TY - JOUR
AU - Sarkar, Bibudhendra
AB - Abstract This paper presents an overview of the global extent of naturally occurring toxic metals in groundwater. Adverse health effects attributed to the toxic metals most commonly found in groundwater are reviewed, as well as chemical, biochemical, and physiological interactions between these metals. Synergistic and antagonistic effects that have been reported between the toxic metals found in groundwater and the dietary trace elements are highlighted, and common behavioural, cultural, and dietary practices that are likely to significantly modify health risks due to use of metal-contaminated groundwater are reviewed. Methods for analytical testing of samples containing multiple metals are discussed, with special attention to analytical interferences between metals and reagents. An overview is presented of approaches to providing safe water when groundwater contains multiple metallic toxins. Graphical Abstract Open in new tabDownload slide This review integrates recent research in hydrogeology, water testing, and metal toxicity, emphasizing interactions between toxic metals. Introduction Over the past 25 years, a health crisis of epic proportions has emerged in the Bengal Delta due to populations switching to groundwater for drinking, cooking, and irrigation rather than surface water. The switch away from using surface water for drinking and cooking was initially hailed as a tremendous boon for public health because of dramatic declines in mortality due to water-borne diseases. However, unbeknownst to the installers of the wells which made this switch possible, groundwater in the region is commonly contaminated with arsenic, manganese, uranium and other toxic metals of hydro-geological origin. In this paper, we present an overview of the global extent of naturally occurring toxic metals in groundwater, noting that multiple metal contamination of groundwater is an issue of global concern, and the risks may be further magnified by climate change. Several metals that occur as natural contaminants of groundwater are associated with severe and potentially lethal adverse health effects, including arsenic, manganese, and uranium. We review the adverse health effects attributed to the toxic metals most commonly found in groundwater, both individually and in combination with each other. We emphasize that exposure to these toxic metals most often involves exposure to a combination of toxic metals rather than to just a single metal; thus, accurate assessment of health risks due to drinking metal-contaminated groundwater must take into account potential interactions between the metals on the chemical, biochemical, and physiological levels. Health effects due to co-exposures to toxic metals are further affected by behavioural and cultural practices (e.g. smoking, sun avoidance) and dietary habits. In this paper, we highlight synergistic and antagonistic effects that have been reported between the toxic metals found in groundwater and the dietary trace elements and we also discuss behavioural, cultural, and dietary practices that are likely to significantly modify health risks due to use of metal-contaminated groundwater. We provide an overview of analytical testing for multiple metals, noting the special considerations that must be taken to avoid analytical interferences when samples contain mixtures of metals. We conclude with a brief summary of current approaches and technologies for providing safe water when groundwater contains multiple metallic toxins. Toxic metals in groundwater The discovery of toxic metals in groundwater Finding sources of pure water is an age-old problem for humans. In desert regions, people have long resorted to wells in order to access water. Folk wisdom of the desert, however, advises users to observe the behaviour of animals, and to avoid wells that animals would not drink from.1 In 1918, this folk wisdom received its first scientific confirmation that water from certain wells is contaminated and causes disease.2 Dr Abel Ayerza, a professor at the Buenos Aires Medical School, reported that a number of villagers from Cordoba had developed palmar keratosis and melanoma, and he argued that this was due to arsenic in the region's groundwater. He described a patient with weeping sores on his lower legs and discoloured toes, whose feet eventually had to be amputated, and patients with liver and heart problems or general weakness. He suggested that problems with the arterial system and the heart were due to the effects of arsenic and vanadium in combination. He noted that villagers were very much aware that some waters in the region were unhealthy despite having no bad taste or colour, and they would go to great lengths to access safe water, including harvesting rainwater from their “zinc” (galvanized) roofs or carrying water from afar. Ayerza observed that the spatial distribution of the contaminants seemed to be quite unpredictable, with some wells heavily contaminated while neighbouring wells had safe water, and he cautioned that foods in the area were also likely to contain high levels of arsenic. Subsequent research in many other parts of the globe has confirmed and replicated Ayerza's observations made almost a century ago on the serious health risks of drinking groundwater contaminated with toxic metals and the difficulty of predicting which wells may be affected. Because groundwater is generally safe, and is almost universally preferable to surface water in terms of biological contaminants, the possibility that it may contain toxic metals has not been considered until widespread health problems have arisen. Throughout the twentieth century, increasing dependence on groundwater due to migration, population pressure, or the introduction of new water technologies, has brought about epidemics of keratosis, blackfoot disease, skeletal fluorosis and other results of metal contamination due to natural sources (e.g.arsenic: Taiwan,3 Chile,4 China,5 Vietnam,6 Burkina Faso.7 In terms of numbers of people affected, arsenic contamination of groundwater in the Bengal Basin has presented the most alarming case, where 60–65 million people8 are estimated to be drinkingwater with excess levels of arsenic. Due to the extent of the contamination and the numbers of people affected, groundwater contamination has been examined more methodically and documented to a greater extent in Bangladesh than in any other country, with national surveys for arsenic in 19979 and multiple metals in 1998–1999.10 These national surveys detected high concentrations of manganese and other toxic metals besides arsenic before any resulting health effects were observed. In other regions, groundwater has typically been tested only after health has been compromised, and sampling has been regional rather than national. However, more researchers are now considering the possibility of multiple-metal contamination, and routinely screening their samples for the presence of such multiple toxins such as manganese, lead, and fluoride, rather than testing for only a single element such as arsenic. As a result, multiple metal contamination of groundwater is now being reported in many regions; see Table 1, Fig. 1. Table 1 Regions with naturally occurring multiple toxic metals in groundwater Country . Co-contaminants reported . China Arsenic, selenium11 Arsenic, manganese, uranium, iron12 Arsenic, nickel, iron13 Taiwan Arsenic, manganese, iron14 Malaysia Arsenic, manganese, uranium15 Mekong River Delta (Cambodia and Vietnam) Arsenic, manganese, cadmium, lead, nickel, selenium, barium16 Arsenic, manganese, lead, barium17 Arsenic, manganese, barium18 Arsenic, manganese, iron19 Arsenic, manganese16,20 Bangladesh Arsenic, manganese, uranium, boron21 Arsenic, manganese, nickel, chromium10b Arsenic, manganese22 India Arsenic, lead, aluminium, cadmium23 Arsenic, manganese, iron24 Arsenic, iron25 Lead, iron26 Manganese, zinc27 Iran Arsenic, cadmium, selenium28 Uganda Manganese, uranium, cadmium, lead, nickel, barium, iron29 Burkina Faso Arsenic, manganese, molybdenum7 Mali Manganese, uranium30 Ghana Arsenic, manganese, iron31 Finland Arsenic,32 uranium,33 manganese, iron34 Italy Arsenic, vanadium35 Greece Arsenic, manganese, uranium36 Arsenic, manganese, antimony37 Canada Arsenic, manganese, iron38 Arsenic, uranium39 United States Arsenic, manganese, uranium, selenium, molybdenum, boron40 Arsenic, manganese, uranium, iron41 Arsenic, manganese42 Selenium, boron43 Argentina Arsenic, manganese, uranium, vanadium, iron, strontium, boron, molybdenum44 Arsenic, uranium, vanadium, selenium45 Arsenic, lithium, cesium, boron46 Arsenic, vanadium2 Country . Co-contaminants reported . China Arsenic, selenium11 Arsenic, manganese, uranium, iron12 Arsenic, nickel, iron13 Taiwan Arsenic, manganese, iron14 Malaysia Arsenic, manganese, uranium15 Mekong River Delta (Cambodia and Vietnam) Arsenic, manganese, cadmium, lead, nickel, selenium, barium16 Arsenic, manganese, lead, barium17 Arsenic, manganese, barium18 Arsenic, manganese, iron19 Arsenic, manganese16,20 Bangladesh Arsenic, manganese, uranium, boron21 Arsenic, manganese, nickel, chromium10b Arsenic, manganese22 India Arsenic, lead, aluminium, cadmium23 Arsenic, manganese, iron24 Arsenic, iron25 Lead, iron26 Manganese, zinc27 Iran Arsenic, cadmium, selenium28 Uganda Manganese, uranium, cadmium, lead, nickel, barium, iron29 Burkina Faso Arsenic, manganese, molybdenum7 Mali Manganese, uranium30 Ghana Arsenic, manganese, iron31 Finland Arsenic,32 uranium,33 manganese, iron34 Italy Arsenic, vanadium35 Greece Arsenic, manganese, uranium36 Arsenic, manganese, antimony37 Canada Arsenic, manganese, iron38 Arsenic, uranium39 United States Arsenic, manganese, uranium, selenium, molybdenum, boron40 Arsenic, manganese, uranium, iron41 Arsenic, manganese42 Selenium, boron43 Argentina Arsenic, manganese, uranium, vanadium, iron, strontium, boron, molybdenum44 Arsenic, uranium, vanadium, selenium45 Arsenic, lithium, cesium, boron46 Arsenic, vanadium2 Open in new tab Table 1 Regions with naturally occurring multiple toxic metals in groundwater Country . Co-contaminants reported . China Arsenic, selenium11 Arsenic, manganese, uranium, iron12 Arsenic, nickel, iron13 Taiwan Arsenic, manganese, iron14 Malaysia Arsenic, manganese, uranium15 Mekong River Delta (Cambodia and Vietnam) Arsenic, manganese, cadmium, lead, nickel, selenium, barium16 Arsenic, manganese, lead, barium17 Arsenic, manganese, barium18 Arsenic, manganese, iron19 Arsenic, manganese16,20 Bangladesh Arsenic, manganese, uranium, boron21 Arsenic, manganese, nickel, chromium10b Arsenic, manganese22 India Arsenic, lead, aluminium, cadmium23 Arsenic, manganese, iron24 Arsenic, iron25 Lead, iron26 Manganese, zinc27 Iran Arsenic, cadmium, selenium28 Uganda Manganese, uranium, cadmium, lead, nickel, barium, iron29 Burkina Faso Arsenic, manganese, molybdenum7 Mali Manganese, uranium30 Ghana Arsenic, manganese, iron31 Finland Arsenic,32 uranium,33 manganese, iron34 Italy Arsenic, vanadium35 Greece Arsenic, manganese, uranium36 Arsenic, manganese, antimony37 Canada Arsenic, manganese, iron38 Arsenic, uranium39 United States Arsenic, manganese, uranium, selenium, molybdenum, boron40 Arsenic, manganese, uranium, iron41 Arsenic, manganese42 Selenium, boron43 Argentina Arsenic, manganese, uranium, vanadium, iron, strontium, boron, molybdenum44 Arsenic, uranium, vanadium, selenium45 Arsenic, lithium, cesium, boron46 Arsenic, vanadium2 Country . Co-contaminants reported . China Arsenic, selenium11 Arsenic, manganese, uranium, iron12 Arsenic, nickel, iron13 Taiwan Arsenic, manganese, iron14 Malaysia Arsenic, manganese, uranium15 Mekong River Delta (Cambodia and Vietnam) Arsenic, manganese, cadmium, lead, nickel, selenium, barium16 Arsenic, manganese, lead, barium17 Arsenic, manganese, barium18 Arsenic, manganese, iron19 Arsenic, manganese16,20 Bangladesh Arsenic, manganese, uranium, boron21 Arsenic, manganese, nickel, chromium10b Arsenic, manganese22 India Arsenic, lead, aluminium, cadmium23 Arsenic, manganese, iron24 Arsenic, iron25 Lead, iron26 Manganese, zinc27 Iran Arsenic, cadmium, selenium28 Uganda Manganese, uranium, cadmium, lead, nickel, barium, iron29 Burkina Faso Arsenic, manganese, molybdenum7 Mali Manganese, uranium30 Ghana Arsenic, manganese, iron31 Finland Arsenic,32 uranium,33 manganese, iron34 Italy Arsenic, vanadium35 Greece Arsenic, manganese, uranium36 Arsenic, manganese, antimony37 Canada Arsenic, manganese, iron38 Arsenic, uranium39 United States Arsenic, manganese, uranium, selenium, molybdenum, boron40 Arsenic, manganese, uranium, iron41 Arsenic, manganese42 Selenium, boron43 Argentina Arsenic, manganese, uranium, vanadium, iron, strontium, boron, molybdenum44 Arsenic, uranium, vanadium, selenium45 Arsenic, lithium, cesium, boron46 Arsenic, vanadium2 Open in new tab Table 2 Toxic effects of arsenic Cancers Skin cancer60 Lung cancer61 Bladder and urinary tract cancers60a,62 Digestive tract cancers60a Liver cancer63 Prostate cancer64 Breast cancer65 Skin conditions Keratosis and pigment change66 Liver disease Enlargement of the liver, cirrhosis and fatty degeneration11,66a,67 Lung disease Pulmonary obstructive and restrictive effects, chronic cough and bronchitis67,68 Changes in mouse lung cells69 and cultured human lung cells70 Heart disease Arteriosclerosis, myocardial infarction, ischemic heart disease, vascular constriction, and blackfoot disease60a,71 Hypertension68d,72 Diabetes Increased risk of diabetes72b,73 Blood disorders Anaemia or leucopoenia68c Kidney disease Renal damage74 Eye disease Pterygium75 Cataracts76 Conjunctivitis77 Immune effects Reduced immune function78 Reproductive effects Endocrine disruption79 Decreased Aberrant morphology and decreased motility of sperm in rabbits81 Neurological effects Peripheral neuropathy of both sensory and motor neurons, causing numbness, loss of reflexes, and muscle weakness2,66a,68d,82 Learning disabilities in children and reduced intellectual function83 Developmental effects Adverse pregnancy outcomes: spontaneous abortion, stillbirth, and preterm delivery,84 Increased infant mortality86 Decreased weight, height, and lung capacities of children87 Cancers Skin cancer60 Lung cancer61 Bladder and urinary tract cancers60a,62 Digestive tract cancers60a Liver cancer63 Prostate cancer64 Breast cancer65 Skin conditions Keratosis and pigment change66 Liver disease Enlargement of the liver, cirrhosis and fatty degeneration11,66a,67 Lung disease Pulmonary obstructive and restrictive effects, chronic cough and bronchitis67,68 Changes in mouse lung cells69 and cultured human lung cells70 Heart disease Arteriosclerosis, myocardial infarction, ischemic heart disease, vascular constriction, and blackfoot disease60a,71 Hypertension68d,72 Diabetes Increased risk of diabetes72b,73 Blood disorders Anaemia or leucopoenia68c Kidney disease Renal damage74 Eye disease Pterygium75 Cataracts76 Conjunctivitis77 Immune effects Reduced immune function78 Reproductive effects Endocrine disruption79 Decreased Aberrant morphology and decreased motility of sperm in rabbits81 Neurological effects Peripheral neuropathy of both sensory and motor neurons, causing numbness, loss of reflexes, and muscle weakness2,66a,68d,82 Learning disabilities in children and reduced intellectual function83 Developmental effects Adverse pregnancy outcomes: spontaneous abortion, stillbirth, and preterm delivery,84 Increased infant mortality86 Decreased weight, height, and lung capacities of children87 Open in new tab Table 2 Toxic effects of arsenic Cancers Skin cancer60 Lung cancer61 Bladder and urinary tract cancers60a,62 Digestive tract cancers60a Liver cancer63 Prostate cancer64 Breast cancer65 Skin conditions Keratosis and pigment change66 Liver disease Enlargement of the liver, cirrhosis and fatty degeneration11,66a,67 Lung disease Pulmonary obstructive and restrictive effects, chronic cough and bronchitis67,68 Changes in mouse lung cells69 and cultured human lung cells70 Heart disease Arteriosclerosis, myocardial infarction, ischemic heart disease, vascular constriction, and blackfoot disease60a,71 Hypertension68d,72 Diabetes Increased risk of diabetes72b,73 Blood disorders Anaemia or leucopoenia68c Kidney disease Renal damage74 Eye disease Pterygium75 Cataracts76 Conjunctivitis77 Immune effects Reduced immune function78 Reproductive effects Endocrine disruption79 Decreased Aberrant morphology and decreased motility of sperm in rabbits81 Neurological effects Peripheral neuropathy of both sensory and motor neurons, causing numbness, loss of reflexes, and muscle weakness2,66a,68d,82 Learning disabilities in children and reduced intellectual function83 Developmental effects Adverse pregnancy outcomes: spontaneous abortion, stillbirth, and preterm delivery,84 Increased infant mortality86 Decreased weight, height, and lung capacities of children87 Cancers Skin cancer60 Lung cancer61 Bladder and urinary tract cancers60a,62 Digestive tract cancers60a Liver cancer63 Prostate cancer64 Breast cancer65 Skin conditions Keratosis and pigment change66 Liver disease Enlargement of the liver, cirrhosis and fatty degeneration11,66a,67 Lung disease Pulmonary obstructive and restrictive effects, chronic cough and bronchitis67,68 Changes in mouse lung cells69 and cultured human lung cells70 Heart disease Arteriosclerosis, myocardial infarction, ischemic heart disease, vascular constriction, and blackfoot disease60a,71 Hypertension68d,72 Diabetes Increased risk of diabetes72b,73 Blood disorders Anaemia or leucopoenia68c Kidney disease Renal damage74 Eye disease Pterygium75 Cataracts76 Conjunctivitis77 Immune effects Reduced immune function78 Reproductive effects Endocrine disruption79 Decreased Aberrant morphology and decreased motility of sperm in rabbits81 Neurological effects Peripheral neuropathy of both sensory and motor neurons, causing numbness, loss of reflexes, and muscle weakness2,66a,68d,82 Learning disabilities in children and reduced intellectual function83 Developmental effects Adverse pregnancy outcomes: spontaneous abortion, stillbirth, and preterm delivery,84 Increased infant mortality86 Decreased weight, height, and lung capacities of children87 Open in new tab Table 3 Toxic effects of manganese Neurological effects Decreased brain function in domestic animals102 Neurological deficits in nonhuman primates103 Disruptions in dopamine, norepinephrin, and acetylcholinesterase levels103 Manganism, a condition characterized by a cock-like walk,104 Compulsive behaviours, emotional lability and hallucinations, and somatisation disorder106 Violent or criminal behaviour107 Hyperactivity in children, learning disabilities, and deficits in children’s manual dexterity and rapidity, short-term memory, and visual identification56,108 Amyotrophic lateral sclerosis102 Possible increased susceptibility to prion diseases109 Liver disease Liver damage and cirrhosis in rats104 Kidney disease Nephritis in rats104 Reproductive effects Degenerative changes in rat testes104,110 Cardiovascular effects Decreased heart muscle respiration in rats111 Ear disorders Hearing loss in mice112 Developmental effects Increased infant mortality, especially with concurrent pregnancy-induced iron deficiency anaemia113 Neurological effects Decreased brain function in domestic animals102 Neurological deficits in nonhuman primates103 Disruptions in dopamine, norepinephrin, and acetylcholinesterase levels103 Manganism, a condition characterized by a cock-like walk,104 Compulsive behaviours, emotional lability and hallucinations, and somatisation disorder106 Violent or criminal behaviour107 Hyperactivity in children, learning disabilities, and deficits in children’s manual dexterity and rapidity, short-term memory, and visual identification56,108 Amyotrophic lateral sclerosis102 Possible increased susceptibility to prion diseases109 Liver disease Liver damage and cirrhosis in rats104 Kidney disease Nephritis in rats104 Reproductive effects Degenerative changes in rat testes104,110 Cardiovascular effects Decreased heart muscle respiration in rats111 Ear disorders Hearing loss in mice112 Developmental effects Increased infant mortality, especially with concurrent pregnancy-induced iron deficiency anaemia113 Open in new tab Table 3 Toxic effects of manganese Neurological effects Decreased brain function in domestic animals102 Neurological deficits in nonhuman primates103 Disruptions in dopamine, norepinephrin, and acetylcholinesterase levels103 Manganism, a condition characterized by a cock-like walk,104 Compulsive behaviours, emotional lability and hallucinations, and somatisation disorder106 Violent or criminal behaviour107 Hyperactivity in children, learning disabilities, and deficits in children’s manual dexterity and rapidity, short-term memory, and visual identification56,108 Amyotrophic lateral sclerosis102 Possible increased susceptibility to prion diseases109 Liver disease Liver damage and cirrhosis in rats104 Kidney disease Nephritis in rats104 Reproductive effects Degenerative changes in rat testes104,110 Cardiovascular effects Decreased heart muscle respiration in rats111 Ear disorders Hearing loss in mice112 Developmental effects Increased infant mortality, especially with concurrent pregnancy-induced iron deficiency anaemia113 Neurological effects Decreased brain function in domestic animals102 Neurological deficits in nonhuman primates103 Disruptions in dopamine, norepinephrin, and acetylcholinesterase levels103 Manganism, a condition characterized by a cock-like walk,104 Compulsive behaviours, emotional lability and hallucinations, and somatisation disorder106 Violent or criminal behaviour107 Hyperactivity in children, learning disabilities, and deficits in children’s manual dexterity and rapidity, short-term memory, and visual identification56,108 Amyotrophic lateral sclerosis102 Possible increased susceptibility to prion diseases109 Liver disease Liver damage and cirrhosis in rats104 Kidney disease Nephritis in rats104 Reproductive effects Degenerative changes in rat testes104,110 Cardiovascular effects Decreased heart muscle respiration in rats111 Ear disorders Hearing loss in mice112 Developmental effects Increased infant mortality, especially with concurrent pregnancy-induced iron deficiency anaemia113 Open in new tab Table 4 Toxic effects of uranium Bone effects Decreased bone formation133 Increased bone resorption134 Increased osteocalcin levels in men, particularly with current smokers134 Kidney disease Decreased kidney function135 Cardiovascular effects Increased blood pressure136 Neurological effects Changes in the brain cholinergic system in rats137 Hormonal effects Endocrine-disruptor138 Reproductive effects Disturbed follicogenesis, oocyte meiosis and oocyte morphology in mice139 Possible fertility problems and reproductive cancers138 Bone effects Decreased bone formation133 Increased bone resorption134 Increased osteocalcin levels in men, particularly with current smokers134 Kidney disease Decreased kidney function135 Cardiovascular effects Increased blood pressure136 Neurological effects Changes in the brain cholinergic system in rats137 Hormonal effects Endocrine-disruptor138 Reproductive effects Disturbed follicogenesis, oocyte meiosis and oocyte morphology in mice139 Possible fertility problems and reproductive cancers138 Open in new tab Table 4 Toxic effects of uranium Bone effects Decreased bone formation133 Increased bone resorption134 Increased osteocalcin levels in men, particularly with current smokers134 Kidney disease Decreased kidney function135 Cardiovascular effects Increased blood pressure136 Neurological effects Changes in the brain cholinergic system in rats137 Hormonal effects Endocrine-disruptor138 Reproductive effects Disturbed follicogenesis, oocyte meiosis and oocyte morphology in mice139 Possible fertility problems and reproductive cancers138 Bone effects Decreased bone formation133 Increased bone resorption134 Increased osteocalcin levels in men, particularly with current smokers134 Kidney disease Decreased kidney function135 Cardiovascular effects Increased blood pressure136 Neurological effects Changes in the brain cholinergic system in rats137 Hormonal effects Endocrine-disruptor138 Reproductive effects Disturbed follicogenesis, oocyte meiosis and oocyte morphology in mice139 Possible fertility problems and reproductive cancers138 Open in new