Cite></EndNote>1. 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ADDIN EN.CITE.DATA 1-3 Due to ingestion of contaminated food, the risk of cadmium exposure is constantly increased.Cadmium was classified as a human carcinogen by the International Agency for Research on Cancer (IRAC) in 1993, and is clearly a potent multi-tissue animal carcinogen. ADDIN EN.CITE <EndNote><Cite><Author>IRAC</Author><Year>1993</Year><RecNum>355</RecNum><DisplayText><style face="superscript">4</style></DisplayText><record><rec-number>355</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1395963220">355</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>IRAC </author></authors></contributors><titles><title>Cadmium and Cadmium Compounds</title><secondary-title>International Agency for Research on Cancer Monographs Press, Lyon</secondary-title></titles><periodical><full-title>International Agency for Research on Cancer Monographs Press, Lyon</full-title></periodical><pages>119-238</pages><volume>58</volume><dates><year>1993</year></dates><urls></urls></record></Cite></EndNote>4 Occupational exposure to cadmium is associated with lung cancer in humans, while cancer of other organs, potentially including the kidney, the prostate and the liver, are not definitively established.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5JUkFDPC9BdXRob3I+PFllYXI+MTk5MzwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA 2, 6 Several animal studies have shown that cadmium exposure may cause liver failure. ADDIN EN.CITE <EndNote><Cite><Author>Waalkes</Author><Year>2003</Year><RecNum>357</RecNum><DisplayText><style face="superscript">6</style></DisplayText><record><rec-number>357</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1395964518">357</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Waalkes, M. P.</author></authors></contributors><auth-address>Inorganic Carcinogenesis Section, Laboratory of Comparative Carcinogenesis, National Cancer Institute at the National Institute of Environmental Health Sciences, Triangle Park, NC 27706, USA. waalkes@niehs.</auth-address><titles><title>Cadmium carcinogenesis</title><secondary-title>Mutat Res</secondary-title><alt-title>Mutation research</alt-title></titles><periodical><full-title>Mutat Res</full-title><abbr-1>Mutation research</abbr-1></periodical><alt-periodical><full-title>Mutat Res</full-title><abbr-1>Mutation research</abbr-1></alt-periodical><pages>107-20</pages><volume>533</volume><number>1-2</number><keywords><keyword>Animals</keyword><keyword>Cadmium/metabolism/pharmacology/*toxicity</keyword><keyword>Carcinogens/*toxicity</keyword><keyword>Environmental Pollutants/*toxicity</keyword><keyword>Humans</keyword><keyword>Models, Biological</keyword><keyword>Neoplasms/*chemically induced</keyword><keyword>Occupational Exposure</keyword><keyword>Rats</keyword></keywords><dates><year>2003</year><pub-dates><date>Dec 10</date></pub-dates></dates><isbn>0027-5107 (Print)
0027-5107 (Linking)</isbn><accession-num>14643415</accession-num><urls><related-urls><url> An epidemiological study from Johns Hopkins University showed that chronic cadmium exposure was associated with liver disease.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IeWRlcjwvQXV0aG9yPjxZZWFyPjIwMTM8L1llYXI+PFJl
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ADDIN EN.CITE.DATA 2 This change in the focus of research is because cadmium also accumulates in the liver as well as the kidney and because of the unique position of the liver in the detoxification process of cadmium. This essay is a literature review intended to communicate to the public the inherit danger of cadmium pollution and the current research status regarding cadmium exposure relative to liver disease. Based on review of previous work, this essay points the way to future potential research regarding the association between cadmium exposure and liver disease. The expectation is that more public concern will be drawn to cadmium pollution and to the potential adverse health effects of cadmium, especially in liver disease. ENVIRONMENTAL BURDEN OF CADMIUM Cadmium Properties Cadmium (Cd) is a toxic heavy metal with atomic number 48. Cadmium, a soft, malleable, bluish white metal, chemically similar to the two other stable metals in group 12, zinc and mercury. ADDIN EN.CITE <EndNote><Cite><Author>Morrow</Author><Year>2010</Year><RecNum>366</RecNum><DisplayText><style face="superscript">7</style></DisplayText><record><rec-number>366</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1396038612">366</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Morrow, H</author></authors></contributors><titles><title> Cadmium and Cadmium Alloys</title><secondary-title>Kirk-Othmer Encyclopedia of Chemical Technology</secondary-title></titles><periodical><full-title>Kirk-Othmer Encyclopedia of Chemical Technology</full-title></periodical><pages><style face="normal" font="default" size="100%">1</style><style face="normal" font="default" charset="134" size="100%">-36</style></pages><dates><year>2010</year></dates><urls></urls></record></Cite></EndNote>7 It was discovered in 1817 simultaneously by the German scientists Stromeyer and Hermann, as an impurity in zinc carbonate. ADDIN EN.CITE <EndNote><Cite><Author>Morrow</Author><Year>2010</Year><RecNum>366</RecNum><DisplayText><style face="superscript">7</style></DisplayText><record><rec-number>366</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1396038612">366</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Morrow, H</author></authors></contributors><titles><title> Cadmium and Cadmium Alloys</title><secondary-title>Kirk-Othmer Encyclopedia of Chemical Technology</secondary-title></titles><periodical><full-title>Kirk-Othmer Encyclopedia of Chemical Technology</full-title></periodical><pages><style face="normal" font="default" size="100%">1</style><style face="normal" font="default" charset="134" size="100%">-36</style></pages><dates><year>2010</year></dates><urls></urls></record></Cite></EndNote>7 The average concentration of cadmium in the Earth's crust is between 0.1 and 0.5 parts per million (ppm). ADDIN EN.CITE <EndNote><Cite><Author>Wedepohl</Author><Year>1995 </Year><RecNum>367</RecNum><DisplayText><style face="superscript">8</style></DisplayText><record><rec-number>367</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1396039003">367</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Wedepohl, K. H. </author></authors></contributors><titles><title>The composition of the continental crust</title><secondary-title>Geochimica et Cosmochimica Acta</secondary-title></titles><periodical><full-title>Geochimica et Cosmochimica Acta</full-title></periodical><pages>1217-1232</pages><volume>59</volume><number>7</number><dates><year>1995 </year></dates><urls></urls></record></Cite></EndNote>8 Cadmium, which is toxic at very low exposure levels, is found widely in the environment and has acute and chronic effects on the environment and health. ADDIN EN.CITE <EndNote><Cite><Year>2003</Year><RecNum>30</RecNum><DisplayText><style face="superscript">1</style></DisplayText><record><rec-number>30</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1395951507">30</key></foreign-keys><ref-type name="Government Document">46</ref-type><contributors><secondary-authors><author>Nordic Council of MInisters</author></secondary-authors></contributors><titles><title>Cadmium Review</title></titles><number>4</number><dates><year>2003</year></dates><isbn>1</isbn><urls></urls><access-date>January 2003</access-date></record></Cite></EndNote>1 Compared to other metals, cadmium (as Cd2+) and cadmium compounds, are relatively water soluble, are more mobile in water and soil, more bioavailable and tend to accumulate in the environment. ADDIN EN.CITE <EndNote><Cite><Year>2003</Year><RecNum>30</RecNum><DisplayText><style face="superscript">1</style></DisplayText><record><rec-number>30</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1395951507">30</key></foreign-keys><ref-type name="Government Document">46</ref-type><contributors><secondary-authors><author>Nordic Council of MInisters</author></secondary-authors></contributors><titles><title>Cadmium Review</title></titles><number>4</number><dates><year>2003</year></dates><isbn>1</isbn><urls></urls><access-date>January 2003</access-date></record></Cite></EndNote>1Production and Consumption Cadmium’s early use as a pigment stems from the ability of its compounds to produce brilliant yellow, orange, and red colors. ADDIN EN.CITE <EndNote><Cite><Author>Rowbotham</Author><Year>1850</Year><RecNum>369</RecNum><DisplayText><style face="superscript">9</style></DisplayText><record><rec-number>369</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1396042898">369</key></foreign-keys><ref-type name="Book">6</ref-type><contributors><authors><author>Rowbotham, T.; Rowbotham, T. L. </author></authors></contributors><titles><title>The Art of Landscape Painting in Water Colours</title></titles><pages>10</pages><section>10</section><dates><year>1850</year></dates><publisher>Windsor and Newton</publisher><urls></urls></record></Cite></EndNote>9 Common industrial uses for cadmium today are in nickel-cadmium (Ni-Cd) rechargeable batteries, alloys, coatings (electroplating), solar cells, plastic stabilizers, and pigments. Cadmium is also used in nuclear reactors as a neutron absorber. ADDIN EN.CITE <EndNote><Cite><Author>OSHA</Author><RecNum>378</RecNum><DisplayText><style face="superscript">10, 11</style></DisplayText><record><rec-number>378</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1396061211">378</key></foreign-keys><ref-type name="Web Page">12</ref-type><contributors><authors><author>OSHA</author></authors></contributors><titles><title>Cadmium</title><secondary-title>Occupational Safety and Health Administration</secondary-title></titles><dates></dates><urls><related-urls><url> app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1396042074">368</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>USGS</author></authors></contributors><titles><title>Cadmium In: Minerals Yearbook</title><secondary-title>U.S. Geological Survey, Reston.</secondary-title></titles><periodical><full-title>U.S. Geological Survey, Reston.</full-title></periodical><dates><year>2012</year></dates><urls></urls></record></Cite></EndNote>10, 11 Lithium ion batteries have made significant gains in popularity for lightweight electronic devices, but new market opportunities for industrial productions of Ni-Cd batteries will continue to fuel cadmium use. ADDIN EN.CITE <EndNote><Cite><Author>USGS</Author><Year>2012</Year><RecNum>368</RecNum><DisplayText><style face="superscript">11</style></DisplayText><record><rec-number>368</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1396042074">368</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>USGS</author></authors></contributors><titles><title>Cadmium In: Minerals Yearbook</title><secondary-title>U.S. Geological Survey, Reston.</secondary-title></titles><periodical><full-title>U.S. Geological Survey, Reston.</full-title></periodical><dates><year>2012</year></dates><urls></urls></record></Cite></EndNote>11 Increased investment in solar power will also prompt cadmium use in the future. ADDIN EN.CITE <EndNote><Cite><Author>OSHA</Author><RecNum>378</RecNum><DisplayText><style face="superscript">10</style></DisplayText><record><rec-number>378</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1396061211">378</key></foreign-keys><ref-type name="Web Page">12</ref-type><contributors><authors><author>OSHA</author></authors></contributors><titles><title>Cadmium</title><secondary-title>Occupational Safety and Health Administration</secondary-title></titles><dates></dates><urls><related-urls><url> Global cadmium production, excluding U.S. production(data unavailable), was 21,100 ton in 2012, a slight increase from the amount produced in 2011. ADDIN EN.CITE <EndNote><Cite><Author>USGS</Author><Year>2012</Year><RecNum>368</RecNum><DisplayText><style face="superscript">11</style></DisplayText><record><rec-number>368</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1396042074">368</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>USGS</author></authors></contributors><titles><title>Cadmium In: Minerals Yearbook</title><secondary-title>U.S. Geological Survey, Reston.</secondary-title></titles><periodical><full-title>U.S. Geological Survey, Reston.</full-title></periodical><dates><year>2012</year></dates><urls></urls></record></Cite></EndNote>11 Most of the world’s re?ned cadmium (63%) was produced in Asia (Australia, China, India, Japan, North Korea, and the Republic of Korea), followed by 20% in Europe and Central Eurasia (Bulgaria, Germany, Kazakhstan, the Netherlands, Norway, Poland, and Russia), 13% in North America (Canada and Mexico), and 4% in South America (Argentina, Brazil, and Peru). ADDIN EN.CITE <EndNote><Cite><Author>USGS</Author><Year>2012</Year><RecNum>368</RecNum><DisplayText><style face="superscript">11</style></DisplayText><record><rec-number>368</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1396042074">368</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>USGS</author></authors></contributors><titles><title>Cadmium In: Minerals Yearbook</title><secondary-title>U.S. Geological Survey, Reston.</secondary-title></titles><periodical><full-title>U.S. Geological Survey, Reston.</full-title></periodical><dates><year>2012</year></dates><urls></urls></record></Cite></EndNote>11 According to the World Bureau of Metal Statistics ADDIN EN.CITE <EndNote><Cite><Year>2012,</Year><RecNum>371</RecNum><DisplayText><style face="superscript">12</style></DisplayText><record><rec-number>371</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1396045088">371</key></foreign-keys><ref-type name="Government Document">46</ref-type><contributors></contributors><titles><title>World metal statistics yearbook 2012:</title><secondary-title>World Bureau of Metal Statistics,</secondary-title></titles><periodical><full-title>World Bureau of Metal Statistics,</full-title></periodical><pages>72</pages><dates><year>2012,</year><pub-dates><date> May 1,</date></pub-dates></dates><urls></urls></record></Cite></EndNote>12, global consumption of primary cadmium was 16,200 ton in 2011 (latest data available). ADDIN EN.CITE <EndNote><Cite><Author>USGS</Author><Year>2012</Year><RecNum>368</RecNum><DisplayText><style face="superscript">11</style></DisplayText><record><rec-number>368</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1396042074">368</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>USGS</author></authors></contributors><titles><title>Cadmium In: Minerals Yearbook</title><secondary-title>U.S. Geological Survey, Reston.