tab Table 5 Toxic effects of lead Neurological effects Reduced children’s capacity to learn, even at very low levels of exposure141 Reduced cognitive function in older adults142 Degenerative dementia143 Bone effects Toxic systemic effects as lead is released from bones during pregnancy or menopause144 Dental caries and tooth loss in adults145 Cardiovascular effects Hypertension146 Ischemic heart disease143 Kidney disease Kidney damage in rats and humans143,147 Liver disease Liver damage in rats147 Diabetes Increased incidence of diabetes146b Reproductive disorders Reduced fertility with paternal exposure148 Eye disorders Cataracts149 Cancer Bladder cancer150 Neurological effects Reduced children’s capacity to learn, even at very low levels of exposure141 Reduced cognitive function in older adults142 Degenerative dementia143 Bone effects Toxic systemic effects as lead is released from bones during pregnancy or menopause144 Dental caries and tooth loss in adults145 Cardiovascular effects Hypertension146 Ischemic heart disease143 Kidney disease Kidney damage in rats and humans143,147 Liver disease Liver damage in rats147 Diabetes Increased incidence of diabetes146b Reproductive disorders Reduced fertility with paternal exposure148 Eye disorders Cataracts149 Cancer Bladder cancer150 Open in new tab Table 5 Toxic effects of lead Neurological effects Reduced children’s capacity to learn, even at very low levels of exposure141 Reduced cognitive function in older adults142 Degenerative dementia143 Bone effects Toxic systemic effects as lead is released from bones during pregnancy or menopause144 Dental caries and tooth loss in adults145 Cardiovascular effects Hypertension146 Ischemic heart disease143 Kidney disease Kidney damage in rats and humans143,147 Liver disease Liver damage in rats147 Diabetes Increased incidence of diabetes146b Reproductive disorders Reduced fertility with paternal exposure148 Eye disorders Cataracts149 Cancer Bladder cancer150 Neurological effects Reduced children’s capacity to learn, even at very low levels of exposure141 Reduced cognitive function in older adults142 Degenerative dementia143 Bone effects Toxic systemic effects as lead is released from bones during pregnancy or menopause144 Dental caries and tooth loss in adults145 Cardiovascular effects Hypertension146 Ischemic heart disease143 Kidney disease Kidney damage in rats and humans143,147 Liver disease Liver damage in rats147 Diabetes Increased incidence of diabetes146b Reproductive disorders Reduced fertility with paternal exposure148 Eye disorders Cataracts149 Cancer Bladder cancer150 Open in new tab Table 6 Effects of vanadium Glucose balance and weight effects Decreased fluid intake161 Weight loss in rats162 Lowered BMI in women163 Insulin mimicker, improved glucose tolerance164 Bone effects Increased bone growth165 Inhibited cancer metastasis in bone cells166 Cardiovascular effects Decreased heart rate in animals167 Lowered or increased blood pressure in animals and humans167,168 Increased total Increased triglyceride levels in impaired glucose tolerance patients170 Reproductive effects Impaired sperm morphology and motility in rabbits81 Reduced sperm count and fertility in mice171 Neurological effects Neurotoxic effects in dopaminergic neuronal cells172 Kidney effects Kidney damage in rats162,168 Immune effects Reduced immune response in rats162 Developmental effects Adverse development in rats162 Necrotic death in neonatal cardiomyocytes in rats173 Cancer Increased chromosome mutations and DNA strand breaks in mammalian cells174 Reduced chromosome mutations in rats175 Glucose balance and weight effects Decreased fluid intake161 Weight loss in rats162 Lowered BMI in women163 Insulin mimicker, improved glucose tolerance164 Bone effects Increased bone growth165 Inhibited cancer metastasis in bone cells166 Cardiovascular effects Decreased heart rate in animals167 Lowered or increased blood pressure in animals and humans167,168 Increased total Increased triglyceride levels in impaired glucose tolerance patients170 Reproductive effects Impaired sperm morphology and motility in rabbits81 Reduced sperm count and fertility in mice171 Neurological effects Neurotoxic effects in dopaminergic neuronal cells172 Kidney effects Kidney damage in rats162,168 Immune effects Reduced immune response in rats162 Developmental effects Adverse development in rats162 Necrotic death in neonatal cardiomyocytes in rats173 Cancer Increased chromosome mutations and DNA strand breaks in mammalian cells174 Reduced chromosome mutations in rats175 Open in new tab Table 6 Effects of vanadium Glucose balance and weight effects Decreased fluid intake161 Weight loss in rats162 Lowered BMI in women163 Insulin mimicker, improved glucose tolerance164 Bone effects Increased bone growth165 Inhibited cancer metastasis in bone cells166 Cardiovascular effects Decreased heart rate in animals167 Lowered or increased blood pressure in animals and humans167,168 Increased total Increased triglyceride levels in impaired glucose tolerance patients170 Reproductive effects Impaired sperm morphology and motility in rabbits81 Reduced sperm count and fertility in mice171 Neurological effects Neurotoxic effects in dopaminergic neuronal cells172 Kidney effects Kidney damage in rats162,168 Immune effects Reduced immune response in rats162 Developmental effects Adverse development in rats162 Necrotic death in neonatal cardiomyocytes in rats173 Cancer Increased chromosome mutations and DNA strand breaks in mammalian cells174 Reduced chromosome mutations in rats175 Glucose balance and weight effects Decreased fluid intake161 Weight loss in rats162 Lowered BMI in women163 Insulin mimicker, improved glucose tolerance164 Bone effects Increased bone growth165 Inhibited cancer metastasis in bone cells166 Cardiovascular effects Decreased heart rate in animals167 Lowered or increased blood pressure in animals and humans167,168 Increased total Increased triglyceride levels in impaired glucose tolerance patients170 Reproductive effects Impaired sperm morphology and motility in rabbits81 Reduced sperm count and fertility in mice171 Neurological effects Neurotoxic effects in dopaminergic neuronal cells172 Kidney effects Kidney damage in rats162,168 Immune effects Reduced immune response in rats162 Developmental effects Adverse development in rats162 Necrotic death in neonatal cardiomyocytes in rats173 Cancer Increased chromosome mutations and DNA strand breaks in mammalian cells174 Reduced chromosome mutations in rats175 Open in new tab Fig. 1 Open in new tabDownload slide Regions with naturally occurring multiple toxic metals in groundwater. Note: Many regions have not been systematically tested for multiple toxic metals in groundwater. The distribution and geology of toxic metals in groundwater In a worldwide review of regions with arsenic in groundwater, Smedley and Kinnibergh observed that arsenic-containing reservoirs tend to be either strongly reducing aquifers derived from alluvium or loess, or inland aquifers in arid or semi-arid environments.47 Both of these types of environments tend to be in geologically young sediments, in flat low-lying areas where groundwater movement is slow, thus allowing for the accumulation rather than flushing of toxic metals released from sediments. In high pH aquifers typical of arid regions, there is desorption of arsenic and other anion-forming elements, including vanadium, fluoride, selenium and uranium. In the strongly reducing aquifers found in some deltaic regions, there is desorption of arsenic and reductive dissolution of iron and manganese oxides.47 Limited flushing is also a factor that may promote elevated concentrations of manganese, particularly where there is manganese enrichment of bedrock.48 The presence of fresh organic matter is likely to be the cause of the reducing conditions which promote the release of iron and manganese as well as arsenic.12 Iron and manganese levels may also be elevated in high pH coastal plains.14,49 Heavy use of phosphatefertilizers can increase uranium content in groundwater,50 and extensive extraction of groundwater can result in increased concentration of uranium in semi-arid areas.51 Research on groundwater has found correlations and co-occurrences between metal contaminants that generally accord with the redox condition predictions. Combinations including arsenic, fluoride and/or vanadium are frequent in arid, high pH environments (e.g., Argentina,45 Mongolia12), and combinations of arsenic, manganese, lead and/or cadmium are frequent in deltaic, low pH environments (e.g. Bangladesh,10b Cambodia52). However, some common contaminants such as manganese and uranium are found in both arid and deltaic environments, often in combination with arsenic (e.g.manganese + arsenic in Argentina,45 uranium + arsenic in Bangladesh21). One strategy that has been suggested for accessing groundwater with safe levels of arsenic in deltaic regions such as Bangladesh is to drill deeper wells. However, it must be kept in mind that arsenic is not the only potential toxic metal contaminant, and that water from deeper wells may contain other toxic metals. In one study in the Kushtia region of Bangladesh, while deeper wells tended to have less arsenic, they were found to have increased levels of uranium.21b Smedley and Kinnibergh emphasized that while arsenic regions tend to share certain geological characteristics, the specific spatial distribution of arsenic contamination is highly variable,47 necessitating the testing of individual wells in high-arsenic regions. The geology and spatial distribution of other toxic contaminants in groundwater reservoirs and wells has received much less attention, but may follow the same pattern of extreme local variability. In a case of neighbourhood uranium groundwater contamination in the United States, concentrations differed widely from one well to the next.53 Unambiguous geological indicators have not been identified for predicting the presence or concentration of one element based on the presence or concentration of another element. It is not clear whether such potential indicators even exist, although Winkel et al. argue that Holocene deltaic and organic-rich surface sediments are key indicators that arsenic contamination of the aquifer is likely.54 Slow moving groundwater with limited flushing is a major risk factor for metal contamination of groundwater, especially when the aquifer occurs in newly deposited sediments. Given the unpredictability of groundwater contamination, the prudent practice would be to screen for multiple toxic elements, including especially arsenic, manganese, lead, fluoride, and uranium, whenever new groundwaters are accessed, whether for public water supply or individual private wells.53,55 Smedley and Kinnibergh noted that arsenic and fluoride are recognized as the most dangerous natural contaminants of groundwater,47 but subsequent research has shown that manganese and uranium should also be of concern. It should be noted that even in developed countries such as the United States and Canada, which have laws governing the testing of public water supplies for toxic elements, private wells are generally unregulated and are not routinely tested for toxic metals. Furthermore, established permissible limits for manganese contamination do not take into consideration recent research demonstrating that manganese is much more toxic than previously believed, especially for children.56 In developed countries, increasing migration away from urban centres is resulting in the drilling of more private wells, and in developing countries, economic gains are permitting more people to drill private wells, increasing the risk that more people will be exposed to toxic elements in groundwater in the future. Climate change and multi-metal exposure through groundwater Global climate change may also increase the numbers of people exposed to combinations of toxic elements through groundwater. With climate change, many arid regions are expected to become more arid,57 increasing dependence on groundwater while simultaneously decreasing aquifer flushing and possibly increasing uranium concentration in groundwater.51 Rising sea levels may promote migration from coastal to arid regions, increasing populations exposed to contaminated groundwater in those regions. In coastal areas, as sea levels rise, there will likely be less flushing of aquifers, resulting in greater accumulation of arsenic, manganese and other contaminants in aquifers where conditions make these elements soluble. Seawater intrusion into aquifers may also promote the release of arsenic into groundwater.58 For example, Bangladesh is located at one of the largest river deltas in the world. The Ganges, Brahmaputra, and Meghna rivers flow south through Bangladesh to the Bay of Bengal and the Indian Ocean. Most of this country is less than 12 meters above sea level. In a normal monsoon season one-third of the cultivated land is flooded with a mixture of fresh and saltwater.59 This flooding is likely to promote the spread of arsenic and other metals in groundwater through enhancing reducing conditions in the aquifers, promoting anion exchange, and causing mixing of waters from deep and shallow aquifers. A graph of arsenic concentration versusoxidation-reduction potential is shown in Fig. 2. This graph suggests that arsenic is released from solids to Bangladesh's groundwater by reduction9 (see Fig. 3). If so, by enhancing reducing conditions, flooding also promotes the release of a wide variety of other ions, such as Fe+2 and Mn+2, into groundwater. Fig. 3 and 4 show contour maps of arsenic and chloride concentration in groundwater from shallow wells (less than 30.5 meters below ground surface). The correlation of arsenic and chloride concentrations shown in these maps suggest that arsenic may be released in the presence of chloride through anion exchange.9 Thus, saltwater intrusion from seawater flooding likely releases a wide variety of other ions, such as U+4, U+6, Mn+2, Ni+2, Cr+2, or Pb+2, into groundwater by both anion and cation exchange. Currently, Bangladesh's deep aquifer is largely free of arsenic,16a enabling the population to access safe water in many parts of the country by drilling deep wells. However, as sea levels rise, the deep aquifer may become contaminated, and deep wells may no longer provide safe water, making water treatment a necessity in large portions of the country. Thus, as global climate change takes effect, there will be an increased need for understanding metal contaminants of groundwater and their potential health effects. Fig. 2 Open in new tabDownload slide Graph of arsenic concentration (mg L−1) versusoxidation-reduction potential in water from sampled Bangladeshi wells.9a Fig. 3 Open in new tabDownload slide Map of Bangladesh showing the average arsenic concentration (mg L−1) in water from tubewells less than 30.5 meters below ground surface (● = village location; Intensity of colour indicates increasing concentration).9a Fig. 4 Open in new tabDownload slide Map of Bangladesh showing the average chloride concentration (mg L−1) in water from tubewells less than 30.5 meters below ground surface (● = village location; Intensity of colour indicates increasing concentration).9a Health effects of toxic metals from groundwater Health effects of individual toxic metals from groundwater Arsenic Arsenic causes, contributes to, or has been associated with the toxic effects listed in Table 2. Arsenic is known to cross the placenta of laboratory animals and similar arsenic concentrations have been found in cord blood and maternal blood of maternal-infant pairs exposed to arsenic in drinkingwater.11 Prenatal arsenic exposure has been associated with increased incidence of arteriosclerosis, carcinogenesis and lung cancer in mature mice88 and young adults.89 Prenatal arsenic exposure is also associated with increased frequency of acute respiratory infections in infants.78c Gender differences with arsenic toxicity are commonly reported. Male subjects tend to show arsenic lesions before women, men have a higher risk of skin cancer associated with arsenic exposure, despite similar exposure levels90 and pulmonary effects associated with arsenic exposure were found to be higher in men than women.68a In contrast, bladder cancer mortality in arsenic-exposed areas in Chile was found to be higher among women than men.91 Women of child-bearing age have been found to methylatearsenic more efficiently than men,90f,92 particularly during pregnancy.93 Arsenicmethylation efficiency in pregnant women was found to be resistant to effects of malnutrition.93 Overweight women had highly efficient arsenicmethylation compared to males of normal weight;94 high body mass index (BMI) is associated with increased oestrogen levels,95 thus, it is likely that oestrogen plays a role in the gender differences with arsenicmethylation and toxicity. Despite any potential protective benefit offered by increased oestrogen levels during pregnancy, epidemiological studies still show adverse effects of arsenic on pregnancy outcomes and infant health. In addition, gestational diabetes rates were found to increase with exposure to arsenic.73f Thus, although oestrogen may provide some protection against the toxic effects of arsenic, it does not eliminate health risks due to arsenic exposure. It is also unclear whether the mother's increased methylation of arsenic extends beneficial effects to the foetus' health. More direct research on the possible role of oestrogen providing some protection against arsenic toxicity is needed, especially research that directly compares human oestrogen levels to arsenicmethylation efficiency. Susceptibility to toxic effects from arsenic has also been shown to be affected by genetic polymorphisms.92a,96 No effective treatments for chronic arsenic poisoning have been found,68a,c,97 although early health effect of arsenic (melanosis and keratosis) can be reversed by switching to water with safe levels of arsenic.98 In Taiwan, some improvement in vascular dysfunction was found after patients switched to arsenic-free water,99 but in other cases, the adverse health effects due to exposure to arsenic persist long after exposure ceases.83c Infant mortality continued to be elevated in an arsenic-affected city in Chile for 5–8 years after exposure to arsenic ceased.86 In Argentina,100 Chile,91 China,101 and Taiwan,90a excess mortality continued to be observed in arsenic-affected cities 5–25 years after arsenic treatment systems were installed; in Taiwan increased heart disease risk in arsenic affected areas began to fall appreciably only 17–25 years after exposure ceased.71d Although some participants in a study in Bangladesh of arsenic exposure and intellectual deficits in children switched to safer wells following initial testing and their urinary arsenic levels decreased, the well-switching did not eliminate the intellectual deficits associated with the arsenic exposure from the original wells.83b Manganese Manganese causes, contributes to, or has been associated with the toxic effects listed in Table 3. Despite the fact that foetuses, infants, and children might be presumed to be highly susceptible to neurological toxins, until very recently, little research has specifically examined the possible health effects of manganese exposure for children. In rats and humans manganese absorption is higher in neonates than with adults due to the immaturity of the biliary manganeseexcretion pathways.102,114 Manganese has been found to accumulate in the brain of infants and young animals.109 Manganese effects in the brain may be particularly of concern for foetuses and infants, due to the high number of transferrin receptors elaborated by neuronal cells during development, coupled with the neural cells' putative need for transferrin for their differentiation and proliferation.102 Neonatal rats have been shown to be more likely to show symptoms of manganese neurotoxicity at the same dosing level than adults.115 Formula-fed infants had higher levels of learning disabilities than breast-fed infants; one possible explanation could be the higher manganese content in infant formulas, particularly those that are soy-based.116 Hair manganese was elevated for formula-fed but not breast-fed infants.117 In two case studies of the exposure of single families exposed to manganese through drinkingwater, in each case, the youngest family member was the first to develop clinical symptoms of manganese poisoning.108a,118 In a population-based study, 10-year-old Bangladeshi children whose drinkingwater contained high levels of manganese were found to have decreased intellectual function; this effect persisted even when co-exposure to arsenic was controlled for.56a It should be noted that this study only examined children attending school, and may have inadvertently excluded those children with intellectual or behavioural impairments severe enough to prevent them from attending school. Thus, the actual deleterious effects on behaviour and learning for the total population could potentially have been stronger than those reported in the study, which only considered the subset of the population enrolled in school. In a study involving schoolchildren in Quebec, children whose water contained high levels of manganese also had elevated levels of manganese in their hair, and a greater likelihood of having learning disabilities, problematical classroom behaviours, and hyperactivity.56b One possible mechanism for manganese increasing risk of hyperactivity may be its effects on the dopaminergic and GABAergic systems.56b,119 It should be noted that the WHO drinkingwater guidelines and US EPA RfDs for manganese are based solely on studies of adult exposures109,120—according to the WHO (World Health Organization) manganese taken by the oral route is “one of the least toxic elements”,109 but this document does take into account recent findings of neurological impairment or elevated infant mortality due to manganese exposure in children.56,113 Significantly, the cognitive deficits associated with manganese exposure in Bangladeshi children, were found with total daily intake of manganese less than 4.5 mg g−1, less than the Institute of Medicine Upper Limit (IOM UL) of 6 mg g−1 for children, which was interpolated from adult risk studies.56a Blood121 and hair56b,120b,122 manganese levels have been reported higher in girls and women, and more manganese is absorbed by women than by men given similar levels of exposures.123 One possible mechanism for manganese concentrations being higher in girls and women is that low iron stores increase manganese absorption,124 and iron deficiency is common amongst menstruating women and girls. Paradoxically, saliva manganese levels have been reported higher in boys than girls125 and symptoms of manganese toxicity were observed at a greater frequency with men than with women given similar levels of exposure.120b,126 In general, hyperactivity is found to be more common amongst boys than girls;127 however, epidemiological data have not been studied to see whether this pattern might correlate with manganese exposure and body burden. Genetic factors seem to at least partially control susceptibility to manganese toxicity. Studies of occupational and environmental exposures to manganese have suggested a genetic involvement128 and there is a great degree of inter-individual variation in manganeseretention.129 Mice with Huntington's genes were found have reduced susceptibility to manganese exposure, but enhanced susceptibility to cadmium toxicity.130 It should be noted that as with arsenic exposure, many of the neurological symptoms associated with manganese exposure persist after manganese levels return to normal,102,131 although some recovery has also been observed.132 In a case study involving learning disabilities possibly associated with manganese exposure, the learning problems persisted at least 18 months after the manganese exposure ceased.108b Chelation has not been shown to reduce symptoms of neurological toxicity.105b Uranium Uranium causes, contributes to, or has been associated with the toxic effects listed in Table 4. Children may be particularly sensitive to this toxic metal both because they consume more water per body weight than adults and because the kidneys mature postnatally.53 In a case study in which a family was exposed to high levels of uranium in their drinkingwater, it was the youngest child in the family (age 3) who first manifested symptoms of kidney damage.53 Incidence of reproductive or gonadal cancer is significantly higher for New Mexico Native American children than age-matched non-Native American children.140 It has been suggested that this may be at least partially due to elevated uranium concentrations in drinkingwater.138 Lead Lead causes, contributes to, or has been associated with the toxic effects listed in Table 5. Early in the twentieth century, the adverse effects of lead exposure on reproductive health were obvious enough for authorities to restrict women of reproductive age from working in the lead industry.151 Adverse effects of lead are often worse prenatally than postnatally.152 In utero exposure to lead is associated with increased rates of schizophrenia.153 Lead is particularly toxic for neonates because of the immaturity of the blood-brain barrier.104 Cord blood levels were found to be associated with greater neurological problems with boys than with girls.154 Boys may be more susceptible to neurotoxic effects of early lead exposure, while girls may be more susceptible to immuntoxic effects.144b Genetic polymorphisms have been reported to affect leadmetabolism;155 in particular, variants in genes associated with ironmetabolism modify leadmetabolism.156 The neurotoxicological effects of lead exposure persist after the exposure ceases.157 Evidence for renal damage can persist years after exposure to lead ceases.158 Vanadium The physiological effects and toxicity of vanadium are reviewed by Coderre and Srivastava159 and Domingo.160 Vanadium causes, contributes to, or has been associated with the effects listed in Table 6. Vanadium has been shown to promote oxidative stress in rats176 and in cell culture.172,177 Hair vanadium levels were reported higher for women than men in one study.163 Nickel Exposure to nickel can lead to lung, cardiovascular, and kidney diseases and it is a potent carcinogen known to induce cancers at any site where it is administered.178 On the cellular level, it increases oxidative products and proteins.179 Most research on the health effects of nickel has been done on industrial exposures; very little is known about the health effects of chronic exposure through drinkingwater. With industrial exposures, nickel is known to increase spontaneous abortion.180 Nickel accumulates in mouse lung and kidney tissue regardless of the route of exposure.181 Rat foetal nickel concentration was found to correspond to maternal nickel concentration.182 Men retain more nickel than women.183 Individual variation in nickel toxicity suggests there may be a genetic component to susceptibility to nickel exposure.178 Chromium Chromium III is an essential element for human nutrition184 and is the form of chromium found most commonly in drinkingwater. Chromium VI is carcinogenic but drinkingwater contamination with chromium VI is generally limited to industrial exposures.185 Chromium III is poorly absorbed from the digestive tract and it is not readily taken up by cells.186 Chromium III has been found to improve glucose intolerance and insulin resistance in mice.187 Although Chromium III is generally considered non-toxic, Chromium III picolinate and tripicolinate have been associated with DNA damage through the generation of hydroxyl radicals.188 Chromium III also inhibits DNA synthesis and the fidelity of synthesome-mediated DNA replication,189 has been found to promote oxidative stress in rats,190 and has adverse effects on human dermal fibroblasts.191 Chromium III has been found to accumulate in the liver186 and has also been found to have adverse hepatic effects in humans.192 Chronic chromium exposure reduced male fertility, implantation of foetuses, and delayed sexual maturity in mice193 and was associated with aberrant morphology and decreased motility of sperm in rabbits.81 Persons with pre-existing liver or kidney disease may be exceptionally susceptible to toxic effects from chromium and exhibit signs of chromium toxicity at concentration levels that might ordinarily be considered safe.186 Iron Iron toxicity is reviewed by Papanikalaou and Pantopoulos.194 High iron in drinkingwater has been identified as a catalyst for oxidative stress, it stimulates the growth of bacteria, and it may increase the likelihood of autoimmune diseases in genetically predisposed individuals.195 Patients with Alzheimer or Parkinson disease frequently have increased brain iron content.196 Iron may also play a role in atherosclerosis and diabetes.196,197 Iron is associated with oxidative free radicals, and thus may be a factor in aging.197a Iron overload causes changes in collagen gene expression in rats and hepatic fibrosis198 and is associated with increased risk of diabetes.199 Excess iron may also contribute to eye diseases including pterygium and macular degeneration.200 Hereditary hemochromatosis makes affected people highly susceptible to iron overload; it is found in Asian as well as European populations and may be overlooked due to iron deficiency or thalassemia.201 Barium Health effects of barium in drinkingwater are reviewed by Kojola et al.202 Barium affects blood pressure in rats and may increase risk of hypertension;203 however, other studies were not able to confirm this effect.204 It may induce cardiac arrhythmias in people over age 60.202 Barium in drinkingwater may reduce incidence of dental caries.205 Combinations of toxic metals Environmental exposure to metals almost always involves simultaneous exposure to a combination of metals as well as other environmental factors.206 When water from high arsenic areas is screened for other metals, it is quite often found to have multiple elements exceeding drinkingwater guidelines (e.g.arsenic + manganese, uranium, lead, nickel, chromium, barium, and/or cadmium in South and Southeast Asia,10b,16,21,56a,207 arsenic + uranium, and/or vanadium in Argentina,2,45,100 arsenic + manganese in China:68c Studies of metal exposure frequently note evidence of co-exposure by other metals.53,56a,83a,83c,113,120a,208 In addition to exposure through drinkingwater, populations are also commonly exposed to various toxic metal through diet, smoking, drug-therapies, and alcohol intake. Smoking and use of tobacco products, including exposure to second-hand smoke, implies significant exposure to cadmium,209 and may also involve lead,145,209 vanadium,171 arsenic,209e uranium,210 antimony,209g or barium.209g For these reasons, heavy metal interactions with drinkingwater contaminants including cadmium and other metals must be considered when populations exposed to metals through drinkingwater include smokers. Environmental lead exposure is also common in countries with metal-contaminated drinkingwater, such as Bangladesh, where many children have blood lead levels above 10 μg/dl WHO guideline.211 When subjects are exposed to metals in combination, the metals may each have their own typical health effects; they may also have synergistic or antagonistic effects on each other. In calculating cancer risks due to drinkingwater contaminants, it is vital to consider not only the health risks due to individual contaminants, but also those risks due to combinations of contaminants. Effects on absorption and excretion Ingestion of metals in combination may increase or decrease the absorption of the individual metals in the digestive tract. Some metals promote the excretion of other metals. The absorption and excretion effects of metals are summarized in Table 7. Table 7 Interaction effects on absorption and excretion of metals Element . Interaction effects on absorption and excretion of metals (arrow shows likely direction of net interaction effect on body burden) . Zinc ↓Arsenic212 ↓Lead157,213 ↓Manganese214 ↓chromium215 ↓Iron216 and haemoglobin217 Selenium ↓Arsenic218 ↓Lead157 Calcium ↓Manganese219 ↓Lead220 ↓Chromium221 ↓Iron222 ↓Zinc223 Iron ↓Arsenic69,195,224 ↓Manganese214 ↓Lead225 ↓Cadmium226 ↓Chromium215 ↓Calcium222 Chromium ↓ Lead157 Vanadium ↓ Chromium227 Barium ↑ Calcium204b Aluminium ↓ Fluoride228 Arsenic ↓ Selenium218a,c Uranium ↓ Calcium134 Nickel ↓Manganese, zinc and magnesium229 șIron230 ↓Calcium231 ↓Ascorbic acid232 Manganese ↑Cadmium157 ↓Iron104,233 ↓Zinc214 ↓Calcium231 Lead ↓Arsenic from bones234 ↓Zinc, iron and manganese from the brain235 ↓Zinc213a ↓Selenium157 Cadmium ↑Nickel236 ↓Selenium237 ↓Iron237,238 ↓Zinc214,239 ↓Calcium231,238,240 Element . Interaction effects on absorption and excretion of metals (arrow shows likely direction of net interaction effect on body burden) . Zinc ↓Arsenic212 ↓Lead157,213 ↓Manganese214 ↓chromium215 ↓Iron216 and haemoglobin217 Selenium ↓Arsenic218 ↓Lead157 Calcium ↓Manganese219 ↓Lead220 ↓Chromium221 ↓Iron222 ↓Zinc223 Iron ↓Arsenic69,195,224 ↓Manganese214 ↓Lead225 ↓Cadmium226 ↓Chromium215 ↓Calcium222 Chromium ↓ Lead157 Vanadium ↓ Chromium227 Barium ↑ Calcium204b Aluminium ↓ Fluoride228 Arsenic ↓ Selenium218a,c Uranium ↓ Calcium134 Nickel ↓Manganese, zinc and magnesium229 șIron230 ↓Calcium231 ↓Ascorbic acid232 Manganese ↑Cadmium157 ↓Iron104,233 ↓Zinc214 ↓Calcium231 Lead ↓Arsenic from bones234 ↓Zinc, iron and manganese from the brain235 ↓Zinc213a ↓Selenium157 Cadmium ↑Nickel236 ↓Selenium237 ↓Iron237,238 ↓Zinc214,239 ↓Calcium231,238,240 Open in new tab Table 7 Interaction effects on absorption and excretion of metals Element . Interaction effects on absorption and excretion of metals (arrow shows likely direction of net interaction effect on body burden) . Zinc ↓Arsenic212 ↓Lead157,213 ↓Manganese214 ↓chromium215 ↓Iron216 and haemoglobin217 Selenium ↓Arsenic218 ↓Lead157 Calcium ↓Manganese219 ↓Lead220 ↓Chromium221 ↓Iron222 ↓Zinc223 Iron ↓Arsenic69,195,224 ↓Manganese214 ↓Lead225 ↓Cadmium226 ↓Chromium215 ↓Calcium222 Chromium ↓ Lead157 Vanadium ↓ Chromium227 Barium ↑ Calcium204b Aluminium ↓ Fluoride228 Arsenic ↓ Selenium218a,c Uranium ↓ Calcium134 Nickel ↓Manganese, zinc and magnesium229 șIron230 ↓Calcium231 ↓Ascorbic acid232 Manganese ↑Cadmium157 ↓Iron104,233 ↓Zinc214 ↓Calcium231 Lead ↓Arsenic from bones234 ↓Zinc, iron and manganese from the brain235 ↓Zinc213a ↓Selenium157 Cadmium ↑Nickel236 ↓Selenium237 ↓Iron237,238 ↓Zinc214,239 ↓Calcium231,238,240 Element . Interaction effects on absorption and excretion of metals (arrow shows likely direction of net interaction effect on body burden) . Zinc ↓Arsenic212 ↓Lead157,213 ↓Manganese214 ↓chromium215 ↓Iron216 and haemoglobin217 Selenium ↓Arsenic218 ↓Lead157 Calcium ↓Manganese219 ↓Lead220 ↓Chromium221 ↓Iron222 ↓Zinc223 Iron ↓Arsenic69,195,224 ↓Manganese214 ↓Lead225 ↓Cadmium226 ↓Chromium215 ↓Calcium222 Chromium ↓ Lead157 Vanadium ↓ Chromium227 Barium ↑ Calcium204b Aluminium ↓ Fluoride228 Arsenic ↓ Selenium218a,c Uranium ↓ Calcium134 Nickel ↓Manganese, zinc and magnesium229 șIron230 ↓Calcium231 ↓Ascorbic acid232 Manganese ↑Cadmium157 ↓Iron104,233 ↓Zinc214 ↓Calcium231 Lead ↓Arsenic from bones234 ↓Zinc, iron and manganese from the brain235 ↓Zinc213a ↓Selenium157 Cadmium ↑Nickel236 ↓Selenium237 ↓Iron237,238 ↓Zinc214,239 ↓Calcium231,238,240 Open in new tab Zinc absorption is also increased by concurrent protein consumption,223 but reduced by concurrent casein consumption,239 phytates, or dietary fibre.238,239 Zinc promotes absorption of vitamin A.241 During pregnancy, zinc and cadmium absorption from oral routes are increased in rats and humans.242 Iron absorption is increased by concurrent consumption of ascorbic acid243 or vitamin A,244 but decreased by concurrent consumption of chilli245 or tea.246 Chromium absorption is reduced by concurrent phytate consumption but increased by concurrent oxalate consumption.247 Manganese absorption is reduced by concurrent consumption of dietary fibre, phytates, phosphorus, oxalic acid or tannic acid.248 Since lead is associated with reduced levels of brain manganese, co-exposure to lead might reduce the neurotoxic effects of manganese. However, it is not clearly whether any potential benefits due to such exposure would outweigh the neurotoxic effects of the lead exposure itself. If nickel also reduces tissue concentrations of manganese in humans as with animals, concurrent exposure to nickel may provide some protection against exposure to manganese; however, it is also possible that ingestion of nickel could increase manganese absorption by reducing calcium stores, since concurrent calcium consumption reduces manganese absorption. It is also possible that ingestion of uranium or cadmium may increase manganese absorption by reducing calcium stores. Deficiencies of essential trace metal elements may also affect absorption of toxic metals, as summarized in Table 8. Table 8 Interaction effects of trace metal deficiencies on absorption and excretion of metals Deficiency . Interaction effects on absorption and excretion of metals (arrow shows likely direction of net interaction effect on body burden) . Iron ↑Manganese absorption214,249 ↑Arsenic in liver250 ↑Lead absorption104,157,214,237,251 ↑Cadmium104,214,237,252 ↑Zinc214 Zinc ↑Lead213a ↑Cadmium237 Calcium ↑ Lead157,253 Deficiency . Interaction effects on absorption and excretion of metals (arrow shows likely direction of net interaction effect on body burden) . Iron ↑Manganese absorption214,249 ↑Arsenic in liver250 ↑Lead absorption104,157,214,237,251 ↑Cadmium104,214,237,252 ↑Zinc214 Zinc ↑Lead213a ↑Cadmium237 Calcium ↑ Lead157,253 Open in new tab Table 8 Interaction effects of trace metal deficiencies on absorption and excretion of metals Deficiency . Interaction effects on absorption and excretion of metals (arrow shows likely direction of net interaction effect on body burden) . Iron ↑Manganese absorption214,249 ↑Arsenic in liver250 ↑Lead absorption104,157,214,237,251 ↑Cadmium104,214,237,252 ↑Zinc214 Zinc ↑Lead213a ↑Cadmium237 Calcium ↑ Lead157,253 Deficiency . Interaction effects on absorption and excretion of metals (arrow shows likely direction of net interaction effect on body burden) . Iron ↑Manganese absorption214,249 ↑Arsenic in liver250 ↑Lead absorption104,157,214,237,251 ↑Cadmium104,214,237,252 ↑Zinc214 Zinc ↑Lead213a ↑Cadmium237 Calcium ↑ Lead157,253 Open in new tab Women with similar exposure histories tend to have higher levels of blood cadmium levels than men, possibly because of lower iron stores.254 Chemical interactions Elements with similar physical and chemical properties may act antagonistically by competing for transport and storage sites and displacing each other from enzymatic and receptor proteins.157,255 Conversely, they may act synergistically by promoting oxidative and other cellular damage. While additivity is generally assumed for low level co-exposures,256 synergistic cytotoxicity effects have been reported with human keratinocyte cells with chemical mixtures including arsenic, cadmium, chromium, and lead at low doses.257 Cadmium, chromium, nickel and lead may interfere with DNA repair, leading to damage not directly attributable to the heavy metals.258 Competition and antagonistic reactions Zinc, selenium, and calcium appear to provide some protection against heavy metal toxicity157,213b,259 and exposure to heavy metals can reduce the anti-oxidative functions of these essential trace elements. Interactions between metals involving oxidative stress are reviewed by Valko.260 Zinc is necessary for DNA repair, and zinc deficiency results in impaired synthesis of DNA.261 Zinc can be replaced as an enzymatic co-factor by mercury, cadmium, or lead with adverse consequences.174,262 Zinc is also important for production of metallothionein, an intracellular metal-binding protein that sequesters heavy metals.104,263 Arsenic is known to promote oxidative stress.264 Arsenic competes with zinc in metal-binding proteins involved in DNA repair265 and exposure to arsenic reduces DNA repair capability in cell culture.266 Co-administration of zinc and arsenic results in a reduction of arsenic-related liver damage in rats;224 similarly, co-administration of zinc with nickel results in a reduction of nickel-related damage.267 Selenium protects against oxidative stress through glutathione peroxidase and other antioxidant activity.218a Selenium and arsenic are chemically similar; thus, they act antagonistically in certain reactions.268 Arsenic inhibits the action of selenium, causing an apparent deficiency in the glutathione peroxidase system.11 Selenium has been found to reduce the toxicity of arsenic,259a,269 selenium deficiencies have been linked to arsenic-induced skin cancers,270 and dietary supplements with selenium may counter some degree of arsenic toxicity.271 Selenium has also been shown to have antagonistic effects on cadmium, lead and nickel,157,263,272 although in order for selenium to have significant protective effects against lead, selenium must be given at levels high enough to have its own toxic effects235 and high doses of selenium appear to exaggerate lead toxicity in rats.273 Smokers are reported to have lower serum selenium levels, and heavy smokers also have depressed serum zinc levels.274 Arsenic is methylated in the liver with an enzymatic reaction that requires glutathione and S-adenosylmethionine.275 Thus, metals that interfere with the required methylation reactions reduce the elimination of arsenic and prolong exposure, potentially increasing the toxic effects. In particular, selenium and zinc may be required for methylation reactions,276 and selenium may increase arsenicmethylation capacity,94 so exposure to arsenic may increase requirements for selenium and zinc; selenium and zinc deficiencies may increase arsenic toxicity. Oestrogen increases choline synthesis,277 which enables the formation of methionine, a necessary amino acid for arsenicmethylation. Smokers and chewers of betel quid were found to have reduced arsenicmethylation efficiency;92b smokers of bidis, hand-rolled cigarettes popular in South Asia, were found to methylatearsenic less efficiently than smokers of mass produced cigarettes.90f Chisholm suggested that heavy metals are likely to interact with immune proteins, particularly those containing sulphur.262 The toxic effects of concurrent exposure to arsenic and antimony may be sub-additive because of competition for sulfhydryl groups.278 Arsenic inhibits the increase in serum creatinine associated with cadmium,279 and lead tends to antagonize the cadmium-induced rise in N-acetyl-β-d-glucosaminidase,279 suggesting that co-exposure to arsenic and/or lead might provide some degree of protection against the renal damage due to cadmium exposure. However, synergistic effects between arsenic and cadmium on nephrotoxicity in a human population co-exposed to both metals have been reported.280 The trivalent arsenical phenylarsine oxide forms thioarsenite complexes with vicinal or paired thio groups of cellular proteins, and this has been shown to inhibit glucose transport in adipocytes.281 Zinc and selenium have been found to protect against cadmium-induced alterations in glucose tolerance282 in rats, but it is not known whether zinc and selenium can protect against arsenic-induced diabetes. Nickel antagonizes manganese-induced neurotoxicity in rats283 and depletes intracellular ascorbate.232 Mimicry is one type of competitive mechanism through which toxic metals may gain access to cells.255 Selenium may be a functional mimicker of oestrogen.255 Oestrogen has been found to provide some protection against oxidative stress mechanisms in mice.284 Other metallomimics of oestrogen include cadmium,285 antimony, arsenic, barium, chromium, lead, nickel, uranium, and vanadium.286 Carcinogenesis and synergistic effects Some metals considered carcinogenic may require co-exposure to other metals or toxins in order for carcinogenesis to occur. Alternatively, the carcinogenicity of some metals may be increased by other oxidative stressors.174 There are some indications that carcinogenesis associated with arsenic may be due to co-exposure to other carcinogens.287 Smoking involves significant exposure to cadmium, and arsenic was found to potentiate the effects of cadmium when co-ingested.288 Smoking has been associated with increased arsenic toxicity90c,d,289 and risk of skin lesions61b,90c,d,290 and lung, bladder and skin cancer is higher in smokers exposed to arsenic through drinkingwater than non-smokers or smokers who are not exposed to arsenic through drinkingwater.289a,290,291,94 Betel nut users were also found to have increased risk of developing arsenic-induced skin lesions;289b the effect of damage observed with oral mucosal cells appeared to show evidence for a synergistic rather than additive effect between betel quid use and arsenic.292 Arsenic may also act as a co-genotoxin for methyl methanesulfonate and UV-induced pyrimidine dimers.293 Mice exposed to arsenic in addition to UV-light showed greater incidence of skin cancers than mice exposed to UV-light alone287f,h,294 and human keratinocytes showed synergistic effects when exposed to UV-light in the presence of arsenic.266,295 A dose-response effect with UV and arsenic exposure was noted in humans,90e while selenium was found to block the cancer enhancement effect of arsenic but not of UVR in mice.296 Exposure to sunlight was also found to predict arsenic lesions in a Bangladeshi population.90d,297 Chen et al. also reported a possible relationship between arsenic toxicity and exposure to fertilizers, but it was not noted in that study whether socio-economic status (SES) had been taken into consideration as a potential confounding factor.90d Ingestion of arsenic has been found to increase the incidence of spontaneous viral cancers.218a Pretreatment with arsenic at low levels has been found to dramatically increase liver damage in mice exposed to lipopolysaccharide.298 Nickel may also require exposure to another toxin to potentiate its mutagenic effects;178 arsenic and nickel may act synergistically in the lungs to produce lung cancer. Nickel has been found to increase skin cancer risk with mice exposed to UVR.299 On its own, chromium III is not known to have carcinogenic effects;300 however, it could potentiate mutagenic effects of other metals by causing DNA damage.188a,301 A synergistic effect on the teratogenecity of lead and cadmium has been reported;302 lead and cadmium are also reported to interact synergistically with testicular effects,303 but co-exposure to zinc may decrease the testicular effects.304 An interaction effect on children's IQ has been reported for lead and manganese.305 A risk assessment study of metal mixtures predicted that lead may have a greater than additive effect when combined with arsenic or cadmium for neurological problems.303 It has been suggested that there could be possible synergistic effects between arsenic and antimony, due to similarities between these metals.306 Exacerbation of health effects The effective toxicity of metals may be increased when multiple metals have adverse effects on the same organs or physiological systems. Effects that might ordinarily be minor may result in critical damage when multi-metal exposure occurs. Conversely, in some instances, multi-metal exposure may provide some degree of protection against adverse effects of some metals. Brain and central nervous system Heavy metal exposure has been found to be above average in violent or aggressive persons.107b,307 Peripheral neuropathy due to arsenic68c may be particularly debilitating if there is co-exposure to manganese, which causes tremors and loss of balance105a and is associated with somatisation disorder.106 Iron deficiency anaemia increases manganese concentrations in the brain,308 and manganese exposure with concurrent iron deficiency magnified deleterious manganese effects in the rat brain,309 making manganese exposure particularly problematic for those with iron deficiency anaemia or low iron intake, especially since iron deficiency anaemia is also linked to increased absorption of lead and cadmium, which each have their own toxic neurological effects. This is of special concern in South Asia where iron deficiency anaemia is endemic310 and manganese concentrations in the drinkingwater are frequently high, and concurrent exposures to lead or cadmium are common. In addition, iron deficiency anaemia is independently associated with problems of neurological development and lower mental