</secondary-title></titles><periodical><full-title>U.S. Geological Survey, Reston.</full-title></periodical><dates><year>2012</year></dates><urls></urls></record></Cite></EndNote>11 The majority of global cadmium consumption was Ni-Cd battery production. Other uses for cadmium included alloys, anticorrosive coatings, pigments, polyvinylchloride stabilizers, and semiconductors for solar cells. Approximately 86% of the cadmium consumed globally was used in Ni-Cd batteries, 9% in pigments, 4% in coatings, and 1% in various uses including alloys, solar cells, and stabilizers. ADDIN EN.CITE <EndNote><Cite><Author>USGS</Author><Year>2012</Year><RecNum>368</RecNum><DisplayText><style face="superscript">11, 13</style></DisplayText><record><rec-number>368</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1396042074">368</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>USGS</author></authors></contributors><titles><title>Cadmium In: Minerals Yearbook</title><secondary-title>U.S. Geological Survey, Reston.</secondary-title></titles><periodical><full-title>U.S. Geological Survey, Reston.</full-title></periodical><dates><year>2012</year></dates><urls></urls></record></Cite><Cite><Author>Morrow</Author><Year>2011</Year><RecNum>370</RecNum><record><rec-number>370</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1396044879">370</key></foreign-keys><ref-type name="Conference Proceedings">10</ref-type><contributors><authors><author>Morrow, H</author></authors></contributors><titles><title> Proceedings of the Eighth International Cadmium Conference </title><secondary-title><style face="normal" font="default" charset="134" size="100%">2011: Brussels, Belgium, International Cadmium Association</style></secondary-title></titles><pages>284</pages><dates><year>2011</year><pub-dates><date><style face="normal" font="default" size="100%">November 10</style><style face="normal" font="default" charset="134" size="100%">-13</style></date></pub-dates></dates><pub-location>Kunming, China</pub-location><urls></urls></record></Cite></EndNote>11, 13 Environmental Exposure and Effects Sources and Emissions Cadmium is released to the biosphere from both natural and anthropogenic sources. Natural sources The major natural sources for mobilizations of cadmium from the earth's crust are volcanoes and weathering of rocks. The volcanoes and weathering of rocks release cadmium to soils and aquatic systems. The major sources for emission to air from natural sources are volcanoes, airborne soil particles, sea spray, biogenic material and forest fires. The emissions of cadmium from natural sources plays a significant role in the global cadmium cycle, but only rarely results in adverse environmental effects. Anthropogenic sources Cadmium is produced mainly as a by-product from mining, smelting, and refining sulphide ores of zinc, and to a lesser degree, lead and copper. ADDIN EN.CITE <EndNote><Cite><Year>2003</Year><RecNum>30</RecNum><DisplayText><style face="superscript">1</style></DisplayText><record><rec-number>30</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1395951507">30</key></foreign-keys><ref-type name="Government Document">46</ref-type><contributors><secondary-authors><author>Nordic Council of MInisters</author></secondary-authors></contributors><titles><title>Cadmium Review</title></titles><number>4</number><dates><year>2003</year></dates><isbn>1</isbn><urls></urls><access-date>January 2003</access-date></record></Cite></EndNote>1 20,900 tons of cadmium was extracted from the earth's crust by mineral refining and brought into circulation in the biosphere in 2012. ADDIN EN.CITE <EndNote><Cite><Author>USGS</Author><Year>2012</Year><RecNum>368</RecNum><DisplayText><style face="superscript">11</style></DisplayText><record><rec-number>368</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1396042074">368</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>USGS</author></authors></contributors><titles><title>Cadmium In: Minerals Yearbook</title><secondary-title>U.S. Geological Survey, Reston.</secondary-title></titles><periodical><full-title>U.S. Geological Survey, Reston.</full-title></periodical><dates><year>2012</year></dates><urls></urls></record></Cite></EndNote>11 Beside this large quantity of cadmium that ended up in metal extraction residues, cadmium was mobilized as an impurity from extraction of other minerals like coal and lime. ADDIN EN.CITE <EndNote><Cite><Author>Morrow</Author><Year>2011</Year><RecNum>370</RecNum><DisplayText><style face="superscript">13</style></DisplayText><record><rec-number>370</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1396044879">370</key></foreign-keys><ref-type name="Conference Proceedings">10</ref-type><contributors><authors><author>Morrow, H</author></authors></contributors><titles><title> Proceedings of the Eighth International Cadmium Conference </title><secondary-title><style face="normal" font="default" charset="134" size="100%">2011: Brussels, Belgium, International Cadmium Association</style></secondary-title></titles><pages>284</pages><dates><year>2011</year><pub-dates><date><style face="normal" font="default" size="100%">November 10</style><style face="normal" font="default" charset="134" size="100%">-13</style></date></pub-dates></dates><pub-location>Kunming, China</pub-location><urls></urls></record></Cite></EndNote>13 Release of cadmium to waste and soil Cadmium is released to waste disposal by several sources, including cadmium processing, coal ash, sewage sludge, phosphate processing, iron and steel processing, cement production, and non-ferrous metals processing. ADDIN EN.CITE <EndNote><Cite><Author>Scoullos</Author><Year>2001</Year><RecNum>372</RecNum><DisplayText><style face="superscript">14</style></DisplayText><record><rec-number>372</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1396048470">372</key></foreign-keys><ref-type name="Book">6</ref-type><contributors><authors><author>Scoullos, M., G. Vonkeman,I. Thornton & Z. Makuch.</author></authors></contributors><titles><title>Mercury, cadmium, lead: Handbook for sustainable heavy metals policy and regulation</title></titles><dates><year>2001</year></dates><pub-location>Dordrecht</pub-location><publisher> Kluwer Academic Publishers</publisher><urls></urls></record></Cite></EndNote>14 A complete wash-out of cadmium may require hundreds to thousands of years and even more in some cases, although the mobility of cadmium inside landfills is low. The accumulation of cadmium in top agricultural soils is supported by risks assessments relating to cadmium in phosphate fertilizers. ADDIN EN.CITE <EndNote><Cite><Author>Hutton</Author><Year>2001</Year><RecNum>373</RecNum><DisplayText><style face="superscript">15</style></DisplayText><record><rec-number>373</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1396048847">373</key></foreign-keys><ref-type name="Conference Paper">47</ref-type><contributors><authors><author>Hutton, M., de Meeus, C. </author></authors></contributors><titles><title>Analysis and conclusions from Member States' Assessment of the Risk to Health and the Environment from Cadmium in Fertilisers</title><secondary-title>European Commision</secondary-title></titles><dates><year>2001</year></dates><pub-location>Enterprise DG.</pub-location><urls></urls></record></Cite></EndNote>15 Environmental Effects Cadmium is non-degradable and relatively water soluble, unlike other heavy metals that tend to stay in circulation and accumulate in the environment. Cadmium accumulates in many organisms, particularly in microorganisms and molluscs where the bioconcentration factors are on the order of thousands. ADDIN EN.CITE <EndNote><Cite><Year>2003</Year><RecNum>30</RecNum><DisplayText><style face="superscript">1</style></DisplayText><record><rec-number>30</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1395951507">30</key></foreign-keys><ref-type name="Government Document">46</ref-type><contributors><secondary-authors><author>Nordic Council of MInisters</author></secondary-authors></contributors><titles><title>Cadmium Review</title></titles><number>4</number><dates><year>2003</year></dates><isbn>1</isbn><urls></urls><access-date>January 2003</access-date></record></Cite></EndNote>1 In animals, cadmium concentrates in the internal organs rather than in muscle or fat. It is typically higher in kidney and liver than in muscle. Cadmium concentration in the body usually increases with age. ADDIN EN.CITE <EndNote><Cite><Author>WHO</Author><Year>1992</Year><RecNum>374</RecNum><DisplayText><style face="superscript">16, 17</style></DisplayText><record><rec-number>374</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1396050419">374</key></foreign-keys><ref-type name="Conference Paper">47</ref-type><contributors><authors><author>WHO </author></authors></contributors><titles><title>Cadmium. Environmental Health Criteria 134</title><secondary-title>World Health Organisation, International Programme on Chemical Safety (IPCS)</secondary-title></titles><dates><year>1992</year></dates><pub-location>Geneva, Switzerland</pub-location><urls></urls></record></Cite><Cite><Author>WHO</Author><Year>1992</Year><RecNum>375</RecNum><record><rec-number>375</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1396050527">375</key></foreign-keys><ref-type name="Conference Paper">47</ref-type><contributors><authors><author>WHO</author></authors></contributors><titles><title>Cadmium - environmental aspects. Environmental Health Criteria 135</title><secondary-title> World Health Organisation, International Programme on Chemical Safety (IPCS)</secondary-title></titles><dates><year>1992</year></dates><pub-location>Geneva, Switzerland</pub-location><urls></urls></record></Cite></EndNote>16, 17 Birds and mammals Certain marine vertebrates contain markedly high cadmium concentrations in the kidney that have been linked to markers of kidney damage in the organisms concerned. ADDIN EN.CITE <EndNote><Cite><Author>WHO</Author><Year>1992</Year><RecNum>375</RecNum><DisplayText><style face="superscript">17</style></DisplayText><record><rec-number>375</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1396050527">375</key></foreign-keys><ref-type name="Conference Paper">47</ref-type><contributors><authors><author>WHO</author></authors></contributors><titles><title>Cadmium - environmental aspects. Environmental Health Criteria 135</title><secondary-title> World Health Organisation, International Programme on Chemical Safety (IPCS)</secondary-title></titles><dates><year>1992</year></dates><pub-location>Geneva, Switzerland</pub-location><urls></urls></record></Cite></EndNote>17 Seabirds are known to easily accumulate high levels of cadmium. ADDIN EN.CITE <EndNote><Cite><Year>2003</Year><RecNum>30</RecNum><DisplayText><style face="superscript">1</style></DisplayText><record><rec-number>30</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1395951507">30</key></foreign-keys><ref-type name="Government Document">46</ref-type><contributors><secondary-authors><author>Nordic Council of MInisters</author></secondary-authors></contributors><titles><title>Cadmium Review</title></titles><number>4</number><dates><year>2003</year></dates><isbn>1</isbn><urls></urls><access-date>January 2003</access-date></record></Cite></EndNote>1 Kidney damages has been reported in wild colonies of pelagic sea birds having cadmium levels of 60-480 ?g/g in the kidney. ADDIN EN.CITE <EndNote><Cite><Author>WHO</Author><Year>1992</Year><RecNum>375</RecNum><DisplayText><style face="superscript">17</style></DisplayText><record><rec-number>375</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1396050527">375</key></foreign-keys><ref-type name="Conference Paper">47</ref-type><contributors><authors><author>WHO</author></authors></contributors><titles><title>Cadmium - environmental aspects. Environmental Health Criteria 135</title><secondary-title> World Health Organisation, International Programme on Chemical Safety (IPCS)</secondary-title></titles><dates><year>1992</year></dates><pub-location>Geneva, Switzerland</pub-location><urls></urls></record></Cite></EndNote>17 Kidney damage and lung emphysema are the primary effects of high cadmium in mammals and birds, which are similar to those in human. ADDIN EN.CITE <EndNote><Cite><Year>2003</Year><RecNum>30</RecNum><DisplayText><style face="superscript">1</style></DisplayText><record><rec-number>30</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1395951507">30</key></foreign-keys><ref-type name="Government Document">46</ref-type><contributors><secondary-authors><author>Nordic Council of MInisters</author></secondary-authors></contributors><titles><title>Cadmium Review</title></titles><number>4</number><dates><year>2003</year></dates><isbn>1</isbn><urls></urls><access-date>January 2003</access-date></record></Cite></EndNote>1 Mammals can tolerate low levels of chronic cadmium exposure by binding the metal to a special protein that renders its harmless. ADDIN EN.CITE <EndNote><Cite><Author>WHO</Author><Year>1992</Year><RecNum>374</RecNum><DisplayText><style face="superscript">16</style></DisplayText><record><rec-number>374</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1396050419">374</key></foreign-keys><ref-type name="Conference Paper">47</ref-type><contributors><authors><author>WHO </author></authors></contributors><titles><title>Cadmium. Environmental Health Criteria 134</title><secondary-title>World Health Organisation, International Programme on Chemical Safety (IPCS)</secondary-title></titles><dates><year>1992</year></dates><pub-location>Geneva, Switzerland</pub-location><urls></urls></record></Cite></EndNote>16 In this combined form, cadmium can accumulate in the kidney and liver, with the body needing decades to remove cadmium from the kidney and liver. ADDIN EN.CITE <EndNote><Cite><Author>WHO</Author><Year>1992</Year><RecNum>375</RecNum><DisplayText><style face="superscript">17</style></DisplayText><record><rec-number>375</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1396050527">375</key></foreign-keys><ref-type