and motor test scores311 and increased levels of neuropsychiatric symptoms106 and iron stores, like manganese, affect the dopaminergic system.106 Zinc is essential for the development and function of the nervous system.261 Zinc deficiency impairs brain function216,261,312 and is associated with increased levels of depression;313 since nickel, lead, and cadmium exposure reduce zinc absorption and increase zincexcretion, they may indirectly affect brain function by reducing essential zinc stores. Neurobehavioral effects and learning disabilities associated with childhood exposure to one toxic metal may be increased synergistically when exposure is to multiple metals. The blood-brain barrier develops only during the first year of life, increasing risks associated with toxic metal exposures to foetus and neonates. Visual-motor performance deficits were reported in children exposed to arsenic and lead in combination, as well as possible problems with attention deficit and distractibility.83a,208a,314 Mentally retarded and learning disabled children show higher than average levels of toxic metals, particularly cadmium and lead.314a,315 Arsenic, and manganese have been independently linked to intelligence deficits and learning disabilities in children; in the absence of evidence for antagonistic effects between these two metals, it is likely that adverse effects due to co-exposure to these metals is at least additive, and further exacerbated by co-exposure to lead. Kidneys, bones, and hypertension The kidneys reabsorb and accumulate bivalent metals, and they are the main route of excretion for heavy metals, making them particularly susceptible to toxicity from heavy metals.316 It has been suggested that if body stores of selenium are low, arsenic will be excreted through the kidneys, increasing risk of kidney and bladder cancer.218a Metallothionein may be responsible for selective accumulation of cadmium in the kidneys, potentiating the nephrotoxic effects of this metal.157,253 It is possible that kidney damage associated with other toxic metals may be due to a similar mechanism. Kidney damage has been observed in children with low level exposures to mixtures of cadmium, mercury, lead, and arsenic.279 A risk assessment study of mixtures of metals predicted that cadmium, arsenic, lead and chromium(vi) will have a less than additive risk for renal effects;303 concurrent exposure to lead and cadmium resulted in lower than expected renal effects in rats.288 In contrast, mice who consumed both arsenic and cadmium showed greater renal effects than when fed either arsenic or cadmium alone.317 Persons with renal insufficiency show increased levels of blood vanadate with vanadium exposure,318 thus co-exposure to metals associated with kidney damage is of special concern when there is exposure to vanadium. Exposure to uranium through drinkingwater has been associated with disturbances of iron homeostasis in the kidney in rats319 and causes kidney damage.135a,320 Nickel, lead, chromium and vanadium exposure are also associated with kidney damage.162,178,321 Patients with kidney disease are advised to restrict intake of chromium because of increased susceptibility to its toxic effects,322 thus exposure to chromium at levels that might ordinarily be considered safe may have increased adverse effects for persons with concurrent exposure to arsenic, uranium, nickel, or lead exposure. Renal disease is also associated with zinc deficiency,323 which is promoted by ingestion of lead, nickel, or cadmium. Chronic renal insufficiency is associated with changes in bone metabolism.324 Kidney damage due to cadmium exposure increases levels of bone resorption markers and may induce osteoporosis through increasing excretion of calcium.240a,325 Cadmium exposure concurrent with low calcium intake may result in Itai-Itai disease.326 Exposure to uranium likewise increases bone resorption markers;134 this is of particular concern for smokers drinkinguranium-enriched water due to their concurrent exposure to cadmium through smoking. Iron deficiency has been shown to decrease bone density in rats.327 Through causing renal insufficiency, metals associated with kidney damage, including uranium, nickel, lead, and chromium may increase risk of osteoporosis, particularly with smokers, who have additional exposure to cadmium, and exposure to uranium, nickel, lead, or chromium may be of added concern for populations with high rates of iron deficiency. Arsenic,72a,328 uranium136 and lead146b exposure have been independently shown to be associated with hypertension. Hypertension is known to be a risk factor for kidney disease and kidney disease itself is also associated with increased levels of hypertension.329 Thus, concurrent exposure to a combination of metals including arsenic, uranium, manganese, nickel, lead, or chromium may synergistically bring about both hypertension and kidney disease; these effects may be further exacerbated by smoking, which is also independently associated with increased hypertension and additional exposure to cadmium, which is itself associated with renal damage.330 Hormones, reproductive system, and fertility Gender differences in arsenic symptoms suggest that oestrogen may provide some protection against arsenic toxicity. Oestrogen may also protect against bone resorption due to uranium exposure.134 Uranium seems to have estrogenic activity.138 It is an open question whether exposure to uranium might mitigate some amount of arsenic toxicity through these estrogenic effects. Arsenic exposure in utero has been found to affect genes encoding oestrogensignalling in mice.331 Zinc supplementation can reduce manganese-induced testicular damage and neurotoxicity.283,332 Cadmium and arsenic are likely endocrine disruptors,333 which may be linked to increased prostate cancer risk associated with exposure to these toxins;334 as an oestrogen mimicker, cadmium may have adverse effects for female offspring.144b Population fertility rates are likely to be affected through exposures to combinations of metals. Population fertility is likely to be lowered because of reduced testosterone levels and erectile dysfunction due to arsenic exposure,80 testes damage due to manganese exposure,110 reduced male fertility due to lead,148 chromium,322 vanadium171 or molybdenum335 exposure, reduced sperm motility due to arsenic, chromium, or vanadium exposure,81 oocyte or follicular changes due to uranium exposure,138,139 reduced implantation due to chromium exposure,193 delayed sexual maturity due to chromium exposure,193 and increased chance of spontaneous abortion and infant mortality due to arsenic, manganese or nickel exposure, acting alone or in combination.84a,b,84d,86,180,336 However, in one study in Bangladesh, excess infant mortality due to manganese exposure may have been reduced in areas with co-exposure to arsenic,113 although SES may have been a potential confounding factor in that study. Pancreas and glucose balance Chromium III and vanadium can reduce blood glucose levels or improve glucose tolerance.164c,227,337 Thus, it is conceivable that consuming water with high levels of chromium or vanadium could provide some protection against adverse effects of arsenic or lead on promoting diabetes. Zinc and selenium may also potentially improve glucose tolerance under conditions of toxic metal exposure.255,282 Zinc is required for the normal function of the pancreas216 and zinc deficiency may promote the development of diabetes;338 thus, exposure to metals which reduce zinc absorption or increase zincexcretion such as lead, cadmium, and nickel, may increase risk of glucose imbalance. Cadmium can also promote hyperglycaemia,339 which may further increase risk of diabetes for smokers in populations exposed to arsenic, lead, and/or nickel through drinkingwater. Liver Concurrent liver disease predisposes patients to symptoms of manganese toxicity under conditions of manganese exposure.128 If liver function is compromised, manganese is not excreted normally, and may result in increased accumulation in the brain,340 where it may cause neurological problems. Arsenic causes liver damage68c,341 and exposure to arsenic increased liver iron concentration in rats.288 Patients with liver disease are advised to limit intake of chromium because of risk of further liver damage.186 Thus, arsenic and chromium exposure are of particular concern if there is concurrent manganese exposure since they may worsen hepatic problems due to the multi-metal exposure and exacerbate neurological problems due to the manganese exposure. Iron-deficiency anaemia has been found to exaggerate hepatic effects of manganese exposure.249b Zinc deficiency is common in patients with cirrhosis,216 thus arsenic-induced liver damage may reduce zinc stores, resulting in adverse systemic effects from reductions in this essential anti-oxidant. Pulmonary system Arsenic exposure may be particularly dangerous for smokers because of the synergistic effects of co-carcinogens such as cadmium and other heavy metals contained in cigarette smoke.209a Also, the increased levels of pulmonary disease found with smokers may be exacerbated by exposure to arsenic since arsenic in the absence of smoking has been found to increase levels of chronic cough and chronic bronchitis.68c Low levels of antioxidants in the lungs may potentiate the adverse effects of arsenic in the pulmonary system.218a Concurrent exposure to arsenic and nickel is of particular concern because both metals are associated with lung diseases. Cardiovascular system Insufficient dietary chromium is associated with increased cardiovascular problems,227 thus concurrent chromium exposure may provide some protection against cardiovascular effects of other metals. Vanadium has been shown to provide some protection against hypertension and vascular diseases,342 so co-exposure to vanadium may decrease cardiac effects of other metals. Both arsenic exposure and nickel exposure have been shown independently to be associated with increased risk of myocardial infarction.68c,178 Thus, concurrent exposure to both arsenic and nickel could potentially further increase this risk. Possible synergistic effects between arsenic and cadmium have been reported for rat heart tissue.343 Dietary interactions with groundwater toxic metals Additional exposure to metals through food For many metals, exposure through drinkingwater is supplemented by exposure through food. Dietary exposure to manganese123 and vanadium171 generally exceeds exposure through drinkingwater. This must be considered when calculating drinkingwater guidelines, since drinkingwater is responsible for supplemental, not sole exposure to metals. Rice, in particular, concentrates arsenic, and contains as much as 10 times the arsenic content as other foods;344 rice is the predominant dietary contributor of inorganic arsenic.11,345 In South Asian regions where groundwater is contaminated by arsenic and rice consumption is high, rice contributes approximately half of daily exposure to arsenic.344–346 Arsenic also accumulates in the skins of root vegetables;346j however, in Bangladesh, rice contributes a substantially higher proportion of arsenic to the diet than other vegetables or legumes.345 Dietary supplementation of arsenic is a more significant factor for those whose drinkingwater contains lower levels of toxic metals.346g,h,347 It has been noted that laboratory studies with animals involving low-dose exposure to arsenic in drinkingwater can be confounded by arsenic that is incidentally supplied in standard laboratory feed.348 While total dietary exposure to manganese is generally highest from food sources,349 manganese has greatest bioavailability in water.350 In foods, manganese levels tend to be relatively low in meats and poultry and higher in nuts, cereals, legumes, and leafy greens;248 blood manganese concentration has been found to be related to frequency of consumption of grains and leafy greens.121 Vegetarian diets may be higher in manganese than non-vegetarian diets.351 Tea is particularly high in manganese, but tannins greatly reduce its bioavailability from this source.248,352 Cadmium levels in food, while generally low, are highest in grains, leafy vegetables, root vegetables, organ meats, and shellfish,353 and rice grown in cadmium-contaminated soils.354 Uranium levels tend to be higher in root vegetables than other foods.50 Certain meat products in Pakistan and India have been found to contain unacceptably high levels of arsenic, cadmium, and lead; the Pakistani products also contain relatively low levels of zinc.355 Drinking water provides only a minor component of overall intake of zinc.216 Zinc is most commonly obtained from and most absorbable from animal products261,356 and a high-protein diet is probably necessary in order to obtain recommended daily allowances of zinc from food.357 Vegetarian diets tend to result in less zinc absorbance than diets that include meat.358 The only significant dietary source of selenium is animal protein, and the levels of selenium in animal protein are dependent on the selenium levels of the plants consumed by the animals, which are in turn, dependent on the selenium content of the soils and irrigation water.218a Elevated levels of arsenic, iron, and manganese were found in soils that received irrigation from groundwater with high concentrations of these contaminants, which could lead to elevated levels of these contaminants in crops.359 Vegetables irrigated with arsenic-rich water have elevated levels of arsenic,346d,k,360 as does tobacco.361 Rice straw is used as animal feed in Bangladesh, and may contribute to arsenic levels in beef.360a Foods grown in Bangladesh and imported to the UK contained 2 to 100 times as much arsenic as similar foods grown in the UK.346c Arsenic content of food was also found to be high in a region of Thailand.362 It has also been suggested that fertilizer and pesticide use may contribute to heavy metal contamination of soils.363 Both soy and rice are known to accumulate manganese.114 Grains and rice may accumulate cadmium if grown in polluted soil or irrigated with contaminated water157,364 and tobacco naturally accumulates cadmium.365 Cadmium levels in Bangladeshi vegetables were lower than those reported in the developed world, but lead levels were higher; zinc levels were also lower.360b In a market basket survey in Bangladesh, dietary intake of manganese and nickel was high, while zinc intake was low;346a however, zinc content of vegetables grown in one region of Bangladesh was high.363 Lead content in chicken eggs has been found to correlate with lead concentrations in soil.366 Preparation and cooking methods can alter the arsenic content and arsenic species found in food.367 Rice cooked in high-arsenic water contained twice as much arsenic as raw rice;347a,368 milling rice or parboiling in arsenic-free water can reduce the arsenic content of cooked rice.360c Even when safe drinkingwater is provided, arsenic levels in hair may still be elevated due to continuing to cook food in arsenic-contaminated water.369 Arsenic levels in cooked food in Bangladesh correlated with arsenic levels in household drinkingwater.346h Beans and legumes absorb arsenic when cooked in water containing arsenic.370 This is of particular concern for vegetarians and people of lower SES in South Asia who often eat legumes in place of meat. Some studies have found reduced arsenic symptoms amongst people who eat animal protein, but one explanation for this finding could be that people who consume little animal protein also consume relatively large amounts of beans and legumes, which when cooked in arsenic-contaminated water, may increase their arsenic exposure. The concentrations of other metals in cooked foods and possible effects of cooking methods have not been studied; for instance, it is not known how total manganese content and bioavailability in tea may be affected by the manganese concentration of the water with which the tea is made. The metallic composition of cooking and serving dishes and potential for leaching metals also needs to be considered when calculating total metal exposure. Leaching from kitchen utensils and water pipes can add significantly to daily intake of nickel, chromium, and lead.227,371 Chromium exposure may be increased when acidic food is prepared or served in stainless steel utensils;186 such utensils are commonly used as serving dishes throughout South Asia. Glass dinnerware, glazed ceramic tea mugs, and pressure cookers produced in India were found to leach lead, cadmium, manganese, nickel, chromium, iron, and/or zinc.372 Interactions with dietary components and deficiencies Certain dietary constituents affect absorption of metals. Nutritional deficiencies and general nutritional levels also affect the outcomes of exposures to toxic metals. Protein S-adenosylmethionine levels in rats are dependent on dietary consumption of methionine and choline;373 adequate protein intake has been identified as the most important dietary factor affecting arsenic toxicity.263 Low protein diets have also been found to be associated with reduced arsenicmethylation efficiency and greater arsenic toxicity71a,289b,374 and subjects who consumed higher levels of animal protein seemed to have decreased adverse health effects due to arsenic exposure.346h Protein intake also affects lead toxicity375 and low protein diets increase absorption of cadmium in animals.263 It should be noted that studies comparing arsenic toxicity to animal protein intake may have zinc and/or selenium intake as a confounding factor, since intake of zinc and selenium are strongly correlated with animal protein intake, and zinc and selenium likely reduce arsenic toxicity. Thus, further study is needed to differentiate the effects that zinc, selenium, protein, and animal protein have on arsenic and other metal toxicity. Vitamins B vitamins have been identified as essential for arsenicmethylation reactions.297,346h,376 Increased intake of B vitamins reduces arsenic toxicity297,346 and people who consume diets with low amounts of niacin or folate were found to have reduced arsenicmethylation efficiency.374d Folate supplementation has been found to increase arsenicmethylation efficiency377 and lower blood arsenic levels. People with higher plasma folate levels were found to have decreased risk of urothelial carcinoma378 and skin lesions.379 Diets low in folate were associated with increased chance of arsenic-induced skin lesions.374c Thus a deficiency in B vitamins may increase the toxic effects of arsenic, and exposure to arsenic may increase dietary requirements for B vitamins.374c Smoking is associated with decreased levels of vitamin B12.380 Increased consumption of antioxidants (in particular, vitamins A, C, and E and beta-carotene) reduces skin cancer incidence and arsenic toxicity,90a,272b,297,346h and vitamin E reduces skin cancer risk for mice exposed to nickel and UVR299 and lead toxicity for rabbits exposed to lead.375 Increased consumption of fruits and yellow and light green vegetables was associated with reduced odds of lung cancer in tin miners exposed to arsenic.263 Smoking, both active and passive, has been associated with decreased blood levels of vitamins A, C, iron, zinc, and selenium.381 Vitamin D increases absorption of iron, zinc, and lead.263 Dietary fibre and other dietary constituents Consumption of large quantities of whole grains, with their high phytate and lignin content, can result in zinc deficiency through interfering with zinc absorption, especially if there is low consumption of animal products.261 Thus, diets high in whole grains, legumes, and other sources of dietary fibre and low in animal products may exacerbate adverse health effects from toxic metals by promoting zinc deficiency. Arsenic has been found to decrease absorption of nutrients and has been associated with weight loss;11 thus, consumption of arsenic may promote nutritional deficiencies that increase absorption and adverse effects of other toxic metals. Higher total food and fat intake are associated with decreased lead uptake.263 Dietary deficiencies, malnutrition, and metal toxicity Dietary deficiencies can increase absorption of toxic metals and present shortfalls of antioxidants important for counteracting toxic effects of metals.157 An animal suffering from multiple nutritional deficiencies may be “highly vulnerable” to the toxic effects of heavy metals and nutritional status plays a significant role in determining risk response measures for a given metal.268 Adverse effects of trace elements usually begin to appear at 20 or more times their required intake levels, but with nutrient deficiencies, this may be reduced to only 2 to 3 times the required intake levels.238 Deficiency in methionine, folate, vitamin B12, or selenium decrease arsenicmethylation ability and increase arsenic toxicity,289b,61 while zinc deficiency is associated with decreased ability for DNA repair.261 Iron deficiency increases lead deposition in the bones, and calcium deficiency increases lead and cadmium deposition in kidneys, bones and other tissues.268 Vitamin E deficiency has been shown to increase the toxic effects of lead in rats; concurrent calcium deficiency further amplifies this effect.268 Zinc, iron, folate, vitamin B12, vitamin A, and selenium deficiencies are common throughout the developing world;382 in particular, they are common in regions affected by multiple metal contamination of groundwater (Bangladesh,310,383 India,384 Nepal,385 Cambodia,386 Vietnam;387 Thailand;388 Mongolia389), factors which may be exacerbating the toxic effects of metal exposures. Smokers have been found to have decreased levels of beta-carotene, vitamin C and selenium compared to non-smokers,390 and female smokers and chewers of betel quid in Pakistan were found to have elevated levels of hair and blood cadmium and depressed levels of zinc,391 further increasing risks of metal toxicity for tobacco users in regions with metal-contaminated drinkingwater. Low-level exposures to metals that would otherwise produce at most subtle effects in healthy subjects may produce full-blown toxicity effects in malnourished subjects.208a Malnutrition is associated with increased sensitivity to arsenic toxicity in animals and humans71a,263,374c,d,392 and good nutrition347a,393 and higher BMI90c are associated with reduced incidence of arsenical skin lesions. Children with poor nutritional status had more arsenic lesions and at lower rates of exposure than well-nourished children.394 Increased learning problems are associated with arsenic-exposure in children with chronic malnutrition.395 However, even being well-nourished is not sufficient to prevent the effects of arsenic altogether.83c,206b,263 South Asian diets, environment, cultural factors and metal toxicity Diets in South Asia are heavily based on rice. Regular access to animal protein is limited to people of middle and upper socioeconomic SES,383e and many individuals follow vegetarian diets. Thus, there is relatively high consumption of legumes for protein. Access to fresh fruit is also somewhat limited to people of middle and upper SES.383e Consumption of dairy products is low396 and tea and chilli peppers high. Consumption of fruits and vegetables is lower among South Asian smokers than non-smokers.397 A market basket survey of foods in West Bengal found high levels of arsenic, manganese and nickel, and low levels of zinc.346a Parasitic infestations398 and H. pylori infection399 are not uncommon in South Asia. In much of South Asia, women cover head, arms and legs in public, which reduces sunlight exposure. Periodic fasting is a common and required practice for many communities. These factors are likely to exacerbate the adverse effects of multi-metal exposure. The high consumption of rice adds to the arsenic load, especially if the rice is irrigated with, and then cooked in, arsenic-contaminated water. The high consumption of legumes also adds to the arsenic load, especially when cooked in arsenic-contaminated water. The primarily vegetarian diet is likely to include relatively high amounts of manganese. While the lignins and hemicelluloses in the legumes may decrease the absorption of manganese, they also decrease absorption of zinc. The low consumption of animal products and high consumption of tea and chilli peppers245 increase likelihood of iron deficiency, which further increases absorption of manganese and lead and also increases absorption of cadmium. The low consumption of animal products also increases the likelihood of zinc and selenium deficiencies, a condition made even more serious by the increased need for zinc and selenium under conditions of toxic metal exposure. Parasitic infestations and H. pylori infections further increase the likelihood of zinc and iron deficiencies.216,383d,399 In turn, iron deficiency may increase absorption of lead, chromium and manganese; manganese and lead absorption may also be increased by the low calcium intake of the diets. The general low overall consumption of food may promote higher absorption of lead. While restricting exposure to sunlight may reduce the incidence of arsenic-caused skin lesions, it may also promote vitamin D deficiency, further exacerbating iron and zinc deficiencies. Fasting alters arsenicmethylation processes400 and increases uranium absorption.401 Intake of riboflavin, pyridoxine, vitamin A, vitamin C, calcium and zinc in Bangladesh fall below RDAs for India.297,374c,383e,402 It has been demonstrated that iron deficiency anaemia could be addressed through ferrous sulphate supplementation of drinkingwater,403 but the extent of iron deficiency anaemia in South Asia suggests that although the groundwater in the region often contains high levels of iron, the iron may not be in a bio-available form. Vitamin D levels have been found to be low in Bangladeshi women,404 which may exacerbate arsenic and manganese toxicity by decreasing absorption of iron and zinc. In South Asia, poverty is sometimes measured in terms of calories available for consumption on a daily basis. By this measure, approximately 33–50% of Bangladeshis are “poor”, with fewer than 2122 kilocalories per family member available on a daily basis.405 In Bangladesh, low BMI is associated with poverty and lack of schooling;406 34% of Bangladeshi women have a BMI of less than 18.5.406b In South Asian populations exposed to high levels of arsenic, BMI has been reported to be inversely correlated with incidence of skin lesions.407 BMI has been reported to be lower among tobacco users in India.408 Incidence of underweight is decreasing throughout South Asia, but is still high by world standards;406b,408c,409 one recent study in rural Bangladesh found 56% of children ages 2–6 underweight.383g Effects of multi-metal exposures seem to be more pronounced in undernourished children in Bangladesh.410 It has also been argued that exposure to arsenic may reduce BMI in children.411 If oestrogen does indeed provide some protection from arsenic, then people with decreased oestrogen levels due to low BMI may show increased risk of adverse health effects due to arsenic exposure; this may provide an additional reason for why the poor of South Asia seem particularly susceptible to the effects of arsenic exposure. Research on diet and metal toxicity The dietary factors surrounding individual dietary components and their effects on arsenic toxicity are extremely complex and require further study to disentangle the conflating factors. For instance, an inverse correlation was found between consumption of fruit and canned foods in Bangladesh and incidence of arsenic lesions amongst those exposed to arsenic through drinkingwater.289b However, consumption of fruit and canned foods are more likely with higher SES, and those with higher SES have been shown to be less susceptible to arsenic toxicity,297,412 to have better overall nutritional levels, and higher BMI. Thus, before it can be concluded that consumption of fruit and canned foods can protect against arsenic lesions, the effects of SES and overall good nutrition must be differentiated. Similarly, increased consumption of animal protein was correlated with decreased arsenic toxicity in a Bangladeshi population,346h but consumption of animal protein is also associated with higher SES, possibly reduced consumption of legumes, higher general protein intake, higher general nutrition levels, and higher BMI. Before concluding that animal protein provides a benefit against arsenic toxicity, animal protein consumption must be separated statistically from the other factors, especially legume consumption, since consumption of animal protein in place of legumes implies reduced dietary arsenic exposure, and increased zinc consumption, since zinc is often contained in animal products and may reduce arsenic toxicity. Other exposures to heavy metals Packaging of food products and sweets can be source of significant metal contamination, particularly lead.413 Use of tobacco products implies additional exposure to heavy metals, especially cadmium.209a In addition, pharmaceutical products and vitamins have been found to contain lead,414 manganese,415 or arsenic,416 and herbal remedies have been reported to contain high levels of lead, cadmium, chromium, nickel, manganese, and iron.417 Cosmetics and personal care products, particularly khol or surma, popular in parts of South Asia, may also increase heavy metal exposure.418 Bathing in arsenic-contaminated water can result in elevated urinary arsenic levels.419 It should also be kept in mind that in addition to naturally occurring metals, groundwater may also be further contaminated by toxic metals from mining, industry, or improper disposal of “e-waste”.420 Research on metals and multiple metal effects The only way to tightly control exposure to metals in order to research their health effects is through laboratory studies. However, animal models are often inadequate since they metabolize metals such as arsenic differently than humans and the metals may be more toxic to humans than animals.275b,421 Subtle psychological effects due to metal exposure such as irritability and emotional lability may be difficult to observe in laboratory animals.422 In addition, laboratory studies examining single metal effects can be undermined by inadvertent co-exposure to other metals such as lead, cadmium, or chromium through feed or bedding.104,348 Human epidemiological studies may be the only way to determine the health effects of metal exposures on humans, however, these studies cannot uncover the complete picture if they do not screen for co-exposure to other metals and account for such co-exposures statistically. Even studies that have found a clear link between exposure to a single metal and a direct health effect would benefit from being re-examined in the light of possible multiple metal effects. For example, some authors have reported that the expected correlation between lead exposure in children and neurological symptoms disappeared when co-exposure to other metals was partialed out.83a,208a A variety of toxic metals can cause similar symptoms making it impossible to differentiate metal exposure by the toxic effects that are observed. Where evidence for a direct effect is clear and the biological pathway or mechanism underlying the effect is identified, screening for multiple metal effects would provide additional confirmation that the single metal is indeed the one responsible for the effect. At the same time, multiple metal screening may provide explanation for any observed variation in predicted health effects152 and ultimately lead to a better understanding of the other metals to which subjects may have been exposed. Studies of effects of toxic metals must assume that the possibility of multiple metal exposure is possible, test for multiple metal exposures, and ensure that there is enough variation in population exposure of the studied metals to provide statistical power for factoring the contributions of the various metals alone and in combination. At present, because of lack of research data, US recommended daily allowances (RDAs) and United States Environmental Protection Agency (U.S. E.P.A) reference doses (RfDs for metals do not take into account possible interactions between one trace element and another, even though the normal context of exposure is with multiple elements.423 A common assumption for risk assessment of mixtures is that the effects will be additive, not synergistic. In order for a model to properly predict risk, published research must be available detailing the nature of effects for chemicals in combination (additive, subtractive, or synergistic), but such data are rarely available.424 Some risk assessment models address mixtures of metals, but are limited by the paucity of research that has explored the toxicity of metals in combination.303 A number of alternative approaches to risk assessment with combinations have been proposed.425 Monitoring for biomarkers of oxidative stress may be vital for understanding the effects of chemical mixtures, particularly at low doses.141i Multiple metal effects in children Relatively little epidemiological research has focused on the health effects of metal exposures in children.153,426 It has been argued the risks of drinking metal-contaminated drinkingwater may be different for children than adults427 and that environmental risk exposure for children requires special attention;428 potential reasons for this include children's greater consumption of water per body weight , their rapid development and undeveloped ability to metabolize or excrete toxic metals, the large amount of time spent in their homes where the exposure occurs, their greater likelihood of further exposure through pica and hand-to-mouth activities, and their long life expectancy which may allow time for delayed toxic effects due to early exposures to develop.53,206b,394,429 Periods of rapid mental or physical growth such as infancy or adolescence are also known to increase requirements for essential elements such as zinc,216 making such periods particularly susceptible to trace element deficiencies or metal interactions that reduce availability of trace elements.263 Mice exposed to arsenic only in utero have been shown to have increased risk of cancers as adults;430 in Chile, men exposed to arsenic only as children or adolescents were found to have increased lung cancer mortality as adults.91 Critical periods in development may also be of concern. Infants and children may also be likely to have micronutrient deficiencies that increase absorbance or toxicity of metals they are exposed to; iron deficiency is common among infants and children, and iron deficiency is known to promote uptake of manganese.249a Many researchers have observed that lead, cadmium, and manganese are more toxic to neonates than adults.104,147,308,431 The bioavailability of manganese is greatly increased for infants than adults102,116,128,350 and manganese exposure causes more damage to mice exposed as juveniles than as adults;432 uranium is also absorbed more readily by infant animals50 and uranium is more likely to be deposited in bone with children than with adults.50 In general, prenatal exposure to heavy metals results in adverse health and neurological effects152 and it has been suggested that early exposure to neurotoxic metals may be resulting in a “global pandemic” of neuro-developmental disorders.206b Nevertheless, studies on the health effects of toxic metals have, by design, almost exclusively included only adults, and sometimes only older adults. Epidemiological studies involving children and metals to date have mostly focused solely on learning and intellectual deficits rather than on more general health effects. While the results of the adult health studies are vital for understanding the effects of metal exposure on humans, they do not shed light on any special health risks that may arise when children are exposed to metals. Since no research has been done on the health effects of toxic metals on children, drinkingwater guidelines and RfDs have been calculated solely on the basis of the adult health risk data. While estimates have been made to extend these data to cover children's risks, there has been no research available to confirm whether such extensions provide adequate protection for children;351 it should be noted that adverse effects of manganese exposure in children were found at manganese levels below the Institute of Medicine Upper Level (IOM UL) interpolated from adult risk studies.56a Clinical observations have noted that children seem to develop adverse health effects due to toxic metals before adults given the same level of exposure.2,4,25a,433 In case studies involving single North American families with multiple family members exposed to high levels of metals in private wells, it was the youngest member of each family to show health symptoms, and who became the sickest from the exposure.53,108b,118 Clinical manifestations of arsenic poisoning may not be as obvious with young patients and hence may be overlooked.426b Children may be more sensitive than adults to arsenic-induced toxicity,434 and instances of myocardial infarction, myocardial ischemia, arterial thickening, and other cardiac problems as well as pulmonary effects have been noted in children exposed to arsenic through drinkingwater.11,435 Thus, it is urgent that epidemiological studies be undertaken to develop understanding of the health risks of metal exposure with children. It is also imperative that current drinkingwater guidelines be re-examined in the light of recent research involving learning deficits caused by children's exposure to metals.56,83 Testing for multiple metals in water The storage, preservation, and analysis of drinkingwater samples is complex. This is especially true when these samples are analyzed for more than one analyte. For example, samples collected for boron analyses must be stored in polyethylene containers and cannot be stored in glass containers because glass is both a potential boron source and sink. In contrast, samples collected for total organic carbon analyses must be stored in glass containers and cannot be stored in polyethylene containers because polyethylene is both a potential carbon source and sink. Therefore, the same sample may need to be divided into several different containers at the time of collection.436 The preservation method chosen for a sample is determined by the analytical method and equipment available for analysis. For example, samples collected for arsenic analyses by atomic absorption (AA) spectrometry or inductively coupled plasma mass spectrometry (ICPMS) must be preserved with nitric acid. However, samples collected for arsenic analyses by colorimetric methods such as silver diethyldithiocarbamate cannot be preserved with nitric acid, since oxidizing agents such as nitrate interfere with this method,436 so they must be preserved with hydrochloric acid. In contrast, if a sample is to be analyzed for arsenic by ICPMS, hydrochloric acid must not be used for preservation since the chloride may combine with calcium from the sample matrix to form the polyatomic interference 40Ca35Cl+ at 75 atomic mass units, which is the same mass as the only natural isotope for arsenic, resulting in inflated measured values for arsenic concentration.437 Thus, a sampling plan for drinkingwater that may contain multiple trace and/or toxic elements must be carefully designed, taking into account the special storage and preservation requirements of the different elements as well as potential analytical interferences. Mitigation of contaminated groundwater Alternative sources of drinkingwater In general, it is usually easier and less expensive to find alternative sources of water than treat contaminated water. Possible alternative sources include deeper wells,9a,21a,438 water sharing,438a,439 rain-water harvesting,2,55 or relying on surface water.55,440 Each of these methods may have utility in a given context; however, none is universally available or effective at providing safe water, and risks inherent with the alternative methods must be compared against potential benefits.441 Even where applicable, water from alternative sources must still be tested to ensure that levels of biological pathogens,440 multiple metal contaminants,442 and carcinogenic by-products from treatment443 meet established drinkingwater guidelines. It should be noted that surface water may be additionally contaminated by arsenic-containing irrigation run-off,21a,442b,444 and while deeper wells in Bangladesh and Vietnam may have less arsenic,21a,444,445 deeper wells in China may have more arsenic.446 Drinking water treatment Treatment technologies include both home scale and community systems. A number of low-cost home treatment technologies for arsenic have recently been developed for Bangladesh.447 Arsenic can be removed from drinkingwater using adsorbents.448 In the developed world, home-scale arsenic treatment systems are also available. These vary in cost and effectiveness, but are not regulated by governments.449 Some home-scale treatment technologies are reported to be effective at removing manganese as well as arsenic (e.g. Bangladesh SONO filter447a), however, no independent peer-reviewed data are available concerning the effectiveness of home scale technologies for removing uranium, nickel, or lead. Home treatment systems must also be regularly monitored for bacteriological contamination, particularly in the developing world where chances of such contamination are high.441 An additional concern with home-scale systems is the problem of toxic sludge disposal once the adsorbents have exceeded their utility; it is essential that proper disposal solutions be made, developed and put in place before home-scale treatment systems are adopted for widespread use. Community treatment systems have often been designed to remove a combination of metals, since community water supplies must typically meet multiple drinkingwater guidelines. The most successful community treatment systems are not mass-produced, but rather designed specifically to meet the unique treatment needs of the community. For example, a treatment system in a Greek community was designed to remove arsenic, manganese, and iron, using a combination of biological and chemical treatments.36 One challenge for community-scale water treatment facilities is that maintenance and water quality standards must be rigorously adhered to. Community-scale arsenic treatment facilities in the West Bengal basin do not have a good track record for supplying safe water.450 Recommendations and conclusions Given the severity of adverse health effects caused by potential exposure to metals in groundwater it is vital for governments to increase their understanding of the specific risks faced by their populations and how these risks can be avoided. Systematic national water testing surveys based on stratified random sampling should be undertaken to test groundwater for multiple elements, including especially those known to commonly appear in groundwater that have recognized toxic effects: arsenic, manganese, fluoride, uranium, lead, and nickel. Laws must also be promulgated requiring testing of public water supplies and governments must ensure that the laws are followed. These laws need to be re-examined regularly and updated to take into consideration continuing research on the toxicity of single and multiple metals. Stakeholders must be educated about the need for testing of private wells, putting special emphasis on the need for testing in areas identified as possible “hot spots” of contamination by national surveys. The reliability of drinkingwater test results must be ensured by monitoring and regulating private water testing laboratories. Governments may find it cost-effective to subsidize water testing for private wells. In terms of public health, it is less expensive to help populations avoid exposure to toxic metals than to treat any resulting diseases or provide support for families if disability or death occurs as a result of exposure. For too many people worldwide, drinkingwater contains biological pathogens, carcinogenic treatment residues, or toxic metals. A variety of factors are pushing populations to rely on groundwater, including increased access to well technology, improved understanding of biological pathogens in surface water, increasing population pressures, migration to decentralized areas, political upheavals, and global climate change. Whenever a new source of water is accessed, particularly groundwater, it is crucial for public health that the water be tested for the presence of multiple metals as well as biological pathogens. It must be kept in mind that multiple metal exposure is the natural form of environmental metal exposure. In human epidemiological research, it must be assumed that multiple metal exposure has occurred, and thus research on single metal effects must test for multiple metals and then factor out other metals and combinations of metals before concluding that a given symptom, disease, or condition is due to exposure to a single specific metal. Mitigation efforts to reduce metal exposure through drinkingwater must consider all possible toxic metals known to occur in the region's water. Before a particular method is declared effective at providing safe water, it must pass tests for all toxins known to occur in the region as well as tests for biological pathogens. Notes and references S. Sambu and R. Wilson, Arsenic in food and water—a brief history , Toxicol. Ind. Health , 2008 , 24 , 217 – 226 . Google Scholar Crossref Search ADS PubMed WorldCat A. Ayerza , Arsenicismo regional endémico , Bol. Acad. Nac. Medicina. , 1918 , 1 , 11 – 24 . Google Scholar OpenURL Placeholder Text WorldCat T. L. Kuo , Arsenic content of artesian well water in endemic area of chronic arsenic poisoning , Rep. Inst. Pathol. Natl. Taiwan Univ. , 1968 , 20 , 7 – 13 . Google Scholar OpenURL Placeholder Text WorldCat J. M. a. G. Borgoño and Rosa, in University of Missouri 5th Annual Conference on Trace Substances in Environmental Health , ed. D. D. Hemphill. University of Missouri , Columbia, MO , 1971 , pp. 13 – 24 . Google Scholar Google Preview OpenURL Placeholder Text WorldCat COPAC Q. X. Huang Y and G. Wang, et al. , A survey of endemic chronic arsenism , Acta Academiac Medicinae Xinjiang , 1983 , 6 , 91 – 96 . Google Scholar OpenURL Placeholder Text WorldCat M. Berg , H. C. Tran, T. C. Nguyen, H. V. Pham, R. Schertenleib and W. Giger, Arsenic contamination of groundwater and drinking water in Vietnam: a human health threat , Environ. Sci. Technol. , 2001 , 35 , 2621 – 6 . Google Scholar Crossref Search ADS PubMed WorldCat P. L. Smedley , J. Knudson and D. Maiga, Arsenic in groundwater from mineralised Proterozoic basement rocks of Burkino Faso , Appl. Geochem. , 2007 , 22 , 1074 – 1092 . Google Scholar Crossref Search ADS WorldCat A. Mukherjee , Fryar, E. Alan, O'Shea and M. Bethany, in Arsenic: Environmental Chemistry, Health Threats and Waste Treatment , ed. K. R. Henke, John Wiley , West Sussex , 2009 , pp. 303 – 350 . Google Scholar Google Preview OpenURL Placeholder Text WorldCat COPAC D. M. Maynard , Frisbie, H. Seth, Hoque and A. Bilqis, Report of the Impact of the Bangladesh Rural Electrification Program on Groundwater Quality , Bangladesh Rural Electrification Board , Dhaka, Bangladesh , 1997 . Google Scholar Google Preview OpenURL Placeholder Text WorldCat COPAC S. H. Frisbie , Maynard, M. Donald, Hoque and A. Bilqis, in Metals and Genetics , ed. B. Sarkar, Plenum Publishing Company , New York , 1999 , pp. 67 – 85 . Google Scholar Crossref Search ADS Google Preview WorldCat COPAC British Geological Survey Phase 1 groundwater studies of arsenic contamination in Bangladesh ; British Geological Survey : Nottingham , 1999 . S. H. Frisbie , R. Ortega, D. M. Maynard and B. Sarkar, The concentrations of arsenic and other toxic elements in Bangladesh's drinking water , Environ. Health Perspect. , 2002 , 110 , 1147 – 1153 . Google Scholar Crossref Search ADS PubMed WorldCat B. K. Mandal and K. T. Suzuki, Arsenic round the world: a review , Talanta , 2002 , 58 , 201 – 235 . Google Scholar Crossref Search ADS PubMed WorldCat P. L. Smedley , M. Zhang, G. Zhang and Z. Luo, Mobilisation of arsenic and other trace elements in fluviolacustrine aquifers of the Huhhot Basin , Inner Mongolia, Applied Geochemistry , 2003 , 18 , 1453 – 1477 . Google Scholar Crossref Search ADS WorldCat J. Virkutyte and M. Sillanpää, Chemical evaluation of potable water in Eastern Qinghai Province , China: Human health aspects, Environment International , 2006 , 32 , 80 – 86 . Google Scholar OpenURL Placeholder Text WorldCat B. Nath , J.