name="Conference Paper">47</ref-type><contributors><authors><author>WHO</author></authors></contributors><titles><title>Cadmium - environmental aspects. Environmental Health Criteria 135</title><secondary-title> World Health Organisation, International Programme on Chemical Safety (IPCS)</secondary-title></titles><dates><year>1992</year></dates><pub-location>Geneva, Switzerland</pub-location><urls></urls></record></Cite></EndNote>17Other organisms In aquatic systems, cadmium is most readily absorbed by organisms directly from the water in its free ionic form Cd2+. ADDIN EN.CITE <EndNote><Cite><Author>AMAP</Author><Year>1998</Year><RecNum>377</RecNum><DisplayText><style face="superscript">18</style></DisplayText><record><rec-number>377</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1396051428">377</key></foreign-keys><ref-type name="Conference Paper">47</ref-type><contributors><authors><author>AMAP</author></authors></contributors><titles><title>Assessment report: Arctic pollution issues</title><secondary-title>Arctic Monitoring and Assessment Programme</secondary-title></titles><dates><year>1998</year></dates><pub-location>Oslo</pub-location><urls></urls></record></Cite></EndNote>18 The acute toxicity of cadmium to aquatic organisms is related to the free ionic concentration of the metal and is variable, e.g. salmonoids being particularly susceptible to cadmium. ADDIN EN.CITE <EndNote><Cite><Author>WHO</Author><Year>1992</Year><RecNum>375</RecNum><DisplayText><style face="superscript">17</style></DisplayText><record><rec-number>375</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1396050527">375</key></foreign-keys><ref-type name="Conference Paper">47</ref-type><contributors><authors><author>WHO</author></authors></contributors><titles><title>Cadmium - environmental aspects. Environmental Health Criteria 135</title><secondary-title> World Health Organisation, International Programme on Chemical Safety (IPCS)</secondary-title></titles><dates><year>1992</year></dates><pub-location>Geneva, Switzerland</pub-location><urls></urls></record></Cite></EndNote>17 Effects of long-term exposure of cadmium may include larval mortality and temporary reduction in growth. ADDIN EN.CITE <EndNote><Cite><Author>AMAP</Author><Year>1998</Year><RecNum>377</RecNum><DisplayText><style face="superscript">18</style></DisplayText><record><rec-number>377</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1396051428">377</key></foreign-keys><ref-type name="Conference Paper">47</ref-type><contributors><authors><author>AMAP</author></authors></contributors><titles><title>Assessment report: Arctic pollution issues</title><secondary-title>Arctic Monitoring and Assessment Programme</secondary-title></titles><dates><year>1998</year></dates><pub-location>Oslo</pub-location><urls></urls></record></Cite></EndNote>18 Sub-lethal effects have been seen on the growth and reproduction of aquatic invertebrates and structural effects on invertebrate gills. ADDIN EN.CITE <EndNote><Cite><Author>WHO</Author><Year>1992</Year><RecNum>375</RecNum><DisplayText><style face="superscript">17</style></DisplayText><record><rec-number>375</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1396050527">375</key></foreign-keys><ref-type name="Conference Paper">47</ref-type><contributors><authors><author>WHO</author></authors></contributors><titles><title>Cadmium - environmental aspects. Environmental Health Criteria 135</title><secondary-title> World Health Organisation, International Programme on Chemical Safety (IPCS)</secondary-title></titles><dates><year>1992</year></dates><pub-location>Geneva, Switzerland</pub-location><urls></urls></record></Cite></EndNote>17 An effect on foraging behavior has been reported in lake trout exposed to different levels of cadmium, leading to lower success at catching prey. ADDIN EN.CITE <EndNote><Cite><Author>AMAP</Author><Year>1998</Year><RecNum>377</RecNum><DisplayText><style face="superscript">18</style></DisplayText><record><rec-number>377</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1396051428">377</key></foreign-keys><ref-type name="Conference Paper">47</ref-type><contributors><authors><author>AMAP</author></authors></contributors><titles><title>Assessment report: Arctic pollution issues</title><secondary-title>Arctic Monitoring and Assessment Programme</secondary-title></titles><dates><year>1998</year></dates><pub-location>Oslo</pub-location><urls></urls></record></Cite></EndNote>18 Terrestrial plants may accumulate cadmium in the roots, which is found bound to the cell walls. ADDIN EN.CITE <EndNote><Cite><Author>AMAP</Author><Year>1998</Year><RecNum>377</RecNum><DisplayText><style face="superscript">18</style></DisplayText><record><rec-number>377</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1396051428">377</key></foreign-keys><ref-type name="Conference Paper">47</ref-type><contributors><authors><author>AMAP</author></authors></contributors><titles><title>Assessment report: Arctic pollution issues</title><secondary-title>Arctic Monitoring and Assessment Programme</secondary-title></titles><dates><year>1998</year></dates><pub-location>Oslo</pub-location><urls></urls></record></Cite></EndNote>18 Litter leaf decomposition is largely inhibited by heavy metal pollution, and cadmium has been identified as the most potentially causative agent for this effect. ADDIN EN.CITE <EndNote><Cite><Author>AMAP</Author><Year>2002</Year><RecNum>376</RecNum><DisplayText><style face="superscript">19</style></DisplayText><record><rec-number>376</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1396051064">376</key></foreign-keys><ref-type name="Conference Paper">47</ref-type><contributors><authors><author>AMAP</author></authors></contributors><titles><title>Arctic Pollution 2002</title><secondary-title>Arctic Monitoring and Assessment Programme</secondary-title></titles><dates><year>2002</year></dates><pub-location>Oslo </pub-location><urls></urls></record></Cite></EndNote>19 The sub-lethal effect of terrestrial snails exposed to cadmium is on food consumption and dormancy, but only at very high dose levels. ADDIN EN.CITE <EndNote><Cite><Author>WHO</Author><Year>1992</Year><RecNum>375</RecNum><DisplayText><style face="superscript">17</style></DisplayText><record><rec-number>375</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1396050527">375</key></foreign-keys><ref-type name="Conference Paper">47</ref-type><contributors><authors><author>WHO</author></authors></contributors><titles><title>Cadmium - environmental aspects. Environmental Health Criteria 135</title><secondary-title> World Health Organisation, International Programme on Chemical Safety (IPCS)</secondary-title></titles><dates><year>1992</year></dates><pub-location>Geneva, Switzerland</pub-location><urls></urls></record></Cite></EndNote>17 Human Exposure General ExposureFor nonsmokers, food is the major route of exposure to cadmium among the non-occupational population; other pathways to total uptake are insignificant. Cadmium levels in some food can be increased by the application of phosphate fertilizers or sewage sludge to farm fields. ADDIN EN.CITE <EndNote><Cite><Author>ATSDR</Author><Year>1997</Year><RecNum>379</RecNum><DisplayText><style face="superscript">20</style></DisplayText><record><rec-number>379</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1396064654">379</key></foreign-keys><ref-type name="Conference Paper">47</ref-type><contributors><authors><author>ATSDR</author></authors><secondary-authors><author> </author></secondary-authors></contributors><titles><title>Toxicological Profile for Cadmium. Draft for Public Comment. Public Health Service, U.S.</title><secondary-title>Department of Health and Human Services</secondary-title></titles><dates><year>1997</year></dates><pub-location>Altanta, GA</pub-location><urls></urls></record></Cite></EndNote>20 Tobacco is an important source of cadmium exposure for smokers, who have about twice as much cadmium in their bodies as nonsmokers. ADDIN EN.CITE <EndNote><Cite><Author>ATSDR</Author><Year>1997</Year><RecNum>379</RecNum><DisplayText><style face="superscript">20</style></DisplayText><record><rec-number>379</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1396064654">379</key></foreign-keys><ref-type name="Conference Paper">47</ref-type><contributors><authors><author>ATSDR</author></authors><secondary-authors><author> </author></secondary-authors></contributors><titles><title>Toxicological Profile for Cadmium. Draft for Public Comment. Public Health Service, U.S.</title><secondary-title>Department of Health and Human Services</secondary-title></titles><dates><year>1997</year></dates><pub-location>Altanta, GA</pub-location><urls></urls></record></Cite></EndNote>20 Data from experimental animals and humans have shown that the inhalational absorption via lungs is higher than the gastrointestinal absorption via the stomach. ADDIN EN.CITE <EndNote><Cite><Author>WHO</Author><Year>1992</Year><RecNum>374</RecNum><DisplayText><style face="superscript">1, 16</style></DisplayText><record><rec-number>374</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1396050419">374</key></foreign-keys><ref-type name="Conference Paper">47</ref-type><contributors><authors><author>WHO </author></authors></contributors><titles><title>Cadmium. Environmental Health Criteria 134</title><secondary-title>World Health Organisation, International Programme on Chemical Safety (IPCS)</secondary-title></titles><dates><year>1992</year></dates><pub-location>Geneva, Switzerland</pub-location><urls></urls></record></Cite><Cite><Year>2003</Year><RecNum>30</RecNum><record><rec-number>30</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1395951507">30</key></foreign-keys><ref-type name="Government Document">46</ref-type><contributors><secondary-authors><author>Nordic Council of MInisters</author></secondary-authors></contributors><titles><title>Cadmium Review</title></titles><number>4</number><dates><year>2003</year></dates><isbn>1</isbn><urls></urls><access-date>January 2003</access-date></record></Cite></EndNote>1, 16 Up to 50% of the inhaled cadmium may be absorbed. Only 5% of the total ingested cadmium is absorbed, because the gastrointestinal absorption of cadmium may be influenced by the type of diet and nutritional status. ADDIN EN.CITE <EndNote><Cite><Author>WHO</Author><Year>1992</Year><RecNum>374</RecNum><DisplayText><style face="superscript">16</style></DisplayText><record><rec-number>374</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1396050419">374</key></foreign-keys><ref-type name="Conference Paper">47</ref-type><contributors><authors><author>WHO </author></authors></contributors><titles><title>Cadmium. Environmental Health Criteria 134</title><secondary-title>World Health Organisation, International Programme on Chemical Safety (IPCS)</secondary-title></titles><dates><year>1992</year></dates><pub-location>Geneva, Switzerland</pub-location><urls></urls></record></Cite></EndNote>16 A major exposure pathway of cadmium in the human diet comes from agricultural products, which are susceptible to increases in soil cadmium. ADDIN EN.CITE <EndNote><Cite><Year>2003</Year><RecNum>30</RecNum><DisplayText><style face="superscript">1</style></DisplayText><record><rec-number>30</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1395951507">30</key></foreign-keys><ref-type name="Government Document">46</ref-type><contributors><secondary-authors><author>Nordic Council of MInisters</author></secondary-authors></contributors><titles><title>Cadmium Review</title></titles><number>4</number><dates><year>2003</year></dates><isbn>1</isbn><urls></urls><access-date>January 2003</access-date></record></Cite></EndNote>1 The important sources of cadmium to agricultural soils are atmospheric deposition and direct additives, including the application of phosphate fertilizers and other soil amendment products. ADDIN EN.CITE <EndNote><Cite><Year>2003</Year><RecNum>30</RecNum><DisplayText><style face="superscript">1, 15</style></DisplayText><record><rec-number>30</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1395951507">30</key></foreign-keys><ref-type name="Government Document">46</ref-type><contributors><secondary-authors><author>Nordic Council of MInisters</author></secondary-authors></contributors><titles><title>Cadmium Review</title></titles><number>4</number><dates><year>2003</year></dates><isbn>1</isbn><urls></urls><access-date>January 2003</access-date></record></Cite><Cite><Author>Hutton</Author><Year>2001</Year><RecNum>373</RecNum><record><rec-number>373</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1396048847">373</key></foreign-keys><ref-type name="Conference Paper">47</ref-type><contributors><authors><author>Hutton, M., de Meeus, C. </author></authors></contributors><titles><title>Analysis and conclusions from Member States' Assessment of the Risk to Health and the Environment from Cadmium in Fertilisers</title><secondary-title>European Commision</secondary-title></titles><dates><year>2001</year></dates><pub-location>Enterprise DG.</pub-location><urls></urls></record></Cite></EndNote>1, 15 Average daily intakes of cadmium from food are 10-40?g in most non-polluted areas. ADDIN EN.CITE <EndNote><Cite><Author>WHO</Author><Year>1992</Year><RecNum>374</RecNum><DisplayText><style face="superscript">16</style></DisplayText><record><rec-number>374</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1396050419">374</key></foreign-keys><ref-type name="Conference Paper">47</ref-type><contributors><authors><author>WHO </author></authors></contributors><titles><title>Cadmium. Environmental Health Criteria 134</title><secondary-title>World Health Organisation, International Programme on Chemical Safety (IPCS)</secondary-title></titles><dates><year>1992</year></dates><pub-location>Geneva, Switzerland</pub-location><urls></urls></record></Cite></EndNote>16 In polluted areas the value has been found to be up to several hundred ?g per day. ADDIN EN.CITE <EndNote><Cite><Author>WHO</Author><Year>1992</Year><RecNum>374</RecNum><DisplayText><style face="superscript">16</style></DisplayText><record><rec-number>374</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1396050419">374</key></foreign-keys><ref-type name="Conference Paper">47</ref-type><contributors><authors><author>WHO </author></authors></contributors><titles><title>Cadmium. Environmental Health Criteria 134</title><secondary-title>World Health Organisation, International Programme on Chemical Safety (IPCS)</secondary-title></titles><dates><year>1992</year></dates><pub-location>Geneva, Switzerland</pub-location><urls></urls></record></Cite></EndNote>16 The World Health Organization (WHO) has established a provisional tolerable weekly intake (PTWI) of 7 ?g/kg body weight for cadmium. ADDIN EN.CITE <EndNote><Cite><Author>WHO</Author><Year>1992</Year><RecNum>374</RecNum><DisplayText><style face="superscript">16, 17</style></DisplayText><record><rec-number>374</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1396050419">374</key></foreign-keys><ref-type name="Conference Paper">47</ref-type><contributors><authors><author>WHO </author></authors></contributors><titles><title>Cadmium. Environmental Health Criteria 134</title><secondary-title>World Health Organisation, International Programme on Chemical Safety (IPCS)</secondary-title></titles><dates><year>1992</year></dates><pub-location>Geneva, Switzerland</pub-location><urls></urls></record></Cite><Cite><Author>WHO</Author><Year>1992</Year><RecNum>375</RecNum><record><rec-number>375</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1396050527">375</key></foreign-keys><ref-type name="Conference Paper">47</ref-type><contributors><authors><author>WHO</author></authors></contributors><titles><title>Cadmium - environmental aspects. Environmental Health Criteria 135</title><secondary-title> World Health Organisation, International Programme on Chemical Safety (IPCS)</secondary-title></titles><dates><year>1992</year></dates><pub-location>Geneva, Switzerland</pub-location><urls></urls></record></Cite></EndNote>16, 17 This PTWI value corresponds to a daily tolerable intake level of 70 ?g of cadmium for the average 70-kg man and 60 ?g of cadmium per day for the average 60-kg woman. ADDIN EN.CITE <EndNote><Cite><Author>WHO</Author><Year>1992</Year><RecNum>374</RecNum><DisplayText><style face="superscript">16, 17</style></DisplayText><record><rec-number>374</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1396050419">374</key></foreign-keys><ref-type name="Conference Paper">47</ref-type><contributors><authors><author>WHO </author></authors></contributors><titles><title>Cadmium. Environmental Health Criteria 134</title><secondary-title>World Health Organisation, International Programme on Chemical Safety (IPCS)</secondary-title></titles><dates><year>1992</year></dates><pub-location>Geneva, Switzerland</pub-location><urls></urls></record></Cite><Cite><Author>WHO</Author><Year>1992</Year><RecNum>375</RecNum><record><rec-number>375</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1396050527">375</key></foreign-keys><ref-type name="Conference Paper">47</ref-type><contributors><authors><author>WHO</author></authors></contributors><titles><title>Cadmium - environmental aspects. Environmental Health Criteria 135</title><secondary-title> World Health Organisation, International Programme on Chemical Safety (IPCS)</secondary-title></titles><dates><year>1992</year></dates><pub-location>Geneva, Switzerland</pub-location><urls></urls></record></Cite></EndNote>16, 17 The PTWI value may be considered lower than actuality in certain areas where the estimated intake of cadmium is 140-260 ?g/day. ADDIN EN.CITE <EndNote><Cite><Author>WHO</Author><Year>1992</Year><RecNum>374</RecNum><DisplayText><style face="superscript">16, 17</style></DisplayText><record><rec-number>374</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1396050419">374</key></foreign-keys><ref-type name="Conference Paper">47</ref-type><contributors><authors><author>WHO </author></authors></contributors><titles><title>Cadmium. Environmental Health Criteria 134</title><secondary-title>World Health Organisation, International Programme on Chemical Safety (IPCS)</secondary-title></titles><dates><year>1992</year></dates><pub-location>Geneva, Switzerland</pub-location><urls></urls></record></Cite><Cite><Author>WHO</Author><Year>1992</Year><RecNum>375</RecNum><record><rec-number>375</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1396050527">375</key></foreign-keys><ref-type name="Conference Paper">47</ref-type><contributors><authors><author>WHO</author></authors></contributors><titles><title>Cadmium - environmental aspects. Environmental Health Criteria 135</title><secondary-title> World Health Organisation, International Programme on Chemical Safety (IPCS)</secondary-title></titles><dates><year>1992</year></dates><pub-location>Geneva, Switzerland</pub-location><urls></urls></record></Cite></EndNote>16, 17 Occupational ExposureCadmium is an important metal for many types of commercial and industrial processes. The Occupational Safety and Health Administration (OSHA) estimates that 300,000 workers are exposed to cadmium in the United States. ADDIN EN.CITE <EndNote><Cite><Author>OSHA</Author><RecNum>378</RecNum><DisplayText><style face="superscript">10</style></DisplayText><record><rec-number>378</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1396061211">378</key></foreign-keys><ref-type name="Web Page">12</ref-type><contributors><authors><author>OSHA</author></authors></contributors><titles><title>Cadmium</title><secondary-title>Occupational Safety and Health Administration</secondary-title></titles><dates></dates><urls><related-urls><url> Cadmium enters human body of the occupational population through inhaling and incidentally ingesting dust or smoke which may contain cadmium. Occupational exposure of cadmium mostly occurs in manufacturing and construction including smelting and refining of metals, and manufacturing batteries, plastics, coatings, and solar panels. The expanding Ni-Cd battery recycling industry is a critical source for cadmium occupational exposure. ADDIN EN.CITE <EndNote><Cite><Author>OSHA</Author><RecNum>378</RecNum><DisplayText><style face="superscript">10, 13</style></DisplayText><record><rec-number>378</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1396061211">378</key></foreign-keys><ref-type name="Web Page">12</ref-type><contributors><authors><author>OSHA</author></authors></contributors><titles><title>Cadmium</title><secondary-title>Occupational Safety and Health Administration</secondary-title></titles><dates></dates><urls><related-urls><url> app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1396044879">370</key></foreign-keys><ref-type name="Conference Proceedings">10</ref-type><contributors><authors><author>Morrow, H</author></authors></contributors><titles><title> Proceedings of the Eighth International Cadmium Conference </title><secondary-title><style face="normal" font="default" charset="134" size="100%">2011: Brussels, Belgium, International Cadmium Association</style></secondary-title></titles><pages>284</pages><dates><year>2011</year><pub-dates><date><style face="normal" font="default" size="100%">November 10</style><style face="normal" font="default" charset="134" size="100%">-13</style></date></pub-dates></dates><pub-location>Kunming, China</pub-location><urls></urls></record></Cite></EndNote>10, 13 Other industrial operations associated with cadmium exposure are electroplating, metal machining, welding and painting. ADDIN EN.CITE <EndNote><Cite><Author>OSHA</Author><RecNum>378</RecNum><DisplayText><style face="superscript">10, 13</style></DisplayText><record><rec-number>378</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1396061211">378</key></foreign-keys><ref-type name="Web Page">12</ref-type><contributors><authors><author>OSHA</author></authors></contributors><titles><title>Cadmium</title><secondary-title>Occupational Safety and Health Administration</secondary-title></titles><dates></dates><urls><related-urls><url> app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1396044879">370</key></foreign-keys><ref-type name="Conference Proceedings">10</ref-type><contributors><authors><author>Morrow, H</author></authors></contributors><titles><title> Proceedings of the Eighth International Cadmium Conference </title><secondary-title><style face="normal" font="default" charset="134" size="100%">2011: Brussels, Belgium, International Cadmium Association</style></secondary-title></titles><pages>284</pages><dates><year>2011</year><pub-dates><date><style face="normal" font="default" size="100%">November 10</style><style face="normal" font="default" charset="134" size="100%">-13</style></date></pub-dates></dates><pub-location>Kunming, China</pub-location><urls></urls></record></Cite></EndNote>10, 13 Compost workers and waste collectors are potentially exposed to cadmium. Other potential exposure to cadmium includes landfill operations, the recycling of electronic parts, the recycling of plastics, and incineration of municipal waste. ADDIN EN.CITE <EndNote><Cite><Author>OSHA</Author><RecNum>378</RecNum><DisplayText><style face="superscript">10</style></DisplayText><record><rec-number>378</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1396061211">378</key></foreign-keys><ref-type name="Web Page">12</ref-type><contributors><authors><author>OSHA</author></authors></contributors><titles><title>Cadmium</title><secondary-title>Occupational Safety and Health Administration</secondary-title></titles><dates></dates><urls><related-urls><url> ADVERSE HEALTH EFFECTS OF CADMIUM EXPOSUREAdverse Health Effects (Noncancer) The adverse health effects of cadmium exposure include effects of acute exposure, effects of chronic exposure and carcinogenicity. Acute inhalational exposure of high level of cadmium may cause delayed bronchial irritation, pulmonary irritation, respiratory failure and even death. ADDIN EN.CITE <EndNote><Cite><Author>Bull</Author><Year>2010</Year><RecNum>382</RecNum><DisplayText><style face="superscript">21, 22</style></DisplayText><record><rec-number>382</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1396137330">382</key></foreign-keys><ref-type name="Conference Paper">47</ref-type><contributors><authors><author>S Bull</author></authors></contributors><titles><title>Cadmium Toxicology Overview</title><secondary-title>Chemical Hazards and Poisons Division, Health Protection Agency</secondary-title></titles><dates><year>2010</year></dates><urls></urls></record></Cite><Cite><Author>E.M.Kenyon</Author><Year>1991</Year><RecNum>383</RecNum><record><rec-number>383</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1396137668">383</key></foreign-keys><ref-type name="Conference Paper">47</ref-type><contributors><authors><author>E.J.Calabress and E.M.Kenyon</author></authors></contributors><titles><title>Air Toxics and Risk Assessment</title><secondary-title>Lewis Publisher</secondary-title></titles><dates><year>1991</year></dates><pub-location>Chelsea, MI</pub-location><urls></urls></record></Cite></EndNote>21, 22 A high level of acute inhalational cadmium exposure may result in long-lasting impairment of lung function.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BVFNEUjwvQXV0aG9yPjxZZWFyPjE5OTc8L1llYXI+PFJl
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ADDIN EN.CITE.DATA 10, 20-22 Acute ingestion exposure to low doses of cadmium may lead to vomiting, abdominal pain, diarrhea and gastrointestinal irritation. ADDIN EN.CITE <EndNote><Cite><Author>ATSDR</Author><Year>2008</Year><RecNum>384</RecNum><DisplayText><style face="superscript">23</style></DisplayText><record><rec-number>384</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1396138523">384</key></foreign-keys><ref-type name="Conference Paper">47</ref-type><contributors><authors><author>ATSDR</author></authors></contributors><titles><title>Toxicological Profile for Cadmium</title><secondary-title>Draft for public comment. U.S. Department of Health and Human Services</secondary-title></titles><dates><year>2008</year></dates><pub-location>Atlanta, U.S.</pub-location><urls></urls></record></Cite></EndNote>23 Acute ingestion exposure to high doses of cadmium may affect the liver, nervous system and cardiovascular system, and may lead to renal failure, liver failure and death. ADDIN EN.CITE <EndNote><Cite><Author>ATSDR</Author><Year>2008</Year><RecNum>384</RecNum><DisplayText><style face="superscript">16, 23</style></DisplayText><record><rec-number>384</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1396138523">384</key></foreign-keys><ref-type name="Conference Paper">47</ref-type><contributors><authors><author>ATSDR</author></authors></contributors><titles><title>Toxicological Profile for Cadmium</title><secondary-title>Draft for public comment. U.S. Department of Health and Human Services</secondary-title></titles><dates><year>2008</year></dates><pub-location>Atlanta, U.S.</pub-location><urls></urls></record></Cite><Cite><Author>WHO</Author><Year>1992</Year><RecNum>374</RecNum><record><rec-number>374</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1396050419">374</key></foreign-keys><ref-type name="Conference Paper">47</ref-type><contributors><authors><author>WHO </author></authors></contributors><titles><title>Cadmium. Environmental Health Criteria 134</title><secondary-title>World Health Organisation, International Programme on Chemical Safety (IPCS)</secondary-title></titles><dates><year>1992</year></dates><pub-location>Geneva, Switzerland</pub-location><urls></urls></record></Cite></EndNote>16, 23 Many studies relating to the adverse health effects of cadmium focus on the chronic exposure and carcinogenicity. The kidney is the crucial organ for cadmium exposure. ADDIN EN.CITE <EndNote><Cite><Author>ATSDR</Author><Year>1997</Year><RecNum>379</RecNum><DisplayText><style face="superscript">20</style></DisplayText><record><rec-number>379</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1396064654">379</key></foreign-keys><ref-type name="Conference Paper">47</ref-type><contributors><authors><author>ATSDR</author></authors><secondary-authors><author> </author></secondary-authors></contributors><titles><title>Toxicological Profile for Cadmium. Draft for Public Comment. Public Health Service, U.S.