-S. Jean, M.-K. Lee, H.-J. Yang and C.-C. Liu, Geochemistry of high arsenic groundwater in Chia-Nan plain, Southwestern Taiwan: possible sources and reactive transport of arsenic , J. Contam. Hydrol. , 2008 , 99 , 85 – 96 . Google Scholar Crossref Search ADS PubMed WorldCat M. Kato , S. Onuma, Y. Kato, N. D. Thang, I. Yajima, M. Z. Hoque and H. U. Shekhar, Toxic elements in well water from Malaysia , Toxicological & Environmental Chemistry , 2010 , 92 , 1609 – 1612 . Google Scholar Crossref Search ADS WorldCat J. Buschmann , M. Berg, C. Stengel, L. Winkel, M. L. Sampson, P. T. K. Trang and P. H. Viet, Contamination of drinking water resources in the Mekong delta floodplains: arsenic and other trace metals pose serious health risks to population , Environ. Int. , 2008 , 34 , 756 – 764 . Google Scholar Crossref Search ADS PubMed WorldCat T. T. G. Luu , S. Sthiannopkao and K.-W. Kim, Arsenic and other trace elements contamination in groundwater and a risk assessment study for the residents in the Kandal Province of Cambodia , Environ. Int. , 2009 , 35 , 455 – 460 . Google Scholar Crossref Search ADS PubMed WorldCat T. Agusa , T. Kunito, J. Fujihara, R. Kubota, T. B. Minh, P. T. K. Trang, H. Iwata, A. Subramanian, P. H. Viet and S. Tanabe, Contamination by arsenic and other trace elements in tube-well water and its risk assessment to humans in Hanoi, Vietnam , Environ. Pollut. , 2006 , 139 , 95 – 106 . Google Scholar Crossref Search ADS PubMed WorldCat V. A. Nguyen , S. Bang, P. H. Viet and K.-W. Kim, Contamination of groundwater and risk assessment for arsenic exposure in Ha Nam province, Vietnam , Environ. Int. , 2009 , 35 , 466 – 472 . Google Scholar Crossref Search ADS PubMed WorldCat P. R. Feldman , J.-W. Rosenboom, M. Saray, P. Navuth, C. Samnang and S. Iddings, Assessment of the chemical quality of drinking water in Cambodia , J. Water Health , 2007 , 5 , 101 – 116 . Google Scholar Crossref Search ADS PubMed WorldCat British Geological Survey Phase 2 groundwater studies of arsenic contamination in Bangladesh ; British Geological Survey : Nottingham , 2001 . S. H. Frisbie , E. J. Mitchell, L. J. Mastera, D. M. Maynard, A. Z. Yusuf, M. Y. Siddiq, R. Ortega, R. K. Dunn, D. S. Westerman, T. Bacquart and B. Sarkar, Public health strategies for western Bangladesh that address arsenic, manganese, uranium, and other toxic elements in drinking water , Environ. Health Perspect. , 2009 , 117 , 410 – 416 . Google Scholar Crossref Search ADS PubMed WorldCat A. van Geen , Z. Cheng, Q. Jia, Y. Zheng, A. A. Seddique, M. W. Rahman, M. M. Rahman and K. M. Ahmed, Monitoring 51 community wells in Araihazar, Bangladesh, for up to 5 years: Implications for arsenic mitigation , J. Environ. Sci. Health, Part A: Toxic/Hazard. Subst. Environ. Eng. , 2007 , 42 , 1729 – 1740 . Google Scholar Crossref Search ADS WorldCat M. Buragohain , B. Bhuyan and H. P. Sarma, Seasonal variations of lead, arsenic, cadmium and aluminium contamination of groundwater in Dhemaji district, Assam, India , Environ. Monit. Assess. , 2009 ,. Google Scholar OpenURL Placeholder Text WorldCat S. Bhattacharjee , S. Chakravarty, S. Maity, V. Dureja and K. K. Gupta, Metal contents in the groundwater of Sahebgunj district, Jharkhand, India, with special reference to arsenic , Chemosphere , 2005 , 58 , 1203 – 1217 . Google Scholar Crossref Search ADS PubMed WorldCat D. Chakraborti , S. C. Mukherjee, S. Pati, M. K. Sengupta, M. M. Rahman, U. K. Chowdhury, D. Lodh, C. R. Chanda, A. K. Chakraborti and G. K. Basu, Arsenic groundwater contamination in Middle Ganga Plain, Bihar, India: a future danger? , Environ. Health Perspect. , 2003 , 111 , 1194 – 1201 . Google Scholar Crossref Search ADS PubMed WorldCat A. K. Singh , S. Bhagowati, T. K. Das, D. Yubbe, B. Rahman, M. Nath, P. Obing, W. S. K. singh, C. Z. Renthlei, L. Pachuau and R. Thakur, Assessment of arsenic, fluoride, iron, nitrate and heavy metals in drinking water of northeastern India , ENVIS Bulletin , 2008 , 16 , 2008 . Google Scholar OpenURL Placeholder Text WorldCat C. K. Jain , A. Bandyopadhyay and A. Bhadra, Assessment of ground water quality for drinking purpose, District Nainital, Uttarakhand, India , Environ. Monit. Assess. , 2010 , 166 , 663 – 676 . Google Scholar Crossref Search ADS PubMed WorldCat K. K. Borah , B. Bhuyan and H. P. Sarma, Lead, arsenic, fluoride, and iron contamination of drinking water in the tea garden belt of Darrang district, Assam, India , Environ. Monit. Assess. , 2009 , 169 , 347 – 352 . Google Scholar Crossref Search ADS PubMed WorldCat N. Rajmohan and L. Elango, Distribution of iron, manganese, zinc and atrazine in groundwater in parts of Palar and Cheyyar river basins, South India , Environ. Monit. Assess. , 2005 , 107 , 115 – 131 . Google Scholar Crossref Search ADS PubMed WorldCat A. H. Barati , A. Maleki and M. Alasvand, Multi-trace elements level in drinking water and the prevalence of multi-chronic arsenical poisoning in residents in the west area of Iran , Sci. Total Environ. , 2010 , 408 , 1523 – 1529 . Google Scholar Crossref Search ADS PubMed WorldCat R. G. Taylor and K. W. F. Howard, in Goundwater Quality , ed. H. Nash and G. J. H. McCall, Chapman & Hall , London, UK , 1994 , pp. 31 – 44 . Google Scholar Google Preview OpenURL Placeholder Text WorldCat COPAC British Geological Survey Groundwater Quality: Mali ; British Geological Survey : London, UK , 2002 . R. Buamah , Adsorptive Removal of Manganese, Arsenic and Iron From Groundwater , Wageningen University , Delft, The Netherlands , 2009 . Google Scholar Google Preview OpenURL Placeholder Text WorldCat COPAC P. W. Lahermo , G. Alfthan and D. Wang, Selenium and arsenic in the environment in Finland , J. Environ. Pathol. Toxicol. Oncol. , 1998 , 17 , 205 – 216 . Google Scholar PubMed OpenURL Placeholder Text WorldCat M. Muikku , M. Puhakainen, T. Heikkinen and T. Ilus, The mean concentration of uranium in drinking water, urine, and hair of the occupationally unexposed Finnish working population , Health Phys. , 2009 , 96 , 646 – 54 . Google Scholar Crossref Search ADS PubMed WorldCat O. Prat , T. Vercouter, E. Ansoborlo, P. Fichet, P. Perret, P. Kurttio and L. Salonen, Uranium speciation in drinking water from drilled wells in southern Finland and its potential links to health effects , Environ. Sci. Technol. , 2009 , 43 , 3941 – 3946 . Google Scholar Crossref Search ADS PubMed WorldCat T. Hatva , Iron and Manganese in Groundwater in Finland: Occurence in Glacifluvial Aquifers and Removal by Biofiltration , National Board of Waters and the Environment , Helsinki, Finland , 1989 . Google Scholar Google Preview OpenURL Placeholder Text WorldCat COPAC R. Vivona , E. Presiosi, B. Madé and G. Giuliano, Occurrence of minor toxic elements in volcanic-sedimentary aquifers: a case study in central Italy , Hydrogeol. J. , 2007 , 15 , 1183 – 1196 . Google Scholar Crossref Search ADS WorldCat I. A. Katsoyiannis , S. J. Hug, A. Ammann, A. Zikoudi and C. Hatziliontos, Arsenic speciation and uranium concentrations in drinking water supply wells in Northern Greece: correlations with redox indicative parameters and implications for groundwater treatment , Sci. Total Environ. , 2007 , 383 , 128 – 140 . Google Scholar Crossref Search ADS PubMed WorldCat A. Kelepertsis , D. Alexakis and K. Skordas, Arsenic, antimony and other toxic elements in the drinking water of Eastern Thessaly in Greece and its possible effects on human health , Environ. Geol. , 2006 , 50 , 76 – 84 . Google Scholar Crossref Search ADS WorldCat British Columbia Ministry of the Environment . British Columbia Ministry of the Environment , Surrey, B.C. , 2010 , vol. 2011 . CBC News , in CBC News, Canada . CBC Radio-Canada : Toronto, ON , 2008 . Government of Nova Scotia . Government of Nova Scotia : Halifax, NS , 2010 , vol. 2011 . F. N. Robertson , Arsenic in ground-water under oxidizing conditions, southwest United States , Environ. Geochem. Health , 1989 , 11 , 171 – 185 . Google Scholar Crossref Search ADS PubMed WorldCat J. S. Stanton and S. L. Qi, Ground-Water Quality of the Northern High Plains Aquifer, 1997, 2002–04 , Publications of the US Geological Survey US Geological Survey , Lincoln, NE , 2006 . Google Scholar Google Preview OpenURL Placeholder Text WorldCat COPAC J. D. Ayotte , M. G. Nielsen, G. Robinson, R. and R. B. Moore, Relation of Arsenic, Iron, and Manganese in Ground Water to Aquifer Type, Bedrock Lithogeochemistry, and Land Use in the New England Coastal Basins , Water-Resources Investigations Report U.S. Geological Survey, National Water-Quality Assessment Program , Pembroke, NH , 1999 . Google Scholar Google Preview OpenURL Placeholder Text WorldCat COPAC J. A. Colman , Arsenic and Uranium in Water from Private Wells Completed in Bedrock of East-Central Massachusetts—Concentrations, Correlations with Bedrock Units, and Estimated Probability Maps , U.S. Geological Survey Scientific Investigations Report U.S. Geological Survey , Northborough, MA , 2011 . Google Scholar Google Preview OpenURL Placeholder Text WorldCat COPAC T. Kresse and J. Fazio, Occurence of Arsenic in Ground Waters of Arkansas and Implications for Source and Release Mechanisms , Arkansas Department of Environmental Quality, Arkansas Ambient Ground-Water Monitoring Program, Little Rock , AR , 2003 . Google Scholar Google Preview OpenURL Placeholder Text WorldCat COPAC P. F. Hudak , Boron and selenium contamination in south Texas groundwater , J. Environ. Sci. Health, Part A: Toxic/Hazard. Subst. Environ. Eng. , 2004 , 39 , 2827 – 2834 . Google Scholar Crossref Search ADS WorldCat S. S. Farías , V. A. Casa, C. Vázquez, L. Ferpozzi, G. N. Pucci and I. M. Cohen, Natural contamination with arsenic and other trace elements in ground waters of Argentine Pampean Plain , Sci. Total Environ. , 2003 , 309 , 187 – 199 . Google Scholar Crossref Search ADS PubMed WorldCat H. B. Nicolli , J. Suriano, M. Gomez Peral, L. H. Ferpozzi and O. A. Balean, Groundwater contamination with arsenic and other trace elements in an area of the Pampa, Province of Córdoba , Environmental Geology and Water Sciences , 1989 , 14 , 3 – 16 . Google Scholar Crossref Search ADS WorldCat G. Concha , K. Broberg, M. Grandér, A. Cardozo, B. Palm and M. Vahter, High-level exposure to lithium, boron, cesium, and arsenic via drinking water in the Andes of northern Argentina , Environ. Sci. Technol. , 2010 , 44 , 6875 – 80 . Google Scholar Crossref Search ADS PubMed WorldCat P. L. Smedley and D. G. Kinniburgh, A review of the source, behaviour and distribution of arsenic in natural waters , Appl. Geochem. , 2002 , 17 , 517 – 568 . Google Scholar Crossref Search ADS WorldCat J. Hamilton-Taylor and N. B. Price, The geochemistry of iron and manganese in the waters and sediments of Bolstadfjord, S.W. Norway , Estuarine, Coastal Shelf Sci. , 1983 , 17 , 1 – 19 . Google Scholar Crossref Search ADS WorldCat M.-K. Lee , J. Griffin, J. Saunders, Y. Wang and J.-S. Jean, Reactive transport of trace elements and isotopes in the Eutaw coastal plain aquifer, Alabama , J. Geophys. Res. , 2007 , 112 ,. Google Scholar OpenURL Placeholder Text WorldCat ATSDR , Draft Toxicological Profile for Uranium ; US Department of Health and Human Services. Public Health Service. Agency for Toxic Substances and Disease Registry , Atlanta, GA , 1999 . B. C. Jurgens , M. S. Fram, K. Belitz, K. R. Burow and M. K. Landon, Effects of Groundwater Development on Uranium, Central Valley, California, USA , Groundwater , 2009 . Google Scholar Google Preview OpenURL Placeholder Text WorldCat COPAC J. Buschmann , M. Berg, C. Stengel and M. L. Sampson, Arsenic and manganese contamination of drinking water resources in Cambodia: coincidence of risk areas with low relief topography , Environ. Sci. Technol. , 2007 , 41 , 2146 – 2152 . Google Scholar Crossref Search ADS PubMed WorldCat H. S. Magdo , J. Forman, N. Graber, B. Newman, K. Klein, L. Satlin, R. W. Amler, J. A. Winston and P. J. Landrigan, Grand rounds: nephrotoxicity in a young child exposed to uranium from contaminated well water , Environ. Health Perspect. , 2007 , 115 , 1237 – 1241 . Google Scholar Crossref Search ADS PubMed WorldCat L. Winkel , M. Berg, M. Amini, S. J. Hug and C. A. Johnson, Predicting groundwater arsenic contamination in Southeast Asia from surface parameters , Nat. Geosci. , 2008 , 1 , 536 – 542 . Google Scholar Crossref Search ADS WorldCat M. Rahman , International research on arsenic contamination and health , J. Health Popul. Nutr. , 2006 , 24 , 123 – 128 . Google Scholar PubMed OpenURL Placeholder Text WorldCat G. A. Wasserman , X. Liu, F. Parvez, H. Ahsan, D. Levy, P. Factor-Litvak, J. Kline, A. van Geen, V. Slavkovich, N. J. LoIacono, Z. Cheng, Y. Zheng and J. H. Graziano, Water manganese exposure and children's intellectual function in Araihazar, Bangladesh , Environ. Health Perspect. , 2006 , 114 , 124 – 129 . Google Scholar Crossref Search ADS PubMed WorldCat M. Bouchard , F. Laforest, L. Vandelac, D. Bellinger and D. Mergler, Hair manganese and hyperactive behaviors: pilot study of school-age children exposed through tap water , Environ. Health Perspect. , 2007 , 115 , 122 – 127 . Google Scholar Crossref Search ADS PubMed WorldCat B. C. Bates , Z. W. Kundzewicz, S. Wu, J. P. Palutik, of Climate change and water, Technical paper of the Intergovernmental Panel on Climate Change , IPCC , Geneva , 2008 . M. M. Sherif and V. P. singh, Effect of climate change on sea water intrusion in coastal aquifers , Hydrol. Processes , 1999 , 13 , 1277 – 1287 . Google Scholar Crossref Search ADS WorldCat Y.-B. Lin , Y.-P. Lin, C.-W. Liu and Y.-C. Tan, Mapping of spatial multi-scale sources of arsenic variation in groundwater on ChiaNan floodplain of Taiwan , Sci. Total Environ. , 2006 , 370 , 168 – 181 . Google Scholar Crossref Search ADS PubMed WorldCat J. Monan , Bangladesh: The strength to succeed , Oxfam , Oxford , 1995 . Google Scholar Google Preview OpenURL Placeholder Text WorldCat COPAC S. C. Besuschio , A. C. Perez Desanzo and M. Croci, Epidemiological associations between arsenic and cancer in Argentina , Biol. Trace Elem. Res. , 1980 , 2 , 41 – 55 . Google Scholar Crossref Search ADS PubMed WorldCat A. H. Smith and C. M. Steinmaus, Health effects of arsenic and chromium in drinking water: recent human findings , Annu. Rev. Public Health , 2009 , 30 , 107 – 22 , DOI: 10.1146/annurev.publhealth.031308.100143 . Google Scholar Crossref Search ADS PubMed WorldCat H. Y. Chiou , Y. M. Hsueh, K. F. Liaw, S. F. Horng, M. H. Chiang, Y. S. Pu, J. S. Lin, C. H. Huang and C. J. Chen, Incidence of internal cancers and ingested inorganic arsenic: a seven-year follow-up study in Taiwan , Cancer Res. , 1995 , 55 , 1296 – 1300 . Google Scholar PubMed OpenURL Placeholder Text WorldCat Y. Chen , F. Parvez, M. Gamble, T. Islam, A. Ahmed, M. Argos, J. H. Graziano and H. Ahsan, Arsenic exposure at low-to-moderate levels and skin lesions, arsenic metabolism, neurological functions, and biomarkers for respiratory and cardiovascular diseases: review of recent findings from the Health Effects of Arsenic Longitudinal Study (HEALS) in Bangladesh , Toxicol. Appl. Pharmacol. , 2009 , 239 , 184 – 192 . Google Scholar Crossref Search ADS PubMed WorldCat J. E. Heck , A. S. Andrew, T. Onega, J. R. Rigas, B. P. Jackson, M. R. Karagas and E. J. Duell, Lung cancer in a U.S. population with low to moderate arsenic exposure , Environ. Health Perspect. , 2009 , 117 , 1718 – 1723 . Google Scholar Crossref Search ADS PubMed WorldCat C.-Y. Yang , H.-F. Chiu, C.-C. Chang, S.-C. Ho and T.-N. Wu, Bladder cancer mortality reduction after installation of a tap-water supply system in an arsenious-endemic area in southwestern Taiwan , Environ. Res. , 2005 , 98 , 127 – 132 . Google Scholar Crossref Search ADS PubMed WorldCat H.-F. Chiu , S.-C. Ho, L. Y. Wang, T. N. Wu and C.-Y. Yang, Does arsenic exposure increase the risk for liver cancer? , J. Toxicol. Environ. Health, Part A , 2004 , 8 , 1491 – 1500 . Google Scholar Crossref Search ADS WorldCat J. Liaw , G. Marshall, Y. Yuan, C. Ferreccio, C. Steinmaus and A. H. Smith, Increased childhood liver cancer mortality and arsenic in drinking water in northern Chile , Cancer Epidemiol., Biomarkers Prev. , 2008 , 17 , 1982 – 1987 . Google Scholar Crossref Search ADS WorldCat J. Liu and M. P. Waalkes, Liver is a target of arsenic carcinogenesis , Toxicol. Sci. , 2008 , 105 , 24 – 32 . Google Scholar Crossref Search ADS PubMed WorldCat D. R. Lewis , J. W. Southwick, R. Ouellet-Hellstrom, J. Rench and R. L. Calderon, Drinking water arsenic in Utah: A cohort mortality study , Environ. Health Perspect. , 1999 , 107 , 359 – 365 . Google Scholar Crossref Search ADS PubMed WorldCat L. Benbrahim-Tallaa and M. P. Waalkes, Inorganic arsenic and human prostate cancer , Environ. Health Perspect. , 2008 , 116 , 158 – 164 . Google Scholar Crossref Search ADS PubMed WorldCat N.-S. Joo , S.-M. Kim, Y.-S. Jung and K.-M. Kim, Hair iron and other minerals' level in breast cancer patients , Biol. Trace Elem. Res. , 2009 , 129 , 28 – 35 . Google Scholar Crossref Search ADS PubMed WorldCat D. N. Guha Mazumder , Chronic arsenic toxicity: Clinical features, epidemiology, and treatment: Experience in West Bengal , J. Environ. Sci. Health, Part A: Toxic/Hazard. Subst. Environ. Eng. , 2003 , 38 , 141 – 163 . Google Scholar Crossref Search ADS WorldCat M. M. Rahman , J. C. Ng and R. Naidu, Chronic exposure of arsenic via drinking water and its adverse health impacts on humans , Environ. Geochem. Health , 2009 , 31 , 189 – 200 . Google Scholar Crossref Search ADS PubMed WorldCat K. K. Majumdar , D. N. G. Mazumder, N. Ghose, A. Ghose and S. Lahiri, Systemic manifestations in chronic arsenic toxicity in absence of skin lesions in West Bengal , Indian J. Med. Res. , 2009 , 129 , 75 – 82 . Google Scholar PubMed OpenURL Placeholder Text WorldCat D. N. Guha Mazumder , R. Haque, N. Ghosh, B. K. De, A. Santra, D. Chakraborti and A. H. Smith, Arsenic in drinking water and the prevalence of respiratory effects in West Bengal, India , Int. J. Epidemiol. , 2000 , 29 , 1047 – 52 . Google Scholar Crossref Search ADS PubMed WorldCat D. N. G. Mazumder , C. Steinmaus, P. Bhattacharya, O. S. von Ehrenstein, N. Ghosh, M. Gotway, A. Sil, J. R. Balmes, R. Haque, M. M. Hira-Smith and A. H. Smith, Bronchiectasis in persons with skin lesions resulting from arsenic in drinking water , Epidemiology , 2005 , 16 , 760 – 765 . Google Scholar Crossref Search ADS PubMed WorldCat S. Kapaj , H. Peterson, K. Liber and P. Bhattacharya, Human health effects from chronic arsenic poisoning—a review , J. Environ. Sci. Health A Tox. Hazard Subst. Environ. Eng. , 2006 , 41 , 2399 – 2428 . Google Scholar Crossref Search ADS PubMed WorldCat J. X. Guo , L. Hu, P. Z. Yand, K. Tanabe, M. Miyatalre and Y. Chen, Chronic arsenic poisoning in drinking water in Inner Mongolia and its associated health effects , J. Environ. Sci. Health A Tox Hazard Subst. Environ. Eng. , 2007 , 42 , 1853 – 1858 . Google Scholar Crossref Search ADS PubMed WorldCat L. N. Islam , A. H. M. N. Nabi, M. M. Rahman and M. S. H. Zahid, Association of respiratory complications and elevated serum immunoglobulins with drinking water arsenic toxicity in human , J. Environ. Sci. Health A Tox. Hazard Subst Environ. Eng. , 2007 , 42 , 1807 – 1814 . Google Scholar Crossref Search ADS PubMed WorldCat F. Parvez , Y. Chen, P. W. Brandt-Rauf, A. Bernard, X. Dumont, V. Slavkovich, M. Argos, J. D'Armiento, R. Foronjy, M. R. Hasan, H. E. M. M. Eunus, J. H. Graziano and H. Ahsan, Nonmalignant respiratory effects of chronic arsenic exposure from drinking water among never-smokers in Bangladesh , Environ. Health Perspect. , 2008 , 116 , 190 – 195 . Google Scholar Crossref Search ADS PubMed WorldCat A. S. Andrew , V. Bernardo, L. A. Warnke, J. C. Davey, T. Hampton, R. A. Mason, J. E. Thorpe, M. A. Ihnat and J. W. Hamilton, Exposure to arsenic at levels found in U.S. drinking water modifies expression in the mouse lung , Toxicol. Sci. , 2007 , 100 , 75 – 87 . Google Scholar Crossref Search ADS PubMed WorldCat A. S. Andrew , R. A. Mason, V. Memoli and E. J. Duell, Arsenic activates EGFR pathway signaling in the lung , Toxicol. Sci. , 2009 , 109 , 350 – 357 . Google Scholar Crossref Search ADS PubMed WorldCat C. J. Chen , M. M. Wu, S. S. Lee, J. D. Wang, S. H. Cheng and H. Y. Wu, Atherogenicity and carcinogenicity of high-arsenic artesian well water. Multiple risk factors and related malignant neoplasms of blackfoot disease , Arteriosclerosis , 1988 , 8 , 452 – 460 . Google Scholar Crossref Search ADS PubMed WorldCat C.-H. Tseng , Blackfoot disease and arsenic: a never-ending story , J. Environ. Sci. Health C Environ. Carcinog Ecotoxicol. Rev. , 2005 , 23 , 55 – 74 . Google Scholar Crossref Search ADS PubMed WorldCat H.-S. Yu , C.-H. Lee and G.-S. Chen, Peripheral vascular diseases resulting from chronic arsenical poisoning , J. Dermatol. , 2002 , 29 , 123 – 130 . Google Scholar Crossref Search ADS PubMed WorldCat C.-C. Chang , S.-C. Ho, S.-S. Tsai and C.-Y. Yang, Ischemic heart disease mortality reduction in an arseniasis-endemic area in southwestern Taiwan after a switch in the tap-water supply system , J. Toxicol. Environ. Health, Part A , 2004 , 67 , 1353 – 1361 . Google Scholar Crossref Search ADS WorldCat P. P. Simeonova and M. I. Luster, Arsenic and atherosclerosis , Toxicol. Appl. Pharmacol. , 2004 , 198 , 444 – 449 . Google Scholar Crossref Search ADS PubMed WorldCat A. Navas-Acien , A. R. Sharrett, E. K. Silbergeld, B. S. Schwartz, K. E. Nachman, T. A. Burke and E. Guallar, Arsenic exposure and cardiovascular disease: a systematic review of the epidemiologic evidence , Am. J. Epidemiol. , 2005 , 162 , 1037 – 1049 . Google Scholar Crossref Search ADS PubMed WorldCat C.-Y. Yang , Does arsenic exposure increase the risk of development of peripheral vascular diseases in humans? , J. Toxicol. Environ. Health, Part A , 2006 , 69 , 1797 – 1804 . Google Scholar Crossref Search ADS WorldCat C.-H. Wang , C.-L. Chen, C. K. Hsiao, F.-T. Chiang, L.-I. Hsu, H.-Y. Chiou, Y.-M. Hsueh, M.-M. Wu and C.-J. Chen, Increased risk of QT prolongation associated with atherosclerotic diseases in arseniasis-endemic area in southwestern coast of Taiwan , Toxicol. Appl. Pharmacol. , 2009 , 239 , 320 – 324 . Google Scholar Crossref Search ADS PubMed WorldCat J. C. States , S. Srivastava, Y. Chen and A. Barchowsky, Arsenic and cardiovascular disease , Toxicol. Sci. , 2009 , 107 , 312 – 323 . Google Scholar Crossref Search ADS PubMed WorldCat C. J. Chen , Y. M. Hsueh, M. S. Lai, M. P. Shyu, S. Y. Chen, M. M. Wu, T. L. Kuo and T. Y. Tai, Increased prevalence of hypertension and long-term arsenic exposure , Hypertension , 1995 , 25 , 53 – 60 . Google Scholar Crossref Search ADS PubMed WorldCat C.-J. Chen , S.-L. Wang, J.-M. Chiou, C.-H. Tseng, H.-Y. Chiou, Y.-M. Hsueh, S.-Y. Chen, M.-M. Wu and M.-S. Lai, Arsenic and diabetes and hypertension in human populations: a review , Toxicol. Appl. Pharmacol. , 2007 , 222 , 298 – 304 . Google Scholar Crossref Search ADS PubMed WorldCat M. S. Lai , Y. M. Hsueh, C. J. Chen, M. P. Shyu, S. Y. Chen, T. L. Kuo, M. M. Wu and T. Y. Tai, Ingested inorganic arsenic and prevalence of diabetes mellitus , Am J Epidemiol , 1994 , 139 , 484 – 492 . Google Scholar Crossref Search ADS PubMed WorldCat C. H. Tseng , T. Y. Tai, C. K. Chong, C. P. Tseng, M. S. Lai, B. J. Lin, H. Y. Chiou, Y. M. Hsueh, K. H. Hsu and C. J. Chen, Long-term arsenic exposure and incidence of non-insulin-dependent diabetes mellitus: a cohort study in arseniasis-hyperendemic villages in Taiwan , Environ. Health Perspect. , 2000 , 108 , 847 – 851 . Google Scholar Crossref Search ADS PubMed WorldCat C.-H. Tseng , The potential biological mechanisms of arsenic-induced diabetes mellitus , Toxicol. Appl. Pharmacol. , 2004 , 197 , 67 – 83 . Google Scholar Crossref Search ADS PubMed WorldCat A. Díaz-Villaseñor , A. L. Burns, M. Hiriart, M. E. Cebrián and P. Ostrosky-Wegman, Arsenic-induced alteration in the expression of genes related to type 2 diabetes mellitus , Toxicol. Appl. Pharmacol. , 2007 , 225 , 123 – 33 . Google Scholar Crossref Search ADS PubMed WorldCat A. Navas-Acien , E. K. Silbergeld, R. Pastor-Barriuso and E. Guallar, Arsenic exposure and prevalence of type 2 diabetes in US adults , JAMA, J. Am. Med. Assoc. , 2008 , 300 , 814 – 822 . Google Scholar Crossref Search ADS WorldCat A. S. Ettinger , A. R. Zota, C. J. Amarasiriwardena, M. R. Hopkins, J. Schwartz, H. Hu and R. O. Wright, Maternal arsenic exposure and impaired glucose tolerance during pregnancy , Environ. Health Perspect. , 2009 , 117 , 1059 – 1064 . Google Scholar Crossref Search ADS PubMed WorldCat H.