</title><secondary-title>Department of Health and Human Services</secondary-title></titles><dates><year>1997</year></dates><pub-location>Altanta, GA</pub-location><urls></urls></record></Cite></EndNote>20 According to current knowledge, kidney damage, including renal tubular dysfunction and renal failure, is the critical health effects of chronic cadmium exposure, both in the general and occupational population. ADDIN EN.CITE <EndNote><Cite><Year>2003</Year><RecNum>30</RecNum><DisplayText><style face="superscript">1, 16</style></DisplayText><record><rec-number>30</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1395951507">30</key></foreign-keys><ref-type name="Government Document">46</ref-type><contributors><secondary-authors><author>Nordic Council of MInisters</author></secondary-authors></contributors><titles><title>Cadmium Review</title></titles><number>4</number><dates><year>2003</year></dates><isbn>1</isbn><urls></urls><access-date>January 2003</access-date></record></Cite><Cite><Author>WHO</Author><Year>1992</Year><RecNum>374</RecNum><record><rec-number>374</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1396050419">374</key></foreign-keys><ref-type name="Conference Paper">47</ref-type><contributors><authors><author>WHO </author></authors></contributors><titles><title>Cadmium. 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ADDIN EN.CITE.DATA 2 For occupational chronic cadmium exposure, cadmium is absorbed by inhalation and may lead to respiratory system damage aside from kidney disease, including bronchiolitis, emphysema and other lung conditions even lung cancer. ADDIN EN.CITE <EndNote><Cite><Author>ATSDR</Author><Year>2008</Year><RecNum>384</RecNum><DisplayText><style face="superscript">21, 23</style></DisplayText><record><rec-number>384</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1396138523">384</key></foreign-keys><ref-type name="Conference Paper">47</ref-type><contributors><authors><author>ATSDR</author></authors></contributors><titles><title>Toxicological Profile for Cadmium</title><secondary-title>Draft for public comment. U.S. Department of Health and Human Services</secondary-title></titles><dates><year>2008</year></dates><pub-location>Atlanta, U.S.</pub-location><urls></urls></record></Cite><Cite><Author>Bull</Author><Year>2010</Year><RecNum>382</RecNum><record><rec-number>382</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1396137330">382</key></foreign-keys><ref-type name="Conference Paper">47</ref-type><contributors><authors><author>S Bull</author></authors></contributors><titles><title>Cadmium Toxicology Overview</title><secondary-title>Chemical Hazards and Poisons Division, Health Protection Agency</secondary-title></titles><dates><year>2010</year></dates><urls></urls></record></Cite></EndNote>21, 23 An increased mortality rate of obstructive lung disease has been reported among workers with chronic cadmium exposure. ADDIN EN.CITE <EndNote><Cite><Author>ATSDR</Author><Year>2008</Year><RecNum>384</RecNum><DisplayText><style face="superscript">16, 23</style></DisplayText><record><rec-number>384</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1396138523">384</key></foreign-keys><ref-type name="Conference Paper">47</ref-type><contributors><authors><author>ATSDR</author></authors></contributors><titles><title>Toxicological Profile for Cadmium</title><secondary-title>Draft for public comment. U.S. Department of Health and Human Services</secondary-title></titles><dates><year>2008</year></dates><pub-location>Atlanta, U.S.</pub-location><urls></urls></record></Cite><Cite><Author>WHO</Author><Year>1992</Year><RecNum>374</RecNum><record><rec-number>374</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1396050419">374</key></foreign-keys><ref-type name="Conference Paper">47</ref-type><contributors><authors><author>WHO </author></authors></contributors><titles><title>Cadmium. Environmental Health Criteria 134</title><secondary-title>World Health Organisation, International Programme on Chemical Safety (IPCS)</secondary-title></titles><dates><year>1992</year></dates><pub-location>Geneva, Switzerland</pub-location><urls></urls></record></Cite></EndNote>16, 23 Carcinogenicity The International Agency for Research on Cancer (IARC) classifies cadmium in Class 1“The agent (mixture) is carcinogenic to humans. The exposure circumstance entails exposures that are carcinogenic to humans.” ADDIN EN.CITE <EndNote><Cite><Author>IRAC</Author><Year>1993</Year><RecNum>355</RecNum><DisplayText><style face="superscript">4</style></DisplayText><record><rec-number>355</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1395963220">355</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>IRAC </author></authors></contributors><titles><title>Cadmium and Cadmium Compounds</title><secondary-title>International Agency for Research on Cancer Monographs Press, Lyon</secondary-title></titles><periodical><full-title>International Agency for Research on Cancer Monographs Press, Lyon</full-title></periodical><pages>119-238</pages><volume>58</volume><dates><year>1993</year></dates><urls></urls></record></Cite></EndNote>4 This classification as a human carcinogen was prompted primarily by repeated studies of an association between occupational cadmium exposure and lung cancer, as well as robust rodent experiments which also showed the pulmonary system as a target site. ADDIN EN.CITE <EndNote><Cite><Author>IRAC</Author><Year>1993</Year><RecNum>355</RecNum><DisplayText><style face="superscript">4, 24</style></DisplayText><record><rec-number>355</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1395963220">355</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>IRAC </author></authors></contributors><titles><title>Cadmium and Cadmium Compounds</title><secondary-title>International Agency for Research on Cancer Monographs Press, Lyon</secondary-title></titles><periodical><full-title>International Agency for Research on Cancer Monographs Press, Lyon</full-title></periodical><pages>119-238</pages><volume>58</volume><dates><year>1993</year></dates><urls></urls></record></Cite><Cite><Year>2011</Year><RecNum>386</RecNum><record><rec-number>386</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1396152165">386</key></foreign-keys><ref-type name="Conference Paper">47</ref-type><contributors></contributors><titles><title>Twelfth Report on Carcinogens</title><secondary-title>National Toxicology Program, U.S. Department of Health and Human Services</secondary-title></titles><dates><year>2011</year></dates><pub-location>Research Triangle Park, NC</pub-location><urls></urls></record></Cite></EndNote>4, 24 Studies have shown an increase in cancer mortality in populations exposed to low levels of cadmium for long periods of time. ADDIN EN.CITE <EndNote><Cite><Author>Scott V. Adams</Author><Year>2012</Year><RecNum>387</RecNum><DisplayText><style face="superscript">25</style></DisplayText><record><rec-number>387</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1396153622">387</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Scott V. Adams, Michael N.Passarelli, Polly A. Newcomb</author></authors></contributors><titles><title>Cadmium Exposure and Cancer Mortality in the Third National Health and Nutrition Examination Survey Cohort</title><secondary-title>Occup Environ Med.</secondary-title></titles><periodical><full-title>Occup Environ Med.</full-title></periodical><pages>153-156</pages><volume>69</volume><number>2</number><dates><year>2012</year></dates><urls></urls></record></Cite></EndNote>25 Cadmium exposure has been related to human prostate and renal cancer, but the linkage is weaker than the association between lung cancer and high-level occupational exposure. ADDIN EN.CITE <EndNote><Cite><Year>2011</Year><RecNum>386</RecNum><DisplayText><style face="superscript">24</style></DisplayText><record><rec-number>386</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1396152165">386</key></foreign-keys><ref-type name="Conference Paper">47</ref-type><contributors></contributors><titles><title>Twelfth Report on Carcinogens</title><secondary-title>National Toxicology Program, U.S. Department of Health and Human Services</secondary-title></titles><dates><year>2011</year></dates><pub-location>Research Triangle Park, NC</pub-location><urls></urls></record></Cite></EndNote>24 Other target sites of cadmium carcinogenesis in human, including liver and stomach, are considered equivocal. ADDIN EN.CITE <EndNote><Cite><Author>Waalkes</Author><Year>2003</Year><RecNum>357</RecNum><DisplayText><style face="superscript">6</style></DisplayText><record><rec-number>357</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1395964518">357</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Waalkes, M. P.</author></authors></contributors><auth-address>Inorganic Carcinogenesis Section, Laboratory of Comparative Carcinogenesis, National Cancer Institute at the National Institute of Environmental Health Sciences, Triangle Park, NC 27706, USA. waalkes@niehs.</auth-address><titles><title>Cadmium carcinogenesis</title><secondary-title>Mutat Res</secondary-title><alt-title>Mutation research</alt-title></titles><periodical><full-title>Mutat Res</full-title><abbr-1>Mutation research</abbr-1></periodical><alt-periodical><full-title>Mutat Res</full-title><abbr-1>Mutation research</abbr-1></alt-periodical><pages>107-20</pages><volume>533</volume><number>1-2</number><keywords><keyword>Animals</keyword><keyword>Cadmium/metabolism/pharmacology/*toxicity</keyword><keyword>Carcinogens/*toxicity</keyword><keyword>Environmental Pollutants/*toxicity</keyword><keyword>Humans</keyword><keyword>Models, Biological</keyword><keyword>Neoplasms/*chemically induced</keyword><keyword>Occupational Exposure</keyword><keyword>Rats</keyword></keywords><dates><year>2003</year><pub-dates><date>Dec 10</date></pub-dates></dates><isbn>0027-5107 (Print)
0027-5107 (Linking)</isbn><accession-num>14643415</accession-num><urls><related-urls><url> CADMIUM EXPOSURE AND LIVER DISEASEBurden of Liver disease In the United States, the burden of liver-related diseases is important. Over the last two decades, liver-related mortality ranked among the top 10 causes of death; it has been repeatedly listed as the fourth leading cause of death in the United States. ADDIN EN.CITE <EndNote><Cite><Author>Hoyert DL</Author><Year>2012</Year><RecNum>388</RecNum><DisplayText><style face="superscript">26</style></DisplayText><record><rec-number>388</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1396159549">388</key></foreign-keys><ref-type name="Conference Paper">47</ref-type><contributors><authors><author>Hoyert DL, Xu JQ.</author></authors></contributors><titles><title>Deaths: preliminary data for 2011. In: National Vital Statistics Reports.</title><secondary-title>National Center for Health Statistics</secondary-title></titles><volume>6</volume><num-vols>6</num-vols><dates><year>2012</year></dates><pub-location>Hyattsville, MD</pub-location><urls></urls></record></Cite></EndNote>26 During the same period, an increase in the number of people has been observed for end-stage liver disease requiring transplantation and hepatocellular carcinoma. ADDIN EN.CITE <EndNote><Cite><Author>Kim WR</Author><Year>2002</Year><RecNum>389</RecNum><DisplayText><style face="superscript">27</style></DisplayText><record><rec-number>389</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1396159954">389</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kim WR, Brown RS Jr., Terrault NA, et al.</author></authors></contributors><titles><title>Burden of liver disease in the United States: summary of a workshop. </title><secondary-title>Hepatology</secondary-title></titles><periodical><full-title>Hepatology</full-title></periodical><pages>227-242</pages><volume>36</volume><number>1</number><dates><year>2002</year></dates><urls></urls></record></Cite></EndNote>27 Nonalcoholic fatty liver disease (NAFLD) is thought to be the most common chronic liver disease in the Western world. ADDIN EN.CITE <EndNote><Cite><Author>Mariana Lazo</Author><Year>2013</Year><RecNum>390</RecNum><DisplayText><style face="superscript">28</style></DisplayText><record><rec-number>390</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1396160358">390</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Mariana Lazo, Ruben Hernaez, Mark S. Eberhardt, Susanne Bonekamp, Ihab Kamel, Eliseo Guallar, Ayman Koteish, Frederick L. Brancati, Jeanne M. Clark</author></authors></contributors><titles><title>Prevalence of Nonalcoholic Fatty Liver Disease in the United States</title><secondary-title>American Journal of Epidemiology</secondary-title></titles><periodical><full-title>American Journal of Epidemiology</full-title></periodical><pages>38-45</pages><volume>178</volume><number>1</number><dates><year>2013</year></dates><urls></urls></record></Cite></EndNote>28 The Third National Health and Nutrition Examination Survey (NHANES III) showed that the prevalence of NAFLD was 20% and the prevalence of nonalcoholic steatohepatitis (NASH) was 2% in the general US population. ADDIN EN.CITE <EndNote><Cite><Author>Kim WR</Author><Year>2002</Year><RecNum>389</RecNum><DisplayText><style face="superscript">27</style></DisplayText><record><rec-number>389</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1396159954">389</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kim WR, Brown RS Jr., Terrault NA, et al.</author></authors></contributors><titles><title>Burden of liver disease in the United States: summary of a workshop. </title><secondary-title>Hepatology</secondary-title></titles><periodical><full-title>Hepatology</full-title></periodical><pages>227-242</pages><volume>36</volume><number>1</number><dates><year>2002</year></dates><urls></urls></record></Cite></EndNote>27 In the United states, liver related disease deaths is up to 2% of all deaths. ADDIN EN.CITE <EndNote><Cite><Author>Kim WR</Author><Year>2002</Year><RecNum>389</RecNum><DisplayText><style face="superscript">27</style></DisplayText><record><rec-number>389</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1396159954">389</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kim WR, Brown RS Jr., Terrault NA, et al.</author></authors></contributors><titles><title>Burden of liver disease in the United States: summary of a workshop. </title><secondary-title>Hepatology</secondary-title></titles><periodical><full-title>Hepatology</full-title></periodical><pages>227-242</pages><volume>36</volume><number>1</number><dates><year>2002</year></dates><urls></urls></record></Cite></EndNote>27 The economic burden linked with liver disease is approximately 1% of the total national health care expenditure devoted to the care of patients. ADDIN EN.CITE <EndNote><Cite><Author>Kim WR</Author><Year>2002</Year><RecNum>389</RecNum><DisplayText><style face="superscript">27</style></DisplayText><record><rec-number>389</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1396159954">389</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kim WR, Brown RS Jr., Terrault NA, et al.</author></authors></contributors><titles><title>Burden of liver disease in the United States: summary of a workshop. </title><secondary-title>Hepatology</secondary-title></titles><periodical><full-title>Hepatology</full-title></periodical><pages>227-242</pages><volume>36</volume><number>1</number><dates><year>2002</year></dates><urls></urls></record></Cite></EndNote>27 Moreover, the burden of liver disease appears to be increasing, due in part to the increasing prevalence of nonalcoholic fatty liver disease, hepatitis C viral hepatitis, and hepatocellular carcinoma. ADDIN EN.CITE <EndNote><Cite><Author>Kim WR</Author><Year>2002</Year><RecNum>389</RecNum><DisplayText><style face="superscript">27</style></DisplayText><record><rec-number>389</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1396159954">389</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kim WR, Brown RS Jr., Terrault NA, et al.</author></authors></contributors><titles><title>Burden of liver disease in the United States: summary of a workshop. </title><secondary-title>Hepatology</secondary-title></titles><periodical><full-title>Hepatology</full-title></periodical><pages>227-242</pages><volume>36</volume><number>1</number><dates><year>2002</year></dates><urls></urls></record></Cite></EndNote>27 Many liver diseases with relatively low frequency have substantial impact on longevity, like fulminant hepatic failure and pediatric liver diseases, or impact on the quality of life like primary sclerosing cholangitis. ADDIN EN.CITE <EndNote><Cite><Author>Kim WR</Author><Year>2002</Year><RecNum>389</RecNum><DisplayText><style face="superscript">27</style></DisplayText><record><rec-number>389</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1396159954">389</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kim WR, Brown RS Jr., Terrault NA, et al.</author></authors></contributors><titles><title>Burden of liver disease in the United States: summary of a workshop. </title><secondary-title>Hepatology</secondary-title></titles><periodical><full-title>Hepatology</full-title></periodical><pages>227-242</pages><volume>36</volume><number>1</number><dates><year>2002</year></dates><urls></urls></record></Cite></EndNote>27Hepatotoxicity of Cadmium The liver is an abdominal organ which plays a crucial role in detoxification and excretion of many endogenous and exogenous substances, and its detoxification systems are easily overloaded. ADDIN EN.CITE <EndNote><Cite><Author>Elias Adikwu</Author><Year>2013</Year><RecNum>395</RecNum><DisplayText><style face="superscript">29</style></DisplayText><record><rec-number>395</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1396211418">395</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Elias Adikwu, Oputiri Deo, Oru-Bo Precious Geoffrey</author></authors></contributors><titles><title>Hepatotoxicity of Cadmium and Roles of Mitigating Agents</title><secondary-title>British Journal of Pharmacology and Toxicology</secondary-title></titles><periodical><full-title>British Journal of Pharmacology and Toxicology</full-title></periodical><pages>222-231</pages><volume>4</volume><number>6</number><dates><year>2013</year></dates><urls></urls></record></Cite></EndNote>29 The liver is a natural chemical factory which aids in anabolism of complex molecules from simple substances absorbed from the gastrointestinal tract (GIT). ADDIN EN.CITE <EndNote><Cite><Author>Buraimoh</Author><Year>2011</Year><RecNum>381</RecNum><DisplayText><style face="superscript">30</style></DisplayText><record><rec-number>381</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1396133055">381</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Buraimoh, A.A., I.G. Bako and F.B. Ibrahim </author></authors></contributors><titles><title>Hepatoprotective effect of ethanolic leaves extract of Moringa Oleifera on the histology of paracetamol induced liver damage in wistar rats</title><secondary-title>Int. J. Anim. Vet. Adv.</secondary-title></titles><periodical><full-title>Int. J. Anim. Vet. Adv.</full-title></periodical><pages>10-13</pages><volume>3</volume><number>1</number><dates><year>2011</year></dates><urls></urls></record></Cite></EndNote>30 Hepatic dysfunction may result from continuous cadmium exposure like other toxicant exposures in rats. ADDIN EN.CITE <EndNote><Cite><Author>Nithya</Author><Year>2012</Year><RecNum>435</RecNum><DisplayText><style face="superscript">31</style></DisplayText><record><rec-number>435</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1396241544">435</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Nithya, N., K. Chandrakumar, V. Ganevan and S. Senthilkumar</author></authors></contributors><titles><title>Efficacy of Momordica charantia in attenuating abnormalities in cyclophosphomide intoxicated rats</title><secondary-title>J. Pharmacol. Toxicol</secondary-title></titles><periodical><full-title>J. Pharmacol. Toxicol</full-title></periodical><pages>38-45</pages><volume>7</volume><number>1</number><dates><year>2012</year></dates><urls></urls></record></Cite></EndNote>31 The outcome of cadmium exposure on the liver are hepatic cell changes, such as hepatocyte swelling, fatty changes, focal necrosis, hepatocyte degeneration and irregularities in biomarkers of liver function. ADDIN EN.CITE <EndNote><Cite><Author>Elias Adikwu</Author><Year>2013</Year><RecNum>395</RecNum><DisplayText><style face="superscript">29</style></DisplayText><record><rec-number>395</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1396211418">395</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Elias Adikwu, Oputiri Deo, Oru-Bo Precious Geoffrey</author></authors></contributors><titles><title>Hepatotoxicity of Cadmium and Roles of Mitigating Agents</title><secondary-title>British Journal of Pharmacology and Toxicology</secondary-title></titles><periodical><full-title>British Journal of Pharmacology and Toxicology</full-title></periodical><pages>222-231</pages><volume>4</volume><number>6</number><dates><year>2013</year></dates><urls></urls></record></Cite></EndNote>29 Mechanisms of Cadmium Hepatotoxicity Several mechanisms have been suggested to potentially induce cadmium-associated hepatotoxicity. One of the potential mechanisms of cadmium induced liver toxicity is mediated by the up-regulation of reactive oxygen species (ROS), including hydroxyl groups, superoxide and hydrogen peroxides, which cause oxidative damage to lipid membranes. ADDIN EN.CITE <EndNote><Cite><Author>Elias Adikwu</Author><Year>2013</Year><RecNum>395</RecNum><DisplayText><style face="superscript">29</style></DisplayText><record><rec-number>395</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1396211418">395</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Elias Adikwu, Oputiri Deo, Oru-Bo Precious Geoffrey</author></authors></contributors><titles><title>Hepatotoxicity of Cadmium and Roles of Mitigating Agents</title><secondary-title>British Journal of Pharmacology and Toxicology</secondary-title></titles><periodical><full-title>British Journal of Pharmacology and Toxicology</full-title></periodical><pages>222-231</pages><volume>4</volume><number>6</number><dates><year>2013</year></dates><urls></urls></record></Cite></EndNote>29 The oxidative stress is normally induced by over-production of ROS, unless ROS is scavenged with endogenous antioxidants. ADDIN EN.CITE <EndNote><Cite><Author>Elias Adikwu</Author><Year>2013</Year><RecNum>395</RecNum><DisplayText><style face="superscript">29</style></DisplayText><record><rec-number>395</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1396211418">395</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Elias Adikwu, Oputiri Deo, Oru-Bo Precious Geoffrey</author></authors></contributors><titles><title>Hepatotoxicity of Cadmium and Roles of Mitigating Agents</title><secondary-title>British Journal of Pharmacology and Toxicology</secondary-title></titles><periodical><full-title>British Journal of Pharmacology and Toxicology</full-title></periodical><pages>222-231</pages><volume>4</volume><number>6</number><dates><year>2013</year></dates><urls></urls></record></Cite></EndNote>29 Thus, overproduction of ROS has been identified as an important factor of cadmium-induced hepatotoxicity, because ROS might deplete antioxidants or directly act with cadmium on peroxidation reactions and iron-mediated peroxidation. ADDIN EN.CITE <EndNote><Cite><Author>Elias Adikwu</Author><Year>2013</Year><RecNum>395</RecNum><DisplayText><style face="superscript">29</style></DisplayText><record><rec-number>395</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1396211418">395</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Elias Adikwu, Oputiri Deo, Oru-Bo Precious Geoffrey</author></authors></contributors><titles><title>Hepatotoxicity of Cadmium and Roles of Mitigating Agents</title><secondary-title>British Journal of Pharmacology and Toxicology</secondary-title></titles><periodical><full-title>British Journal of Pharmacology and Toxicology</full-title></periodical><pages>222-231</pages><volume>4</volume><number>6</number><dates><year>2013</year></dates><urls></urls></record></Cite></EndNote>29 Another possible mechanism of toxicity of cadmium toward the liver is primary injury of cells resulting from binding of cadmium to sulfhydryl groups in mitochondria and secondary injury initiated by the activation of Kupffer cells. ADDIN EN.CITE <EndNote><Cite><Author>Elias Adikwu</Author><Year>2013</Year><RecNum>395</RecNum><DisplayText><style face="superscript">29</style></DisplayText><record><rec-number>395</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1396211418">395</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Elias Adikwu, Oputiri Deo, Oru-Bo Precious Geoffrey</author></authors></contributors><titles><title>Hepatotoxicity of Cadmium and Roles of Mitigating Agents</title><secondary-title>British Journal of Pharmacology and Toxicology</secondary-title></titles><periodical><full-title>British Journal of Pharmacology and Toxicology</full-title></periodical><pages>222-231</pages><volume>4</volume><number>6</number><dates><year>2013</year></dates><urls></urls></record></Cite></EndNote>29 Oxidative stress will be initiated by inactivation of sulfhydryl groups, which could also cause a mitochondrial permeability transition and mitochondrial dysfunction. ADDIN EN.CITE <EndNote><Cite><Author>Elias Adikwu</Author><Year>2013</Year><RecNum>395</RecNum><DisplayText><style face="superscript">29</style></DisplayText><record><rec-number>395</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1396211418">395</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Elias Adikwu, Oputiri Deo, Oru-Bo Precious Geoffrey</author></authors></contributors><titles><title>Hepatotoxicity of Cadmium and Roles of Mitigating Agents</title><secondary-title>British Journal of Pharmacology and Toxicology</secondary-title></titles><periodical><full-title>British Journal of Pharmacology and Toxicology</full-title></periodical><pages>222-231</pages><volume>4</volume><number>6</number><dates><year>2013</year></dates><urls></urls></record></Cite></EndNote>29 Kupffer cells may release pro-inflammatory cytokines and chemokines which stimulate the migration and accumulation of neutrophils and monocytes in the liver. ADDIN EN.CITE <EndNote><Cite><Author>Elias Adikwu</Author><Year>2013</Year><RecNum>395</RecNum><DisplayText><style face="superscript">29</style></DisplayText><record><rec-number>395</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1396211418">395</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Elias Adikwu, Oputiri Deo, Oru-Bo Precious Geoffrey</author></authors></contributors><titles><title>Hepatotoxicity of Cadmium and Roles of Mitigating Agents</title><secondary-title>British Journal of Pharmacology and Toxicology</secondary-title></titles><periodical><full-title>British Journal of Pharmacology and Toxicology</full-title></periodical><pages>222-231</pages><volume>4</volume><number>6</number><dates><year>2013</year></dates><urls></urls></record></Cite></EndNote>29 Apoptosis plays a predominant role on cadmium-associated hepatotoxicity in in vitro studies of rat, mouse and human hepatocytes.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BcnJveW88L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFyPjxS
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ADDIN EN.CITE.DATA 32, 33 Cadmium, in isolated mitochondria from mouse liver, could directly lead to the dysfunction of mitochondria. Endonuclease G (Endo G), the mitochondria derived protein, has been identified as potential caspase-independent apoptotic mediator in human hepatoma cell line Hep3B.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MZW1hcmllPC9BdXRob3I+PFllYXI+MjAwNDwvWWVhcj48
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ADDIN EN.CITE.DATA 34 The mechanism involves the alteration of mitochondrial homeostasis and the subsequent release of Endo G and AIF.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MZW1hcmllPC9BdXRob3I+PFllYXI+MjAwNDwvWWVhcj48
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ADDIN EN.CITE.DATA 35As mentioned above, cadmium induces hepatocellular damage via imbalance of the cellular redox status, which leads to oxidative stress. Over-production of ROS can deplete antioxidants, which benefits in the detoxification process of cadmium. Although there are other mechanisms of hepatic toxicity with cadmium, over-production of ROS is the major reason linked to cadmium hepatotoxicity from in vitro studies. Calcium mediated apoptosis, which is also initiated by ROS, is another possible pathway to explain cadmium hepatotoxicity from human hepatic cell studies.Animal Studies of Cadmium-induced Liver Disease The major features of liver injuries in mice induced by repeated cadmium exposure are nonspecific chronic inflammation, granulomatous inflammation, apoptosis, liver cell regeneration, and pre-neoplastic proliferating nodules.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IYWJlZWJ1PC9BdXRob3I+PFllYXI+MjAwMDwvWWVhcj48