-F. Chiu and C.-Y. Yang, Decreasing trend in renal disease mortality after cessation from arsenic exposure in a previous arseniasis-endemic area in southwestern Taiwan , J. Toxicol. Environ. Health, Part A , 2005 , 68 , 319 – 327 . Google Scholar Crossref Search ADS WorldCat W. Lin , S.-L. Wang, H.-J. Wu, K.-H. Chang, P. Yeh, C.-J. Chen and H.-R. Guo, Associations between arsenic in drinking water and pterygium in southwestern Taiwan , Environ. Health Perspect. , 2008 , 116 , 952 – 955 . Google Scholar Crossref Search ADS PubMed WorldCat L.-C. See , H.-Y. Chiou, J.-S. Lee, Y.-M. Hsueh, S.-M. Lin, M.-C. Tu, M.-L. Yang and C.-J. Chen, Dose-response relationship between ingested arsenic and cataracts among residents in Southwestern Taiwan , J. Environ. Sci. Health A Tox. Hazard Subst. Environ. Eng. , 2007 , 42 , 1843 – 1851 . Google Scholar Crossref Search ADS PubMed WorldCat B. Krishnapada , R. Akash, M. Lakshmikanta, B. Gautam and T. Amit, Persistent conjunctivitis associated with drinking arsenic-contaminated water , J. Ocul. Pharmacol. Ther. , 2006 , 22 , 208 – 211 . Google Scholar Crossref Search ADS PubMed WorldCat A. S. Andrew , D. A. Jewell, R. A. Mason, M. L. Whitfield, J. H. Moore and M. R. Karagas, Drinking-water arsenic exposure modulates gene expression in human lymphocytes from a U.S. population , Environ. Health Perspect. , 2008 , 116 , 524 – 531 . Google Scholar Crossref Search ADS PubMed WorldCat C. D. Kozul , K. H. Ely, R. I. Enelow and J. W. Hamilton, Low-dose arsenic compromises the immune response to influenza A infection in vivo , Environ. Health Perspect. , 2009 , 117 , 1441 – 1447 . Google Scholar Crossref Search ADS PubMed WorldCat R. Raqib , S. Ahmed, R. Sultana, Y. Wagatsuma, D. Mondal, A. M. W. Hoque, B. Nermell, M. Yunus, S. Roy, L. A. Persson, S. E. Arifeen, S. Moore and M. Vahter, Effects of in utero arsenic exposure on child immunity and morbidity in rural Bangladesh , Toxicol. Lett. , 2009 , 185 , 197 – 202 . Google Scholar Crossref Search ADS PubMed WorldCat J. C. Davey , A. P. Nomikos, M. Wungjiranirun, J. R. Sherman, L. Ingram, C. Batki, J. P. Lariviere and J. W. Hamilton, Arsenic as an endocrine disruptor: arsenic disrupts retinoic acid receptor-and thyroid hormone receptor-mediated gene regulation and thyroid hormone-mediated amphibian tail metamorphosis , Environ. Health Perspect. , 2008 , 116 , 165 – 172 . Google Scholar Crossref Search ADS PubMed WorldCat F.-I. Hsieh , T.-S. Hwang, Y.-C. Hsieh, H.-C. Lo, C.-T. Su, H.-S. Hsu, H.-Y. Chiou and C.-J. Chen, Risk of erectile dysfunction induced by arsenic exposure through well water consumption in Taiwan , Environ. Health Perspect. , 2008 , 116 , 532 – 536 . Google Scholar Crossref Search ADS PubMed WorldCat C. Castellini , E. Mourvaki, B. Sartini, R. Cardinali, E. Moretti, G. Collodel, S. Fortaner, E. Sabbioni and T. Renieri, In vitro toxic effects of metal compounds on kinetic traits and ultrastructure of rabbit spermatozoa , Reprod. Toxicol. , 2009 , 27 , 46 – 54 . Google Scholar Crossref Search ADS PubMed WorldCat S. C. Mukherjee , M. M. Rahman, U. K. Chowdhury, M. K. Sengupta, D. Lodh, C. R. Chanda, K. C. Saha and D. Chakraborti, Neuropathy in arsenic toxicity from groundwater arsenic contamination in West Bengal, India , J. Environ. Sci. Health A Tox. Hazard Subst. Environ. Eng. , 2003 , 38 , 165 – 183 . Google Scholar Crossref Search ADS PubMed WorldCat C. Moon , M. Marlowe, J. Stellern and J. Errera, Main and interaction effects of metallic pollutants on cognitive functioning , J. Learn. Disabil. , 1985 , 18 , 217 – 221 . Google Scholar Crossref Search ADS PubMed WorldCat G. A. Wasserman , X. Liu, F. Parvez, H. Ahsan, P. Factor-Litvak, A. van Geen, V. Slavkovich, N. J. LoIacono, Z. Cheng, I. Hussain, H. Momotaj and J. H. Graziano, Water arsenic exposure and children's intellectual function in Araihazar, Bangladesh , Environ. Health Perspect. , 2004 , 112 , 1329 – 1333 . Google Scholar Crossref Search ADS PubMed WorldCat J. L. Rosado , D. Ronquillo, K. Kordas, O. Rojas, J. Alatorre, P. Lopez, G. Garcia-Vargas, M. D. C. Caamaño, M. E. Cebrián and R. J. Stoltzfus, Arsenic exposure and cognitive performance in Mexican schoolchildren , Environ. Health Perspect. , 2007 , 115 , 1371 – 1375 . Google Scholar Crossref Search ADS PubMed WorldCat A. Aschengrau , S. Zierler and A. Cohen, Quality of community drinking water and the occurrence of spontaneous abortion , Arch. Environ. Health , 1989 , 44 , 283 – 290 . Google Scholar Crossref Search ADS PubMed WorldCat M. Börzsönyi , A. Bereczky, P. Rudnai, M. Csanady and A. Horvath, Epidemiological studies on human subjects exposed to arsenic in drinking water in southeast Hungary , Arch. Toxicol. , 1992 , 66 , 77 – 78 . Google Scholar Crossref Search ADS PubMed WorldCat S. A. Ahmad , M. H. Sayed, S. Barua, M. H. Khan, M. H. Faruquee, A. Jalil, S. A. Hadi and H. K. Talukder, Arsenic in drinking water and pregnancy outcomes , Environ. Health Perspect. , 2001 , 109 , 629 – 631 . Google Scholar Crossref Search ADS PubMed WorldCat A. Ashraf , S. M. Mustanzid, S. A. Rahman and B. Sarkar, A community based survey on pregnancy outcome in patients with arsenicosis in rural Bangladesh , Clinical Biochemistry , 2004 , 37 , 1135 . Google Scholar OpenURL Placeholder Text WorldCat N. Cherry , K. Shaikh, C. McDonald and Z. Chowdhury, Stillbirth in rural Bangladesh: arsenic exposure and other etiological factors: a report from Gonoshasthaya Kendra , Bull. W. H. O. , 2008 , 86 , 172 – 177 . Google Scholar Crossref Search ADS WorldCat M. Vahter , Effects of arsenic on maternal and fetal health , Annu. Rev. Nutr. , 2009 , 29 , 381 – 399 . Google Scholar Crossref Search ADS PubMed WorldCat C. Hopenhayn-Rich , S. R. Browning, I. Hertz-Picciotto, C. Ferreccio, C. Peralta and H. Gibb, Chronic arsenic exposure and risk of infant mortality in two areas of Chile , Environ. Health Perspect. , 2000 , 108 , 667 – 673 . Google Scholar Crossref Search ADS PubMed WorldCat S.-X. Wang , Z.-H. Wang, X.-T. Cheng, J. Li, Z.-P. Sang, X.-D. Zhang, L.-L. Han, X.-Y. Qiao, Z.-M. Wu and Z.-Q. Wang, Arsenic and fluoride exposure in drinking water: children's IQ and growth in Shanyin county, Shanxi province, China , Environ. Health Perspect. , 2007 , 115 , 643 – 647 . Google Scholar Crossref Search ADS PubMed WorldCat J. Shen , J. Liu, Y. Xie, B. A. Diwan and M. P. Waalkes, Fetal onset of aberrant gene expression relevant to pulmonary carcinogenesis in lung adenocarcinoma development induced by in utero arsenic exposure , Toxicol. Sci. , 2007 , 95 , 313 – 320 . Google Scholar Crossref Search ADS PubMed WorldCat S. Srivastava , S. E. D'Souza, U. Sen and J. C. States, In utero arsenic exposure induces early onset of atherosclerosis in ApoE-/- mice , Reprod. Toxicol. , 2007 , 23 , 449 – 456 . Google Scholar Crossref Search ADS PubMed WorldCat Y. Xie , J. Liu, L. Benbrahim-Tallaa, J. M. Ward, D. Logsdon, B. A. Diwan and M. P. Waalkes, Aberrant DNA methylation and gene expression in livers of newborn mice transplacentally exposed to a hepatocarcinogenic dose of inorganic arsenic , Toxicology , 2007 , 236 , 7 – 15 . Google Scholar Crossref Search ADS PubMed WorldCat M. Vahter , Health effects of early life exposure to arsenic , Basic Clin. Pharmacol. Toxicol. , 2008 , 102 , 204 – 211 . Google Scholar Crossref Search ADS PubMed WorldCat Y. M. Hsueh , H. Y. Chiou, Y. L. Huang, W. L. Wu, C. C. Huang, M. H. Yang, L. C. Lue, G. S. Chen and C. J. Chen, Serum beta-carotene level, arsenic methylation capability , and incidence of skin cancer, Cancer Epidemiol. Biomarkers Prev. , 1997 , 6 , 589 – 596 . Google Scholar OpenURL Placeholder Text WorldCat C. Watanabe , T. Inaoka, T. Kadono, M. Nagano, S. Nakamura, K. Ushijima, N. Murayama, K. Miyazaki and R. Ohtsuka, Males in rural Bangladeshi communities are more susceptible to chronic arsenic poisoning than females: analyses based on urinary arsenic , Environ. Health Perspect. , 2001 , 109 , 1265 – 1270 . Google Scholar Crossref Search ADS PubMed WorldCat H. Ahsan , Y. Chen, F. Parvez, L. Zablotska, M. Argos, I. Hussain, H. Momotaj, D. Levy, Z. Cheng, V. Slavkovich, A. van Geen, G. R. Howe and J. H. Graziano, Arsenic exposure from drinking water and risk of premalignant skin lesions in Bangladesh: baseline results from the Health Effects of Arsenic Longitudinal Study , Am. J. Epidemiol. , 2006 , 163 , 1138 – 1148 . Google Scholar Crossref Search ADS PubMed WorldCat Y. Chen , J. H. Graziano, F. Parvez, I. Hussain, H. Momotaj, A. van Geen, G. R. Howe and H. Ahsan, Modification of risk of arsenic-induced skin lesions by sunlight exposure, smoking, and occupational exposures in Bangladesh , Epidemiology , 2006 , 17 , 459 – 467 . Google Scholar Crossref Search ADS PubMed WorldCat M. Rahman , M. Vahter, N. Sohel, M. Yunus, M. A. Wahed, P. K. Streatfield, E.-C. Ekström and L. A. Persson, Arsenic exposure and age and sex-specific risk for skin lesions: a population-based case-referent study in Bangladesh , Environ. Health Perspect. , 2006 , 114 , 1847 – 1852 . Google Scholar Crossref Search ADS PubMed WorldCat A.-L. Lindberg , E.-C. Ekström, B. Nermell, M. Rahman, B. Lönnerdal, L.-A. Persson and M. Vahter, Gender and age differences in the metabolism of inorganic arsenic in a highly exposed population in Bangladesh , Environ. Res. , 2008 , 106 , 110 – 120 . Google Scholar Crossref Search ADS PubMed WorldCat G. Marshall , C. Ferreccio, Y. Yuan, M. N. Bates, C. Steinmaus, S. Selvin, J. Liaw and A. H. Smith, Fifty-year study of lung and bladder cancer mortality in Chile related to arsenic in drinking water , J. Natl. Cancer Inst. , 2007 , 99 , 920 – 928 . Google Scholar Crossref Search ADS PubMed WorldCat C. A. Loffredo , H. V. Aposhian, M. E. Cebrian, H. Yamauchi and E. K. Silbergeld, Variability in human metabolism of arsenic , Environ. Res. , 2003 , 92 , 85 – 91 . Google Scholar Crossref Search ADS PubMed WorldCat M. L. Kile , E. Hoffman, Y.-M. Hsueh, S. Afroz, Q. Quamruzzaman, M. Rahman, G. Mahiuddin, L. Ryan and D. C. Christiani, Variability in biomarkers of arsenic exposure and metabolism in adults over time , Environ. Health Perspect. , 2009 , 117 , 455 – 460 . Google Scholar Crossref Search ADS PubMed WorldCat L. Li , E.-C. Ekström, W. Goessler, B. Lönnerdal, B. Nermell, M. Yunus, A. Rahman, S. E. Arifeen, L. A. Persson and M. Vahter, Nutritional status has marginal influence on the metabolism of inorganic arsenic in pregnant Bangladeshi women , Environ. Health Perspect. , 2008 , 116 , 315 – 321 . Google Scholar Crossref Search ADS PubMed WorldCat A.-L. Lindberg , R. Kumar, W. Goessler, R. Thirumaran, E. Gurzau, K. Koppova, P. Rudnai, G. Leonardi, T. Fletcher and M. Vahter, Metabolism of low-dose inorganic arsenic in a central European population: influence of sex and genetic polymorphisms , Environ. Health Perspect. , 2007 , 115 , 1081 – 1086 . Google Scholar Crossref Search ADS PubMed WorldCat T. J. Key , P. N. Appleby, G. K. Reeves, A. Roddam, J. F. Dorgan, C. Longcope, F. Z. Stanczyk, H. E. Stephenson, R. T. Falk, R. Miller, A. Schatzkin, D. S. Allen, I. S. Fentiman, D. Y. Wang, M. Dowsett, H. V. Thomas, S. E. Hankinson, P. Toniolo, A. Akhmedkhanov, K. Koenig, R. E. Shore, A. Zeleniuch-Jacquotte, F. Berrino, P. Muti, A. Micheli, V. Krogh, S. Sieri, V. Pala, E. Venturelli, G. Secreto, E. Barrett-Connor, G. A. Laughlin, M. Kabuto, S. Akiba, R. G. Stevens, K. Neriishi, C. E. Land, J. A. Cauley, L. H. Kuller, S. R. Cummings, K. J. Helzlsouer, A. J. Alberg, T. L. Bush, G. W. Comstock, G. B. Gordon and S. R. Miller, E. H. B. C. C. Group, Body mass index, serum sex hormones, breast cancer risk in postmenopausal women , J. Natl. Cancer Inst. , 2003 , 95 , 1218 – 1226 . Google Scholar Crossref Search ADS PubMed WorldCat M. Vahter , G. Concha, B. Nermell, R. Nilsson, F. Dulout and A. T. Natarajan, A unique metabolism of inorganic arsenic in native Andean women , Eur. J. Pharmacol., Environ. Toxicol. Pharmacol. Sect. , 1995 , 293 , 455 – 462 . Google Scholar Crossref Search ADS WorldCat M. Vahter , Genetic polymorphism in the biotransformation of inorganic arsenic and its role in toxicity , Toxicol. Lett. , 2000 , 112–113 , 209 – 217 . Google Scholar Crossref Search ADS PubMed WorldCat H. Ahsan , Y. Chen, Q. Wang, V. Slavkovich, J. H. Graziano and R. M. Santella, DNA repair gene XPD and susceptibility to arsenic-induced hyperkeratosis , Toxicol. Lett. , 2003 , 143 , 123 – 131 . Google Scholar Crossref Search ADS PubMed WorldCat M. Meza , A. J. Gandolfi and W. T. Klimecki, Developmental and genetic modulation of arsenic biotransformation: a gene by environment interaction? , Toxicol. Appl. Pharmacol. , 2007 , 222 , 381 – 387 . Google Scholar Crossref Search ADS PubMed WorldCat K. M. Applebaum , M. R. Karagas, D. J. Hunter, P. J. Catalano, S. H. Byler, S. Morris and H. H. Nelson, Polymorphisms in nucleotide excision repair genes, arsenic exposure, and non-melanoma skin cancer in New Hampshire , Environ. Health Perspect. , 2007 , 115 , 1231 – 1236 . Google Scholar Crossref Search ADS PubMed WorldCat S. D. Chaudhuri , M. Kundu, M. Banerjee, J. K. Das, P. Majumdar, S. Basu, S. Roychoudhury, K. K. Singh and A. K. Giri, Arsenic-induced health effects and genetic damage in keratotic individuals: involvement of p53 arginine variant and chromosomal aberrations in arsenic susceptibility , Mutat. Res., Rev. Mutat. Res. , 2008 , 659 , 118 – 125 . Google Scholar Crossref Search ADS WorldCat C.-J. Chung , C.-J. Huang, Y.-S. Pu, C.-T. Su, Y.-K. Huang, Y.-T. Chen and Y.-M. Hsueh, Polymorphisms in cell cycle regulatory genes, urinary arsenic profile and urothelial carcinoma , Toxicol. Appl. Pharmacol. , 2008 , 232 , 203 – 209 . Google Scholar Crossref Search ADS PubMed WorldCat A. Hernández and R. Marcos, Genetic variations associated with interindividual sensitivity in the response to arsenic exposure , Pharmacogenomics , 2008 , 9 , 1113 – 1132 . Google Scholar Crossref Search ADS PubMed WorldCat O. L. Valenzuela , Z. Drobná, E. Hernández-Castellanos, L. C. Sánchez-Peña, G. G. García-Vargas, V. H. Borja-Aburto, M. Stýblo and L. M. D. Razo, Association of AS3MT polymorphisms and the risk of premalignant arsenic skin lesions , Toxicol. Appl. Pharmacol. , 2009 , 239 , 200 – 207 . Google Scholar Crossref Search ADS PubMed WorldCat S. J. S. Flora , M. Mittal and A. Mehta, Heavy metal induced oxidative stress & its possible reversal by chelation therapy , Indian J. Med. Res. , 2008 , 128 , 501 – 523 . Google Scholar PubMed OpenURL Placeholder Text WorldCat S. H. Frisbie , R. Ortega, D. Maynard and B. Sarkar, in Bangladesh Environment , ed. M. F. Ahmed, S. A. Tanveer and A. B. M. Badruzzaman, BAPA , Dhaka, Bangladesh , 2002 , pp. 259 – 273 . Google Scholar Google Preview OpenURL Placeholder Text WorldCat COPAC J. Pi , H. Yamauchi, G. Sun, T. Yoshida, H. Aikawa, W. Fujimoto, H. Iso, R. Cui, M. P. Waalkes and Y. Kumagai, Vascular dysfunction in patients with chronic arsenicosis can be reversed by reduction of arsenic exposure , Environ. Health Perspect. , 2005 , 113 , 339 – 341 . Google Scholar Crossref Search ADS PubMed WorldCat P. L. Smedley , H. B. Nicolli, D. M. J. Macdonald, A. J. Barros and J. O. Tullio, Hydrogeochemistry of arsenic and other inorganic constituents in groundwaters from La Pampa , Argentina, Applied Geochemistry , 2002 , 17 , 259 – 284 . Google Scholar Crossref Search ADS WorldCat G. Sun , X. Li, J. Pi, Y. Sun, B. Li, Y. Jin and Y. Xu, Current research problems of chronic arsenicosis in China , J. Health Popul. Nutr. , 2006 , 24 , 176 – 181 . Google Scholar PubMed OpenURL Placeholder Text WorldCat G. Yu , D. Sun and Y. Zheng, Health effects of exposure to natural arsenic in groundwater and coal in China: an overview of occurrence , Environ. Health Perspect. , 2007 , 115 , 636 – 642 . Google Scholar Crossref Search ADS PubMed WorldCat C. L. Keen and S. Zidenberg-Cherr, in Manganese in Health and Disease , ed. D. J. Klimis-Tavantzis, CRC Press , Boca Raton, FL , 1994 , pp. 193 – 205 . Google Scholar Google Preview OpenURL Placeholder Text WorldCat COPAC N. C. Burton and T. R. Guilarte, Manganese neurotoxicity: lessons learned from longitudinal studies in nonhuman primates , Environ. Health Perspect. , 2009 , 117 , 325 – 332 . Google Scholar Crossref Search ADS PubMed WorldCat G. S. Shukla and R. L. Singhal, The present status of biological effects of toxic metals in the environment: lead , Can. J. Physiol. Pharmacol. , 1984 , 62 , 1015 – 1031 . Google Scholar Crossref Search ADS PubMed WorldCat D. B. Calne , N. S. Chu, C. C. Huang, C. S. Lu and W. Olanow, Manganism and idiopathic parkinsonism: similarities and differences , Neurology , 1994 , 44 , 1583 – 1586 . Google Scholar Crossref Search ADS PubMed WorldCat D. G. Barceloux , Manganese , Clin. Toxicol. , 1999 , 37 , 293 – 307 . Google Scholar OpenURL Placeholder Text WorldCat A. Beuter , R. Edwards, A. deGeoffroy, D. Mergler and K. Hundnell, Quantification of neuromotor function for detection of the effects of manganese , Neurotoxicology , 1999 , 20 , 355 – 366 . Google Scholar PubMed OpenURL Placeholder Text WorldCat M. Aschner , T. R. Guilarte, J. S. Schneider and W. Zheng, Manganese: recent advances in understanding its transport and neurotoxicity , Toxicol. Appl. Pharmacol. , 2007 , 221 , 131 – 147 . Google Scholar Crossref Search ADS PubMed WorldCat J. S. Standridge , A. Bhattacharya, P. Succop, C. Cox and E. Haynes, Effect of chronic low level manganese exposure on postural balance: a pilot study of residents in southern Ohio , J. Occup. Environ. Med. , 2008 , 50 , 1421 – 1429 . Google Scholar Crossref Search ADS PubMed WorldCat I. Hossain , S. N. Islam, M. N. I. Khan, S. Islam and A. Hasnat, Serum level of copper, zinc and manganese in somatization disorder patients , German Journal of Psychiatry , 2007 , 10 , 13 – 17 . Google Scholar OpenURL Placeholder Text WorldCat J. Cawte , Accounts of a mystery illness: The Groote Eylandt syndrome , Aust. NZ J. Psychiatry , 1984 , 18 , 179 – 187 . Google Scholar Crossref Search ADS WorldCat L. A. Gottschalk , T. Rebello, M. S. Buchsbaum, H. G. Tucker and E. L. Hodges, Abnormalities in hair trace elements as indicators of aberrant behavior , Comprehensive Psychology , 1991 , 32 , 229 – 237 . Google Scholar Crossref Search ADS WorldCat P. J. Barlow , A pilot study on the metal levels in the hair of hyperactive children , Med. Hypotheses , 1983 , 11 , 309 – 318 . Google Scholar Crossref Search ADS PubMed WorldCat A. Woolf , R. Wright, C. Amarasiriwardena and D. Bellinger, A child with chronic manganese exposure from drinking water , Environ. Health Perspect. , 2002 , 110 , 613 – 616 . Google Scholar Crossref Search ADS PubMed WorldCat L. Takser , D. Mergler, S. de Grosbois, A. Smargiassi and J. Lafond, Blood manganese content at birth and cord serum prolactin levels , Neurotoxicol. Teratol. , 2004 , 26 , 811 – 815 . Google Scholar Crossref Search ADS PubMed WorldCat P. D. Howe , H. M. Malcolm and S. Dobson, Manganese and its compounds: environmental aspects , Concise International Chemical Assessment Document World Health Organization , Geneva , 2004 . Google Scholar Google Preview OpenURL Placeholder Text WorldCat COPAC G. S. Shukla and S. V. Chandra, Levels of sulfhydryls and sulfhydryl-containing enzymes in brain, liver and testis of manganese treated rats , Arch. Toxicol. , 1977 , 37 , 319 – 325 . Google Scholar Crossref Search ADS PubMed WorldCat K. B. Miller , J. S. Caton and J. W. Finley, Manganese depresses rat heart muscle respiration , BioFactors , 2006 , 28 , 33 – 46 . Google Scholar Crossref Search ADS PubMed WorldCat C. Ma , S. N. Schneider, M. Miller, D. W. Nebert, C. Lind, S. M. Roda, S. E. Afton, J. A. Caruso and M. B. Genter, Manganese accumulation in the mouse ear following systemic exposure , J. Biochem. Mol. Toxicol. , 2008 , 22 , 305 – 310 . Google Scholar Crossref Search ADS PubMed WorldCat D. Hafeman , P. Factor-Litvak, Z. Cheng, A. van Geen and H. Ahsan, Association between manganese exposure through drinking water and infant mortality in Bangladesh , Environ. Health Perspect. , 2007 , 115 , 1107 – 1112 . Google Scholar Crossref Search ADS PubMed WorldCat B. Lönnerdal , C. L. Keen and L. S. Hurley, in Manganese in Health and Disease , ed. D. J. Klimis-Tavantzis, CRC Press , Boca Raton , 1994 , pp. 175 – 191 . Google Scholar Google Preview OpenURL Placeholder Text WorldCat COPAC D. C. Dorman , M. F. Struve, D. Vitarella, F. L. Byerly, J. Goetz and R. Miller, Neurotoxicity of manganese chloride in neonatal and adult CD rats following subchronic (21-day) high-dose oral exposure , J. Appl. Toxicol. , 2000 , 20 , 179 – 187 . Google Scholar Crossref Search ADS PubMed WorldCat K. A. Cockell , G. Bonacci and B. Belonje, Manganese content of soy or rice beverages is high in comparison to infant formulas , J. Am. Coll. Nutr. , 2004 , 23 , 124 – 130 . Google Scholar Crossref Search ADS PubMed WorldCat P. J. Collipp , S. Y. Chen and S. Maitinsky, Manganese in infant formulas and learning disability , Ann. Nutr. Metab. , 1983 , 27 , 488 – 494 . Google Scholar Crossref Search ADS PubMed WorldCat V. Sahni , Y. Léger, L. Panaro, M. Allen, S. Giffin, D. Fury and N. Hamm, Case report: a metabolic disorder presenting as pediatric manganism , Environ. Health Perspect. , 2007 , 115 , 1776 – 1779 . Google Scholar Crossref Search ADS PubMed WorldCat V. A. Fitsanakis , C. Au, K. M. Erikson and M. Aschner, The effects of manganese on glutamate, dopamine and gamma-aminobutyric acid regulation , Neurochemistry International , 2006 , 48 , 426 – 433 . Google Scholar Crossref Search ADS PubMed WorldCat R. H. Kawamura , S. Ikuta, S. Fukuzumi, R. Yamada and S. Tsubaki, Intoxication by manganese in well water , Kitasato Archives of Experimental Medicine , 1941 , 18 , 145 – 171 . Google Scholar OpenURL Placeholder Text WorldCat X. G. Kondakis , N. Makris, M. Leotsinidis, M. Prinou and T. Papapetropoulos, Possible health effects of high manganese concentration in drinking water , Arch. Environ. Health , 1989 , 44 ,. Google Scholar OpenURL Placeholder Text WorldCat P. Vieregge , B. Heinzow, G. Kork, H. M. Teichert, P. Schleifenbaum and H. U. Mosinger, Long term exposure to manganese in rural well water has no neurological effects , Canadian Journal of Neurological Sciences , 1995 , 22 , 286 – 289 . Google Scholar Crossref Search ADS WorldCat M. Baldwin , D. Mergler, F. Larribe, S. Bélanger, R. Tardif, L. Bilodeau and K. Hudnell, Bioindicator and exposure data for a population based study of manganese , Neurotoxicology , 1999 , 20 , 343 – 353 . Google Scholar PubMed OpenURL Placeholder Text WorldCat A. Khalique , S. Ahmad, T. Anjum, M. Jaffar, M. H. Shah, N. Shaheen, S. R. Tariq and S. Manzoor, and age dependence of selected metals in scalp hair , Environ. Monit. Assess. , 2005 , 104 , 45 – 57 . Google Scholar Crossref Search ADS PubMed WorldCat ATSDR , Draft Toxicological Profile for Manganese , US Department of Health and Human Services. Public Health Service. Agency for Toxic Substances and Disease Registry , Atlanta, GA , 2000 . J. W. Finley , Manganese absorption and retention by young women is associated with serum ferritin concentration , Am. J. Clin. Nutr. , 1999 , 70 , 37 – 43 . Google Scholar Crossref Search ADS PubMed WorldCat K. Watanabe , T. Tanaka, T. Shigemi, Y. Hayashida and K. Maki, Mn and Cu concentrations in mixed saliva of elementary school children in relation to sex, age, and dental caries , J. Trace Elem. Med. Biol. , 2009 , 23 , 93 – 99 . Google Scholar Crossref Search ADS PubMed WorldCat D. Mergler , M. Baldwin, S. Bélanger, F. Larribe, A. Beuter, R. Bowler, M. Panisset, R. Edwards, A. de Geoffroy, M. P. Sassine and K. Hudnell, Manganese neurotoxicity, a continuum of dysfunction: results from a community based study , Neurotoxicology , 1999 , 20 , 327 – 342 . Google Scholar PubMed OpenURL Placeholder Text WorldCat R. Bowler , D. Mergler, M. P. Sassine, F. Larribe and H. K. Hudnell, Neuropsychiatric effects of manganese on mood , Neurotoxicology , 1999 , 20 , 367 – 378 . Google Scholar PubMed OpenURL Placeholder Text WorldCat R. T. Brown , W. S. Freeman, J. M. Perrin, M. T. Stein, R. W. Amler, H. M. Feldman, K. Pierce and M. L. Wolraich, Prevalence and assessment of attention-deficit/hyperactivity disorder in primary care settings , Pediatrics , 2001 , 107 , E43 . Google Scholar Crossref Search ADS PubMed WorldCat H. K. Hudnell , Effects from environmental Mn exposures: a review of the evidence from non-occupational exposure studies , Neurotoxicology , 1999 , 20 , 379 – 397 . Google Scholar PubMed OpenURL Placeholder Text WorldCat L. Davidsson , A. Cederblad, B. Lönnerdal and B. Sandström, Manganese retention in man: A method for estimating manganese absorption in man , Am. J. Clin. Nutr. , 1989 , 49 , 170 – 179 . Google Scholar Crossref Search ADS PubMed WorldCat B. B. Williams , D. Li, M. Wegrzynowicz, B. K. Vadodaria, J. G. Anderson, G. F. Kwakye, M. Aschner, K. M. Erikson and A. B. Bowman, Disease-toxicant screen reveals a neuroprotective interaction between Huntington's disease and manganese exposure , J. Neurochem. , 2010 , 112 , 227 – 237 . Google Scholar Crossref Search ADS PubMed WorldCat C. C. Huang , N. S. Chu, C. S. Lu, R. S. Chen and D. B. Calne, Long-term progression in chronic manganism: ten years of follow-up , Neurology , 1998 , 50 , 698 – 700 . Google Scholar Crossref Search ADS PubMed WorldCat H. A. Roels , M. I. O. Eslava, E. Ceulemans, A. Robert and D. Lison, Prospective study on the reversibility of neurobehavioral effects in workers exposed to manganese dioxide , Neurotoxicology , 1999 , 20 , 255 – 271 . Google Scholar PubMed OpenURL Placeholder Text WorldCat P. L. Diaz Sylvester , R. Lopez, A. M. Ubios and R. L. Cabrini, Exposure to subcutaneously implanted uranium dioxide impairs bone formation , Arch. Environ. Health , 2002 , 57 , 320 – 325 . Google Scholar Crossref Search ADS PubMed WorldCat P. Kurttio , H. Komulainen, A. Leino, L. Salonen, A. Auvinen and H. Saha, Bone as a possible target of chemical toxicity of natural uranium in drinking water , Environ. Health Perspect. , 2005 , 113 , 68 – 72 . Google Scholar Crossref Search ADS PubMed WorldCat M. L. Zamora , B. L. Tracy, J. M. Zielinski, D. P. Meyerhof and M. A. Moss, Chronic ingestion of uranium in drinking water: a study of kidney bioeffects in humans , Toxicol. Sci. , 1998 , 43 , 68 – 77 . Google Scholar Crossref Search ADS PubMed WorldCat M. L. L. Zamora , J. M. Zielinski, G. B. Moodie, R. A. F. Falcomer, W. C. Hunt and K. Capello, Uranium in drinking water: renal effects of long-term ingestion by an aboriginal community , Arch. Environ. Occup. Health , 2009 , 64 , 228 – 241 . Google Scholar Crossref Search ADS PubMed WorldCat P. Kurttio , A. Harmoinen, H. Saha, L. Salonen, Z. Karpas, H. Kornulainen and A. Anuvinen, Kidney toxicity of ingested uranium from drinking water , Am. J. Kidney Dis. , 2006 , 47 , 972 – 982 . Google Scholar Crossref Search ADS PubMed WorldCat H. Bensoussan , L. Grancolas, B. Dhieux-Lestaevel, O. Delissen, C.