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ADDIN EN.CITE.DATA 36 A mouse study reported that repeated cadmium exposure might have a carcinogenic potential in mouse liver and that intracellular metallothionein (MT) is an important protein that may protect against cadmium-induced liver injury.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IYWJlZWJ1PC9BdXRob3I+PFllYXI+MjAwMDwvWWVhcj48
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ADDIN EN.CITE.DATA 36 This study also suggested that repeated cadmium exposure induced nonspecific chronic inflammation, apoptosis and liver cell regeneration in a null-MT mouse model.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IYWJlZWJ1PC9BdXRob3I+PFllYXI+MjAwMDwvWWVhcj48
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ADDIN EN.CITE.DATA 36 Animal studies deemed questionable relevance to humans due to the anatomical differences between humans and animals.There are some studies suggesting that chronic cadmium exposure may cause liver cancer in animals, but the amount of such research is small. Waalkes’s study revealed that cadmium-treated mice had a higher rate of hepatocellular adenomas and carcinomas than the control group, when experimental mice were exposed to repeated high doses of cadmium.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XYWFsa2VzPC9BdXRob3I+PFllYXI+MTk5NDwvWWVhcj48
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ADDIN EN.CITE.DATA 37 This effect only occurs with the high dose of cadmium exposure, which is improbable for humans who do not expose to such high doses. Moreover, another study from Waalkes reported that cadmium had preventive effects on NDEA-induced liver tumors. ADDIN EN.CITE <EndNote><Cite><Author>M.P. Waalkes</Author><Year>1993</Year><RecNum>437</RecNum><DisplayText><style face="superscript">38</style></DisplayText><record><rec-number>437</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1396249882">437</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>M.P. Waalkes, B.A. Diwan, C.M. Weghorst, J.M. Ward, J.M. Rice, M.G. Cherian, R.A. Goyer</author></authors></contributors><titles><title>Further evidence of tumor suppressive effects of cadmium in the B6C3F1 mouse liver and lung: late stage vulnerability of tumors to cadmium and the role of metallothionein</title><secondary-title> J. Pharmacol. Exp. Therap.</secondary-title></titles><pages>1656-1663</pages><volume>266</volume><dates><year>1993</year></dates><urls></urls></record></Cite></EndNote>38 However, another study reported that cadmium could prevent liver tumors induced by N-nitrosodiethylamine (NDEA) and sodium barbital. The incidence of NDEA-induced liver tumors in the cadmium treated group was lower than in controls, regardless of the period of administration. ADDIN EN.CITE <EndNote><Cite><Author>M.P. Waalkes</Author><Year>1993</Year><RecNum>437</RecNum><DisplayText><style face="superscript">38</style></DisplayText><record><rec-number>437</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1396249882">437</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>M.P. Waalkes, B.A. Diwan, C.M. Weghorst, J.M. Ward, J.M. Rice, M.G. Cherian, R.A. Goyer</author></authors></contributors><titles><title>Further evidence of tumor suppressive effects of cadmium in the B6C3F1 mouse liver and lung: late stage vulnerability of tumors to cadmium and the role of metallothionein</title><secondary-title> J. Pharmacol. Exp. Therap.</secondary-title></titles><pages>1656-1663</pages><volume>266</volume><dates><year>1993</year></dates><urls></urls></record></Cite></EndNote>38 Thus, it is difficult to draw a conclusion regarding liver cancer associated with cadmium exposure based on above two animal studies.Epidemiological Studies of Cadmium-dependent Liver-related Disease Liver diseaseLast year, Hyder and his colleagues analyzed data about 12,732 participants from the Third National Health and Nutrition Examination Survey (NHANES III), which included interviews, physical examinations, blood and urine tests and ultrasound scans.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IeWRlcjwvQXV0aG9yPjxZZWFyPjIwMTM8L1llYXI+PFJl
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ADDIN EN.CITE.DATA 2 The levels of cadmium in urine samples, as well as records of ultrasound results were used to diagnose various liver diseases. This study found that chronic cadmium exposure was associated with hepatic necroinflammation and increased risk of liver disease mortality.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IeWRlcjwvQXV0aG9yPjxZZWFyPjIwMTM8L1llYXI+PFJl
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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IeWRlcjwvQXV0aG9yPjxZZWFyPjIwMTM8L1llYXI+PFJl
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ADDIN EN.CITE.DATA 2 In this study, cadmium levels in the urine were separated into four quartiles, and those in the highest quartile were approximately 3.5 times as likely to die of liver-related diseases than those in the lower three quartiles.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IeWRlcjwvQXV0aG9yPjxZZWFyPjIwMTM8L1llYXI+PFJl
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ADDIN EN.CITE.DATA 2 Information from NHANES III might increase the reliability of this study, because this survey is the only nationwide cohort involving liver damage, hepatic enzymes as well as cadmium exposure. However, limitation existed in this study due to some information in this survey was self-reported. This study did not show that cadmium directly causes liver disease, but did suggest an association which needs more investigation to develop a cause-and-effect relationship.There was only one published epidemiological study reported that primary liver cancer was associated with mean daily intake of cadmium from food of plant origin in a cross-sectional ecological survey in China. ADDIN EN.CITE <EndNote><Cite><Author>T. Colin Campbell</Author><Year>1990</Year><RecNum>438</RecNum><DisplayText><style face="superscript">39</style></DisplayText><record><rec-number>438</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1396342905">438</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>T. Colin Campbell, Junshi Chen, Chongbo Liu, Junyao Li, and Banoo Parpia</author></authors></contributors><titles><title>Nonassociation of Aflatoxin with Primary Liver Cancer in a Cross-Sectional Ecological Survey in the People's Republic of China1</title><secondary-title>CANCER RESEARCH</secondary-title></titles><periodical><full-title>Cancer Res</full-title><abbr-1>Cancer research</abbr-1></periodical><pages>6882-6893</pages><volume>50</volume><dates><year>1990</year></dates><urls></urls></record></Cite></EndNote>39 Cadmium intake was estimated by analyzing the county-based composites of plant origin food selected in each survey county, not from the experimental measurement. ADDIN EN.CITE <EndNote><Cite><Author>T. Colin Campbell</Author><Year>1990</Year><RecNum>438</RecNum><DisplayText><style face="superscript">39</style></DisplayText><record><rec-number>438</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1396342905">438</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>T. Colin Campbell, Junshi Chen, Chongbo Liu, Junyao Li, and Banoo Parpia</author></authors></contributors><titles><title>Nonassociation of Aflatoxin with Primary Liver Cancer in a Cross-Sectional Ecological Survey in the People's Republic of China1</title><secondary-title>CANCER RESEARCH</secondary-title></titles><periodical><full-title>Cancer Res</full-title><abbr-1>Cancer research</abbr-1></periodical><pages>6882-6893</pages><volume>50</volume><dates><year>1990</year></dates><urls></urls></record></Cite></EndNote>39 This study also detected the link with primary liver cancer and several heavy metals, such as arsenic, lead, mercury and cadmium, but only intake for cadmium showed a significant association with primary liver cancer mortality. ADDIN EN.CITE <EndNote><Cite><Author>T. Colin Campbell</Author><Year>1990</Year><RecNum>438</RecNum><DisplayText><style face="superscript">39</style></DisplayText><record><rec-number>438</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1396342905">438</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>T. Colin Campbell, Junshi Chen, Chongbo Liu, Junyao Li, and Banoo Parpia</author></authors></contributors><titles><title>Nonassociation of Aflatoxin with Primary Liver Cancer in a Cross-Sectional Ecological Survey in the People's Republic of China1</title><secondary-title>CANCER RESEARCH</secondary-title></titles><periodical><full-title>Cancer Res</full-title><abbr-1>Cancer research</abbr-1></periodical><pages>6882-6893</pages><volume>50</volume><dates><year>1990</year></dates><urls></urls></record></Cite></EndNote>39 There were three significant risk factors for primary liver cancer mortality, including plasma cholesterol, hepatitis B virus surface antigen (HBsAg+) prevalence and cadmium intakes. ADDIN EN.CITE <EndNote><Cite><Author>T. Colin Campbell</Author><Year>1990</Year><RecNum>438</RecNum><DisplayText><style face="superscript">39</style></DisplayText><record><rec-number>438</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1396342905">438</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>T. Colin Campbell, Junshi Chen, Chongbo Liu, Junyao Li, and Banoo Parpia</author></authors></contributors><titles><title>Nonassociation of Aflatoxin with Primary Liver Cancer in a Cross-Sectional Ecological Survey in the People's Republic of China1</title><secondary-title>CANCER RESEARCH</secondary-title></titles><periodical><full-title>Cancer Res</full-title><abbr-1>Cancer research</abbr-1></periodical><pages>6882-6893</pages><volume>50</volume><dates><year>1990</year></dates><urls></urls></record></Cite></EndNote>39 No information about occupational cadmium exposure of subjects was reported. The result of this study do not definitely established the relationship between cadmium exposure and liver cancer.Potential Mitigating AgentsThere are increasing research on the potential mitigating agents which ameliorate with the hepatotoxicity induced by cadmium exposure. Administration of vitamin C and/or vitamin E have been reported to inhibit cadmium induced hepatotoxicity. Co-administration of vitamin C and E produced synergistic protection against cadmium induced hepatotoxicity compared to individual agents. ADDIN EN.CITE <EndNote><Cite><Author>Layachi</Author><Year>2012</Year><RecNum>403</RecNum><DisplayText><style face="superscript">40</style></DisplayText><record><rec-number>403</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1396219339">403</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Layachi, N. and Z. Kechrid</author></authors></contributors><titles><title>Combined protective effect of vitamins C and E on cadmium induced oxidative liver injury in rats</title><secondary-title>Afr. J. Biotechnol</secondary-title></titles><periodical><full-title>Afr. J. Biotechnol</full-title></periodical><pages>16013-16020</pages><volume>11</volume><number>93</number><dates><year>2012</year></dates><urls></urls></record></Cite></EndNote>40 The mitigating effects of vitamin C and E can be attributed to their water and lipid soluble antioxidant properties respectively. ADDIN EN.CITE <EndNote><Cite><Author>Elias Adikwu</Author><Year>2013</Year><RecNum>395</RecNum><DisplayText><style face="superscript">29</style></DisplayText><record><rec-number>395</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1396211418">395</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Elias Adikwu, Oputiri Deo, Oru-Bo Precious Geoffrey</author></authors></contributors><titles><title>Hepatotoxicity of Cadmium and Roles of Mitigating Agents</title><secondary-title>British Journal of Pharmacology and Toxicology</secondary-title></titles><periodical><full-title>British Journal of Pharmacology and Toxicology</full-title></periodical><pages>222-231</pages><volume>4</volume><number>6</number><dates><year>2013</year></dates><urls></urls></record></Cite></EndNote>29 Vitamin C is known to cause regeneration of oxidized vitamin E molecule and both vitamins have sparing effect on each other. ADDIN EN.CITE <EndNote><Cite><Author>Obianime</Author><Year>2010</Year><RecNum>404</RecNum><DisplayText><style face="superscript">41</style></DisplayText><record><rec-number>404</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1396219930">404</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Obianime, A.W.,N.J. Ahiwe and J.S. Aprioku</author></authors></contributors><titles><title>Effects of vitamins C and E pretreatments on cadmium induced serum levels of some biochemical and hormonal parameters in the female guinea spig</title><secondary-title>Afr. J. Biotechnol</secondary-title></titles><periodical><full-title>Afr. J. Biotechnol</full-title></periodical><pages>6582-6587</pages><volume>9</volume><number>39</number><dates><year>2010</year></dates><urls></urls></record></Cite></EndNote>41Pretreatment with MnCl2 24 hours before cadmium intoxication completely prevented or significantly attenuated hepatic damage identified by increases in hepatic lipid peroxidation and the depletion of endogenous antioxidants. ADDIN EN.CITE <EndNote><Cite><Author>Eybl</Author><Year>2010</Year><RecNum>405</RecNum><DisplayText><style face="superscript">42</style></DisplayText><record><rec-number>405</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1396222029">405</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Eybl, V.</author><author>Kotyzova, D.</author></authors></contributors><auth-address>Department of Pharmacology and Toxicology, Charles University in Prague, Faculty of Medicine in Pilsen, CZ-301 00 Pilsen, Czech Republic.</auth-address><titles><title>Protective effect of manganese in cadmium-induced hepatic oxidative damage, changes in cadmium distribution and trace elements level in mice</title><secondary-title>Interdiscip Toxicol</secondary-title><alt-title>Interdisciplinary toxicology</alt-title></titles><periodical><full-title>Interdiscip Toxicol</full-title><abbr-1>Interdisciplinary toxicology</abbr-1></periodical><alt-periodical><full-title>Interdiscip Toxicol</full-title><abbr-1>Interdisciplinary toxicology</abbr-1></alt-periodical><pages>68-72</pages><volume>3</volume><number>2</number><dates><year>2010</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>1337-9569 (Electronic)
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ADDIN EN.CITE.DATA 43 NAC is a kind of antioxidant with direct and indirect activities. The direct effect acts when its thiol group reacts with the electrophyllic group of ROS. The indirect effect acts by providing intracellular cysteine for the production of glutathione. ADDIN EN.CITE <EndNote><Cite><Author>Dekhuijzen</Author><Year>2004</Year><RecNum>420</RecNum><DisplayText><style face="superscript">44</style></DisplayText><record><rec-number>420</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1396223129">420</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Dekhuijzen, P. N.</author></authors></contributors><auth-address>Dept of Pulmonary Diseases, University Medical Centre Nijmegen, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands. r.dekhuijzen@long.umcn.nl</auth-address><titles><title>Antioxidant properties of N-acetylcysteine: their relevance in relation to chronic obstructive pulmonary disease</title><secondary-title>Eur Respir J</secondary-title><alt-title>The European respiratory journal</alt-title></titles><periodical><full-title>Eur Respir J</full-title><abbr-1>The European respiratory journal</abbr-1></periodical><alt-periodical><full-title>Eur Respir J</full-title><abbr-1>The European respiratory journal</abbr-1></alt-periodical><pages>629-36</pages><volume>23</volume><number>4</number><keywords><keyword>Acetylcysteine/*therapeutic use</keyword><keyword>Antioxidants/*therapeutic use</keyword><keyword>Disease Progression</keyword><keyword>Free Radical Scavengers/*therapeutic use</keyword><keyword>Humans</keyword><keyword>Oxidative Stress/immunology/physiology</keyword><keyword>Pulmonary Disease, Chronic Obstructive/*drug therapy/immunology/physiopathology</keyword><keyword>Reactive Oxygen Species/adverse effects</keyword></keywords><dates><year>2004</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>0903-1936 (Print)
0903-1936 (Linking)</isbn><accession-num>15083766</accession-num><urls><related-urls><url> The hepatic-protective effects of selenium (Na2Se2O3) against cadmium induced toxicity, oxidative stress and tissue damage could be attributed to its antioxidant and possible chelating effects with cadmium. ADDIN EN.CITE <EndNote><Cite><Author>Jabeen</Author><Year>2011</Year><RecNum>425</RecNum><DisplayText><style face="superscript">45</style></DisplayText><record><rec-number>425</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1396223954">425</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Jabeen, F.</author><author>Chaudhry, A. S.</author></authors></contributors><auth-address>Department of Zoology, GC University Faisalabad, Faisalabad, Pakistan. farjabeen2004@yahoo.co.in</auth-address><titles><title>Effects of cadmium chloride and sodium selenite alone or in combination on the liver of male Sprague-Dawley rats assessed by different assays</title><secondary-title>Biol Trace Elem Res</secondary-title><alt-title>Biological trace element research</alt-title></titles><periodical><full-title>Biol Trace Elem Res</full-title><abbr-1>Biological trace element research</abbr-1></periodical><alt-periodical><full-title>Biol Trace Elem Res</full-title><abbr-1>Biological trace element research</abbr-1></alt-periodical><pages>1077-90</pages><volume>143</volume><number>2</number><keywords><keyword>Animals</keyword><keyword>Biological Assay/*methods</keyword><keyword>Cadmium Chloride/*toxicity</keyword><keyword>Comet Assay</keyword><keyword>In Situ Nick-End Labeling</keyword><keyword>Lipid Peroxidation/drug effects</keyword><keyword>Liver/*drug effects/*metabolism</keyword><keyword>Male</keyword><keyword>Rats</keyword><keyword>Rats, Sprague-Dawley</keyword><keyword>Sodium Selenite/*toxicity</keyword></keywords><dates><year>2011</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>1559-0720 (Electronic)
0163-4984 (Linking)</isbn><accession-num>21213067</accession-num><urls><related-urls><url> The administration of Solanum tuberosum extract normalized cadmium-induced biochemical changes of liver function. ADDIN EN.CITE <EndNote><Cite><Author>Lawal</Author><Year>2011</Year><RecNum>429</RecNum><DisplayText><style face="superscript">46</style></DisplayText><record><rec-number>429</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1396224346">429</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Lawal, O.A., E.O. Farombi and A.F. Lawal</author></authors></contributors><titles><title>Aqueous extract of potato (Solanum tuberosum) modulates cadmium-induced liver damage in female Wistar rats</title><secondary-title>Int. J. Pharmacol.</secondary-title></titles><periodical><full-title>Int. J. Pharmacol.</full-title></periodical><pages>599-607</pages><volume>7</volume><dates><year>2011</year></dates><urls></urls></record></Cite></EndNote>46 Blood samples from animals treated with ethanolic leaf extract from Calycopteris floribunda showed significant reduction in the serum markers which indicating normal functional ability of the hepatocytes compared to cadmium treated rats. ADDIN EN.CITE <EndNote><Cite><Author>Rajasekaran</Author><Year>2012</Year><RecNum>430</RecNum><DisplayText><style face="superscript">47</style></DisplayText><record><rec-number>430</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1396224841">430</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Rajasekaran, A. and M. Periasamy</author></authors></contributors><titles><title>Hepatoprotective effect of ethanolic leaf extract of Calycopteris floribunda Lam on cadmium induced hepatotoxicity in rats</title><secondary-title>Res. J. Pharmaceut. Biol. Chem. Sci.</secondary-title></titles><periodical><full-title>Res. J. Pharmaceut. Biol. Chem. Sci.</full-title></periodical><pages>382-390</pages><volume>3</volume><number>3</number><dates><year>2012</year></dates><urls></urls></record></Cite></EndNote>47 Administration of calyx extract from Hibiscus sabdariffa normalized cadmium induced changes in serum activities of protein related to liver function. ADDIN EN.CITE <EndNote><Cite><Author>Muhammad</Author><Year>2008</Year><RecNum>421</RecNum><DisplayText><style face="superscript">48</style></DisplayText><record><rec-number>421</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1396223674">421</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Muhammad, Y.Y. and U.U. Charles</author></authors></contributors><titles><title>Effect of calyx extract of hibiscus sabdariffa against cadmium-induced liver damage.</title><secondary-title>Bayero J. Pure Appl. Sci.</secondary-title></titles><periodical><full-title>Bayero J. Pure Appl. Sci.</full-title></periodical><pages>80-82</pages><volume>1</volume><number>1</number><dates><year>2008</year></dates><urls></urls></record></Cite></EndNote>48 It has been reported that honey may ameliorate the hepatotoxic effect of cadmium in Wister rats. ADDIN EN.CITE <EndNote><Cite><Author>Abdel-Moneim</Author><Year>2007</Year><RecNum>400</RecNum><DisplayText><style face="superscript">49</style></DisplayText><record><rec-number>400</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1396216953">400</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Abdel-Moneim, W.M. and H.H. Ghafeer</author></authors></contributors><titles><title>The potential protective effect of natural honey against cadmium-induced hepatotoxicity and nephrotoxicity</title><secondary-title>Mansoura J. Forensic Med. Clin. Toxicol</secondary-title></titles><periodical><full-title>Mansoura J. Forensic Med. Clin. Toxicol</full-title></periodical><pages>75-98</pages><volume>15</volume><number>2</number><dates><year>2007</year></dates><urls></urls></record></Cite></EndNote>49 It was also noticed that concurrent administration of honey with cadmium chloride improved histopathological changes in the liver compared to cadmium only-treated rats. ADDIN EN.CITE <EndNote><Cite><Author>Abdel-Moneim</Author><Year>2007</Year><RecNum>400</RecNum><DisplayText><style face="superscript">49</style></DisplayText><record><rec-number>400</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1396216953">400</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Abdel-Moneim, W.M. and H.H. Ghafeer</author></authors></contributors><titles><title>The potential protective effect of natural honey against cadmium-induced hepatotoxicity and nephrotoxicity</title><secondary-title>Mansoura J. Forensic Med. Clin. Toxicol</secondary-title></titles><periodical><full-title>Mansoura J. Forensic Med. Clin. Toxicol</full-title></periodical><pages>75-98</pages><volume>15</volume><number>2</number><dates><year>2007</year></dates><urls></urls></record></Cite></EndNote>49 The possible mechanism was that honey via its antioxidant activity has the ability to protect against cadmium induced hepatotoxicity. ADDIN EN.CITE <EndNote><Cite><Author>Abdel-Moneim</Author><Year>2007</Year><RecNum>400</RecNum><DisplayText><style face="superscript">49</style></DisplayText><record><rec-number>400</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1396216953">400</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Abdel-Moneim, W.M. and H.H. Ghafeer</author></authors></contributors><titles><title>The potential protective effect of natural honey against cadmium-induced hepatotoxicity and nephrotoxicity</title><secondary-title>Mansoura J. Forensic Med. Clin. Toxicol</secondary-title></titles><periodical><full-title>Mansoura J. Forensic Med. Clin. Toxicol</full-title></periodical><pages>75-98</pages><volume>15</volume><number>2</number><dates><year>2007</year></dates><urls></urls></record></Cite></EndNote>49The addition of Camel's milk to cadmium chloride has been found to normalize the levels of albumin, hemoglobin, calcium, serum alanine aminotransferase, aspartate aminotransferase, and serum alkaline phosphatase. The levels of hydro-peroxides, superoxide dismutase, catalase and glutathione were also normalized in cadmium and camel’s milk additive treated rats. ADDIN EN.CITE <EndNote><Cite><Author>Al-Hashem</Author><Year>2009</Year><RecNum>402</RecNum><DisplayText><style face="superscript">50</style></DisplayText><record><rec-number>402</rec-number><foreign-keys><key app="EN" db-id="sfarpvzpsp5pt1evs0nxwf2lsvrdsxvfvwvx" timestamp="1396217831">402</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Al-Hashem, F., M. Dallak, N. Bashir and M. Abbas</author></authors></contributors><titles><title>Camel's milk protects against cadmium chloride induced toxicity in white albino rats</title><secondary-title>Am. J. Pharm. Toxicol.</secondary-title></titles><periodical><full-title>Am. J. Pharm. Toxicol.</full-title></periodical><pages>107-117</pages><volume>4</volume><number>3</number><dates><year>2009</year></dates><urls></urls></record></Cite></EndNote>50 CONCLUSIONCadmium is a serious environmental hazard discovered in the 19th century and will continue to adversely impact the environment in future. Cadmium in the environment comes from both natural sources and industrial activities. Cadmium emissions from industrial activity related to Ni-Cd batteries, refinery of cadmium minerals and by-products of zinc production. Cadmium emitted to the environment stays in the atmosphere, water and soil. Cadmium can accumulate in organisms, including humans, because cadmium is not degraded in the environment and its relative water solubility is high compared to other heavy metals. Due to bioaccumulation, cadmium causes serious environmental effects, such as reproductive effects and behavior change of aquatic invertebrates. Cadmium-dependent liver and kidney damage may occur in mammals and birds. Other environmental effects are related to plants, which absorb the cadmium from contaminated water or soil. Cadmium pollution prolongs the decomposition of plants including agricultural products intended for consumption, which is the major route for non-smoking human exposure to cadmium. For the occupational population, cadmium is absorbed into the body by inhaling industrial dust and/or accidentally ingesting it. For the general population, cadmium is absorbed by inhaling tobacco products and ingesting contaminated water and food. Adverse health effects of cadmium occur due to acute exposure and chronic exposure. Acute exposure to cadmium usually occurs when occupational workers are exposed to high doses of cadmium in industrial processes. The outcomes due to acute exposure are respiratory system damage, renal failure and liver failure. Acute exposure with cadmium happens occasionally, so the effects of chronic exposure with cadmium is more critical to public health. According to the IRAC, cadmium has been classified as a group 1 agent which means that cadmium is carcinogenic to humans. Therefore, more works of the association with chronic cadmium exposure and cancer should be needed in the future.Although occupational exposure to cadmium has decreased by protective equipment and monitoring systems, environmental exposure continues. If such exposure is ultimately found to cause liver disease, further efforts should be made to reduce it, including regulation of cadmium in food products and tobacco products and potential mitigating agents.Studies suggested that insufficient evidence to support the relationship of cadmium exposure to liver cancer. A paucity of research, only two studies on animals, related to cadmium-induced liver cancer. Further study is needed to develop an unambiguous conclusion about cadmium with regard to liver cancer in animal models, before approaching an epidemiological study in humans. There are many kinds of possible mechanisms to explain liver damage induced by cadmium exposure, but the complete mechanism of hepatocellular damage is not clear. Thus, further research isneeded to identify this problem, which might help to set up clinical approaches for cadmium intoxication.There is no confirmed clinical treatment of the hepatotoxicity induced by cadmium exposure, but some treatment have been proved to mitigate hepatotoxicity induced by cadmium exposure in animal models. However, future studies are required to investigate the effects of mitigative agents on chronic cadmium exposure in humans and evaluate their possible therapeutic value in the clinic. BIBLIOGRAPHY ADDIN EN.REFLIST 1.Cadmium Review. In: MInisters NCo, ed; 2003.2.Hyder O, Chung M, Cosgrove D, et al. Cadmium exposure and liver disease among US adults. J Gastrointest Surg. Jul 2013;17(7):1265-1273.3.Satarug S, Moore MR. 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