-M. Vacher, I. Dublineau, P. Voisin, P. Gourmelon, M. Taouis and P. Lestaevel, Heavy metal uranium affects the brain cholinergic system in rat following sub-chronic and chronic exposure , Toxicology , 2009 , 261 , 59 – 67 . Google Scholar Crossref Search ADS PubMed WorldCat S. Raymond-Whish , L. P. Mayer, T. O'Neal, A. Martinez, M. A. Sellers, P. J. Christian, S. L. Marion, C. Begay, C. R. Propper, P. B. Hoyer and C. A. Dyer, Drinking water with uranium below the U.S. EPA water standard causes estrogen receptor-dependent responses in female mice , Environ. Health Perspect. , 2007 , 115 , 1711 – 1716 . Google Scholar Crossref Search ADS PubMed WorldCat E. Arnault , M. Doussau, A. Pesty, B. Gouget, A. V. der Meeren, P. Fouchet and B. Lefèvre, Natural uranium disturbs mouse folliculogenesis in vivo and oocyte meiosis in vitro , Toxicology , 2008 , 247 , 80 – 87 . Google Scholar Crossref Search ADS PubMed WorldCat M. S. Kundt , C. Martinez-Taibo, M. C. Muhlmann and J. C. Furnari, Uranium in drinking water: effects on mouse oocyte quality , Health Phys. , 2009 , 96 , 568 – 574 . Google Scholar Crossref Search ADS PubMed WorldCat M. H. Duncan , C. L. Wiggins, J. M. Samet and C. R. Key, Childhood cancer epidemiology in New Mexico's American Indians, Hispanic whites, and non-Hispanic whites, 1970–82 , J. Natl. Cancer Inst. , 1986 , 76 , 1013 – 1018 . Google Scholar PubMed OpenURL Placeholder Text WorldCat R. Bornschein , D. Pearson and L. Reiter, Behavioral effects of moderate lead exposure in children and animal models: part 1, clinical studies , Crit. Rev. Toxicol. , 1980 , 8 , 43 – 99 . Google Scholar Crossref Search ADS PubMed WorldCat L. M. Chiodo , S. W. Jacobson and J. L. Jacobson, Neurodevelopmental effects of postnatal lead exposure at very low levels , Neurotoxicol. Teratol. , 2004 , 26 , 359 – 371 . Google Scholar Crossref Search ADS PubMed WorldCat M. M. Téllez-Rojo , D. C. Bellinger, C. Arroyo-Quiroz, H. Lamadrid-Figueroa, A. Mercado-García, L. Schnaas-Arrieta, R. O. Wright, M. Hernández-Avila and H. Hu, Longitudinal associations between blood lead concentrations lower than 10 microg/dL and neurobehavioral development in environmentally exposed children in Mexico City , Pediatrics , 2006 , 118 , e323 – e330 . Google Scholar Crossref Search ADS PubMed WorldCat M. L. Miranda , D. Kim, M. A. O. Galeano, C. J. Paul, A. P. Hull and S. P. Morgan, The relationship between early childhood blood lead levels and performance on end-of-grade tests , Environ. Health Perspect. , 2007 , 115 , 1242 – 1247 . Google Scholar Crossref Search ADS PubMed WorldCat D. C. Bellinger , Very low lead exposures and children's neurodevelopment , Curr. Opin. Pediatr. , 2008 , 20 , 172 – 177 . Google Scholar Crossref Search ADS PubMed WorldCat J. M. Braun , T. E. Froehlich, J. L. Daniels, K. N. Dietrich, R. Hornung, P. Auinger and B. P. Lanphear, Association of environmental toxicants and conduct disorder in U.S. children: NHANES 2001–2004 , Environ. Health Perspect. , 2008 , 116 , 956 – 962 . Google Scholar Crossref Search ADS PubMed WorldCat J. T. Nigg , G. M. Knottnerus, M. M. Martel, M. Nikolas, K. Cavanagh, W. Karmaus and M. D. Rappley, Low blood lead levels associated with clinically diagnosed attention-deficit/hyperactivity disorder and mediated by weak cognitive control , Biol. Psychiatry , 2008 , 63 , 325 – 331 . Google Scholar Crossref Search ADS PubMed WorldCat J. T. Nigg , M. Nikolas, G. M. Knottnerus, K. Cavanagh and K. Friderici, Confirmation and extension of association of blood lead with attention-deficit/hyperactivity disorder (ADHD) and ADHD symptom domains at population-typical exposure , J. Child. Psychol. Psychiatry. , 2010 , 51 , 58 – 65 . Google Scholar Crossref Search ADS PubMed WorldCat G. Wang and B. A. Fowler, Roles of biomarkers in evaluating interactions among mixtures of lead, cadmium and arsenic , Toxicol. Appl. Pharmacol. , 2008 , 233 , 92 – 99 . Google Scholar Crossref Search ADS PubMed WorldCat K. Chandramouli , C. D. Steer, M. Ellis and A. M. Emond, Effects of early childhood lead exposure on academic performance and behaviour of school age children , Arch. Dis. Child. , 2009 , 94 , 844 – 848 . Google Scholar Crossref Search ADS PubMed WorldCat M. Ha , H.-J. Kwon, M.-H. Lim, Y.-K. Jee, Y.-C. Hong, J.-H. Leem, J. Sakong, J.-M. Bae, S.-J. Hong, Y.-M. Roh and S.-J. Jo, Low blood levels of lead and mercury and symptoms of attention deficit hyperactivity in children: a report of the children's health and environment research (CHEER) , NeuroToxicology , 2009 , 30 , 31 – 36 . Google Scholar Crossref Search ADS PubMed WorldCat A. Roy , D. Bellinger, H. Hu, J. Schwartz, A. S. Ettinger, R. O. Wright, M. Bouchard, K. Palaniappan and K. Balakrishnan, Lead exposure and behavior among young children in Chennai, India , Environ. Health Perspect. , 2009 , 117 , 1607 – 1611 . Google Scholar Crossref Search ADS PubMed WorldCat J. Weuve , S. A. Korrick, M. G. Weisskopf, M. A. Weisskopf, L. M. Ryan, J. Schwartz, H. Nie, F. Grodstein and H. Hu, Cumulative exposure to lead in relation to cognitive function in older women , Environ. Health Perspect. , 2009 , 117 , 574 – 580 . Google Scholar Crossref Search ADS PubMed WorldCat A. Rosin , The long-term consequences of exposure to lead , Isr. Med. Assoc. J. , 2009 , 11 , 689 – 694 . Google Scholar PubMed OpenURL Placeholder Text WorldCat M. Vahter , M. Berglund and A. Akesson, Toxic metals and the menopause , J. Br. Menopause Soc. , 2004 , 10 , 60 – 64 . Google Scholar Crossref Search ADS PubMed WorldCat M. Vahter , A. Akesson, C. Lidén, S. Ceccatelli and M. Berglund, Gender differences in the disposition and toxicity of metals , Environ. Res. , 2007 , 104 , 85 – 95 . Google Scholar Crossref Search ADS PubMed WorldCat M. Arora , J. Weuve, M. G. Weisskopf, D. Sparrow, H. Nie, R. I. Garcia and H. Hu, Cumulative lead exposure and tooth loss in men: the normative aging study , Environ. Health Perspect. , 2009 , 117 , 1531 – 1534 . Google Scholar Crossref Search ADS PubMed WorldCat A. Navas-Acien , E. Guallar, E. K. Silbergeld and S. J. Rothenberg, Lead exposure and cardiovascular disease—a systematic review , Environ. Health Perspect. , 2007 , 115 , 472 – 482 . Google Scholar Crossref Search ADS PubMed WorldCat G. Nagaraj , A. Sukumar, B. Nandlal, S. Vellaichamy, K. Thanasekaran and A. L. Ramanathan, Tooth element levels indicating exposure profiles in diabetic and hypertensive subjects from Mysore, India , Biol. Trace Elem. Res. , 2009 , 131 , 255 – 262 . Google Scholar Crossref Search ADS PubMed WorldCat A. A. Berrahal , M. Lasram, N. E. Elj, A. Kerkeni, N. Gharbi and El-Fazâa, Effect of age-dependent exposure to lead on hepatotoxicity and nephrotoxicity in male rats , Environmental Toxicology , 2009 ,. Google Scholar OpenURL Placeholder Text WorldCat D. C. Bellinger , Teratogen update: lead and pregnancy , Birth Defects Res., Part A , 2005 , 73 , 409 – 420 . Google Scholar Crossref Search ADS WorldCat D. A. Schaumberg , F. Mendes, M. Balaram, M. R. Dana, D. Sparrow and H. Hu, Accumulated lead exposure and risk of age-related cataract in men , JAMA, J. Am. Med. Assoc. , 2004 , 292 , 2750 – 2754 . Google Scholar Crossref Search ADS WorldCat T. Golabek , B. Darewicz, M. Borawska, R. Markiewicz, K. Socha and J. Kudelski, Lead concentration in the bladder tissue and blood of patients with bladder cancer , Scandinavian Journal of Urology and Nephrology , 2009 , 43 , 467 – 470 . Google Scholar Crossref Search ADS PubMed WorldCat T. W. Clarkson , G. F. Nordberg and P. R. Sager, Reproductive and developmental toxicity of metals , Scand. J. Work Environ. Health , 1985 , 11 , 145 – 154 . Google Scholar Crossref Search ADS PubMed WorldCat M. Lewis , J. Worobey, D. S. Ramsay and M. K. McCormack, Prenatal exposure to heavy metals: effect on childhood cognitive skills and health status , Pediatrics , 1992 , 89 , 1010 – 1015 . Google Scholar PubMed OpenURL Placeholder Text WorldCat D. C. Bellinger , Children's cognitive health: the influence of environmental chemical exposures , Altern. Ther. Health Med. , 2007 , 13 , S140 – S144 . Google Scholar PubMed OpenURL Placeholder Text WorldCat W. Jedrychowski , F. Perera, J. Jankowski, D. Mrozek-Budzyn, E. Mroz, E. Flak, S. Edwards, A. Skarupa and I. Lisowska-Miszczyk, Gender specific differences in neurodevelopmental effects of prenatal exposure to very low-lead levels: the prospective cohort study in three-year olds , Early Hum. Dev. , 2009 , 85 , 503 – 510 . Google Scholar Crossref Search ADS PubMed WorldCat C. Gundacker , K. J. Wittmann, M. Kukuckova, G. Komarnicki, I. Hikkel and M. Gencik, Genetic background of lead and mercury metabolism in a group of medical students in Austria , Environ. Res. , 2009 , 109 , 786 – 796 . Google Scholar Crossref Search ADS PubMed WorldCat M. R. Hopkins , A. S. Ettinger, M. Hernández-Avila, J. Schwartz, M. M. Téllez-Rojo, H. Lamadrid-Figueroa, D. Bellinger, H. Hu and R. O. Wright, Variants in iron metabolism genes predict higher blood lead levels in young children , Environ. Health Perspect. , 2008 , 116 , 1261 – 1266 . Google Scholar Crossref Search ADS PubMed WorldCat S. K. Park , H. Hu, R. O. Wright, J. Schwartz, Y. Cheng, D. Sparrow, P. S. Vokonas and M. G. Weisskopf, Iron metabolism genes, low-level lead exposure and QT interval , Environ. Health Perspect. , 2009 , 117 , 80 – 85 . Google Scholar Crossref Search ADS PubMed WorldCat B. A. Chowdhury and R. K. Chandra, Biological and health implications of toxic heavy metal and essential trace element interactions , Prog. Food Nutr. Sci. , 1987 , 11 , 55 – 113 . Google Scholar PubMed OpenURL Placeholder Text WorldCat M. Loghman-Adham , Renal effects of environmental and occupational lead exposure , Environ. Health Perspect. , 1997 , 105 , 928 – 938 . Google Scholar Crossref Search ADS PubMed WorldCat L. Coderre and A. K. Srivastava, Vanadium and the cardiovascular functions , Can. J. Physiol. Pharmacol. , 2004 , 82 , 833 – 839 . Google Scholar Crossref Search ADS PubMed WorldCat J. L. Domingo , Vanadium and diabetes. What about vanadium toxicity? , Mol. Cell. Biochem. , 2000 , 203 , 185 – 187 . Google Scholar Crossref Search ADS PubMed WorldCat A. Scibior , H. Zaporowska, J. a. Ostrowski and A. Banach, Combined effect of vanadium(v) and chromium(iii) on lipid peroxidation in liver and kidney of rats , Chem.-Biol. Interact. , 2006 , 159 , 213 – 222 . Google Scholar Crossref Search ADS PubMed WorldCat ATSDR Draft toxicological profile for vanadium ; US Department of Health and Human Services. Public Health Service. Agency for Toxic Substances and Disease Registry : 2009 . E. Stefańska , L. Ostrowska, D. Czapska, J. Karczewski and M. Borawska, [Hair vanadium content and nutritional status of students of the Medical University of Białystok] , Rocz Panstw Zakl Hig , 2005 , 56 , 157 – 163 . Google Scholar PubMed OpenURL Placeholder Text WorldCat O. S. al Attas , N. M. al Dagheri and N. T. Vigo, Vanadate enhances insulin-receptor binding in gestational diabetic human placenta , Cell Biochem. Funct. , 1995 , 13 , 9 – 14 . Google Scholar Crossref Search ADS PubMed WorldCat P. Poucheret , S. Verma, M. D. Grynpas and J. H. McNeill, Vanadium and diabetes , Mol. Cell. Biochem. , 1998 , 188 , 73 – 80 . Google Scholar Crossref Search ADS PubMed WorldCat K. H. Thompson , J. Lichter, C. LeBel, M. C. Scaife, J. H. McNeill and C. Orvig, Vanadium treatment of type 2 diabetes: a view to the future , J. Inorg. Biochem. , 2009 , 103 , 554 – 558 . Google Scholar Crossref Search ADS PubMed WorldCat D. A. Barrio and S. B. Etcheverry, Vanadium and bone development: putative signaling pathways , Can. J. Physiol. Pharmacol. , 2006 , 84 , 677 – 686 . Google Scholar Crossref Search ADS PubMed WorldCat M. S. Molinuevo , A. M. Cortizo and S. B. Etcheverry, Vanadium(iv) complexes inhibit adhesion, migration and colony formation of UMR106 osteosarcoma cells , Cancer Chemother. Pharmacol. , 2008 , 61 , 767 – 773 . Google Scholar Crossref Search ADS PubMed WorldCat T. Akera , K. Temma and K. Takeda, Cardiac actions of vanadium , Fed. Proc. , 1983 , 42 , 2984 – 2988 . Google Scholar PubMed OpenURL Placeholder Text WorldCat H. G. Preuss , S. T. Jarrell, R. Scheckenbach, S. Lieberman and R. A. Anderson, Comparative effects of chromium, vanadium and gymnema sylvestre on sugar-induced blood pressure elevations in SHR , J. Am. Coll. Nutr. , 1998 , 17 , 116 – 123 . Google Scholar Crossref Search ADS PubMed WorldCat P. Boscolo , M. Carmignani, A. R. Volpe, M. Felaco, G. D. Rosso, G. Porcelli and G. Giuliano, Renal toxicity and arterial hypertension in rats chronically exposed to vanadate , Occup. Environ. Med. , 1994 , 51 , 500 – 503 . Google Scholar Crossref Search ADS PubMed WorldCat S. J. Shi , H. G. Preuss, D. R. Abernethy, X. Li, S. T. Jarrell and N. S. Andrawis, Elevated blood pressure in spontaneously hypertensive rats consuming a high sucrose diet is associated with elevated angiotensin II and is reversed by vanadium , J. Hypertens. , 1997 , 15 , 857 – 862 . Google Scholar Crossref Search ADS PubMed WorldCat T. Vodichenska , [An experimental study of the atherogenic effect of vanadium in body uptake with drinking water] , Probl. Khig. , 1994 , 1994 , 32 – 40 . Google Scholar OpenURL Placeholder Text WorldCat O. Jacques-Camarena , M. González-Ortiz, E. Martínez-Abundis, J. F. López-Madrueño and R. Medina-Santillán, Effect of vanadium on insulin sensitivity in patients with impaired glucose tolerance , Ann. Nutr. Metab. , 2008 , 53 , 195 – 198 . Google Scholar Crossref Search ADS PubMed WorldCat D. G. Barceloux , Vanadium. Journal of Toxicology: Clinical Toxicology , 1999 , 37 . H. Afeseh Ngwa , A. Kanthasamy, V. Anantharam, C. Song, T. Witte, R. Houk and A. G. Kanthasamy, Vanadium induces dopaminergic neurotoxicity via protein kinase Cdelta dependent oxidative signaling mechanisms: relevance to etiopathogenesis of Parkinson's disease , Toxicol. Appl. Pharmacol. , 2009 , 240 , 273 – 285 . Google Scholar Crossref Search ADS PubMed WorldCat S. S. Soares , F. Henao, M. Aureliano and C. Gutiérrez-Merino, Vanadate induces necrotic death in neonatal rat cardiomyocytes through mitochondrial membrane depolarization , Chem. Res. Toxicol. , 2008 , 21 , 607 – 618 . Google Scholar Crossref Search ADS PubMed WorldCat D. Beyersmann and A. Hartwig, Carcinogenic metal compounds: recent insight into molecular and cellular mechanisms , Arch. Toxicol. , 2008 , 82 , 493 – 512 . Google Scholar Crossref Search ADS PubMed WorldCat R. S. Ray , M. Basu, B. Ghosh, K. Samanta and M. Chatterjee, Vanadium, a versatile biochemical effector in chemical rat mammary carcinogenesis , Nutr. Cancer , 2005 , 51 , 184 – 196 . Google Scholar Crossref Search ADS PubMed WorldCat A. Scibior , H. Zaporowska and I. Niedźwiecka, Lipid peroxidation in the liver of rats treated with V and/or Mg in drinking water , J. Appl. Toxicol. , 2009 , 29 , 619 – 628 . Google Scholar Crossref Search ADS PubMed WorldCat I. Zwolak and H. Zaparowska, Preliminary studies on the effect of zinc and selenium on vanadium-induced cytotoxicity in vitro , Acta Biol. Hung. , 2009 , 60 , 55 – 67 . Google Scholar Crossref Search ADS PubMed WorldCat E. Denkhaus and K. Salnikow, Nickel essentiality, toxicity, and carcinogenicity , Crit. Rev. Oncol. Hematol. , 2002 , 42 , 35 – 56 . Google Scholar Crossref Search ADS PubMed WorldCat M. Costa , K. Salnikow, S. Cosentino, C. B. Klein, X. Huang and Z. Zhuang, Molecular mechanisms of nickel carcinogenesis , Environ. Health Perspect. , 1994 , 102 ( Suppl 3 ), 127 – 130 . Google Scholar Crossref Search ADS PubMed WorldCat V. P. Chashschin , G. P. Artunina and T. Norseth, Congenital defects, abortion and other health effects in nickel refinery workers , Sci. Total Environ. , 1994 , 148 , 287 – 91 . Google Scholar Crossref Search ADS PubMed WorldCat M. C. Herlant-Peers , H. F. Hildebrand and J.-P. Kerckaert, In vitro and in vivo incorporatino of 63NiCl2 in mice , Ann. Clin. Lab. Sci. , 1983 , 9 , 47 – 59 . Google Scholar OpenURL Placeholder Text WorldCat E. Szakmáry , V. Morvai, M. Náray and G. Ungváry, Haemodynamic effect of nickel chloride in pregnant rats , Acta Physiol. Hung. , 1995 , 83 , 3 – 12 . Google Scholar PubMed OpenURL Placeholder Text WorldCat M. Anke , L. Angelow, M. Glei, M. Müller and H. Illing, The biological importance of nickel in the food chain , J. Anal. Chem. , 1995 , 352 , 92 – 96 . Google Scholar OpenURL Placeholder Text WorldCat M. L. Dourson in Risk assessment of essential elements , ed. W. Mertz, C. O. Abernathy and S. S. Olin, ILSI Press , Washington, DC , 1994 , pp. 207 – 212 . Google Scholar Google Preview OpenURL Placeholder Text WorldCat COPAC C. Pellerin and S. M. Booker, Reflections on hexavalent chromium: health hazards of an industrial heavyweight , Environ. Health Perspect. , 2000 , 108 , A402 – A407 . Google Scholar Crossref Search ADS PubMed WorldCat ATSDR Draft Toxicological Profile for Chromium ; US Department of Health and Human Services. Public Health Service. Agency for Toxic Substances and Disease Registry : Atlanta, GA , 2008 . X. Yang , S.-Y. Li, F. Dong, J. Ren and N. Sreejayan, Insulin-sensitizing and cholesterol-lowering effects of chromium (D-Phenylalanine)3 , J. Inorg. Biochem. , 2006 , 100 , 1187 – 1193 . Google Scholar Crossref Search ADS PubMed WorldCat N. Sreejayan , F. Dong, M. R. Kandadi, X. Yang and J. Ren, Chromium alleviates glucose intolerance, insulin resistance, and hepatic ER stress in obese mice , Obesity , 2008 , 16 , 1331 – 1337 . Google Scholar Crossref Search ADS PubMed WorldCat J. K. Speetjens , R. A. Collins, J. B. Vincent and S. A. Woski, The nutrional supplement chromium(iii) tris (picolate) cleaves DNA , Chem. Res. Toxicol. , 1999 , 12 , 483 – 487 . Google Scholar Crossref Search ADS PubMed WorldCat A. Levina and P. A. Lay, Chemical properties and toxicity of chromium(iii) nutritional supplements , Chem. Res. Toxicol. , 2008 , 21 , 563 – 571 . Google Scholar Crossref Search ADS PubMed WorldCat N. S. Raja and B. U. Nair, Chromium(iii) complexes inhibit transcription factors binding to DNA and associated gene expression , Toxicology , 2008 , 251 , 61 – 65 . Google Scholar Crossref Search ADS PubMed WorldCat H. Dai , J. Liu, L. H. Malkas, J. Catalano, S. Alagharu and R. J. Hickey, Chromium reduces the in vitro activity and fidelity of DNA replication mediated by the human cell DNA synthesome , Toxicol. Appl. Pharmacol. , 2009 , 236 , 154 – 165 . Google Scholar Crossref Search ADS PubMed WorldCat A. Scibior and H. Zaporowska, Effects of vanadium(v) and/or chromium(iii) on l-ascorbic acid and glutathione as well as iron, zinc, and copper levels in rat liver and kidney , J. Toxicol. Environ. Health, Part A , 2007 , 70 , 696 – 704 . Google Scholar Crossref Search ADS WorldCat H. Y. Shrivastava , T. Ravikumar, N. Shanmugasundaram, M. Babu and B. U. Nair, Cytotoxicity studies of chromium(iii) complexes on human dermal fibroblasts , Free Radical Biol. Med. , 2005 , 38 , 58 – 69 . Google Scholar Crossref Search ADS WorldCat Y. A. Loubieres , A. de Lassence, M. Bernier, A. Viellard-Baron, J. M. Schmitt, B. Page and F. Jardin, Acute, fatal, oral chromic acid poisoning , Clin. Toxicol. , 1999 , 37 , 333 – 336 . Google Scholar OpenURL Placeholder Text WorldCat A. Elbetieha and M. H. Al-Hamood, Long-term exposure of male and female mice to trivalent and hexavalent chromium compounds: effect on fertility , Toxicology , 1997 , 116 , 39 – 47 . Google Scholar Crossref Search ADS PubMed WorldCat G. Papanikolaou and K. Pantopoulos, Iron metabolism and toxicity , Toxicol. Appl. Pharmacol. , 2005 , 202 , 199 – 211 . Google Scholar Crossref Search ADS PubMed WorldCat G. Aamodt , G. Bukholm, J. Jahnsen, B. Moum and M. H. Vatn, I. B. S. E. N. S. Group, The association between water supply and inflammatory bowel disease based on a 1990–1993 cohort study in southeastern Norway , Am. J. Epidemiol. , 2008 , 168 , 1065 – 1072 . Google Scholar Crossref Search ADS PubMed WorldCat S. Altamura and M. U. Muckenthaler, Iron toxicity in diseases of aging: Alzheimer's disease, Parkinson's disease and atherosclerosis , J. Alzheimers Dis. , 2009 , 16 , 879 – 895 . Google Scholar Crossref Search ADS PubMed WorldCat G. J. Brewer , Risks of copper and iron toxicity during aging in humans , Chem. Res. Toxicol. , 2010 , 23 , 319 – 326 . Google Scholar Crossref Search ADS PubMed WorldCat S. Swaminathan , V. A. Fonseca, M. G. Alam and S. V. Shah, The role of iron in diabetes and its complications , Diabetes Care , 2007 , 30 , 1926 – 1933 . Google Scholar Crossref Search ADS PubMed WorldCat R. S. Britton , G. A. Ramm, J. Olynyk, R. Singh, R. O'Neill and B. R. Bacon, Pathophysiology of iron toxicity , Adv. Exp. Med. Biol. , 1994 , 356 , 239 – 253 . Google Scholar Crossref Search ADS PubMed WorldCat Q. Liu , L. Sun, Y. Tan, G. Wang, X. Lin and L. Cai, Role of iron deficiency and overload in the pathogenesis of diabetes and diabetic complications , Curr. Med. Chem. , 2009 , 16 , 113 – 129 . Google Scholar Crossref Search ADS PubMed WorldCat A. Loh , M. Hadziahmetovic and J. L. Dunaief, Iron homeostasis and eye disease , Biochim. Biophys. Acta, Gen. Subj. , 2009 , 1790 , 637 – 649 . Google Scholar Crossref Search ADS WorldCat C. Y. Lok , A. T. Merryweather-Clarke, V. Viprakasit, Y. Chinthammitr, S. Srichairatanakool, C. Limwongse, D. Oleesky, A. J. Robins, J. Hudson, P. Wai, A. Premawardhena, H. J. de Silva, A. Dassanayake, C. McKeown, M. Jackson, R. Gama, N. Khan, W. Newman, G. Banait, A. Chilton, I. Wilson-Morkeh, D. J. Weatherall and K. J. H. Robson, Iron overload in the Asian community , Blood , 2009 , 114 , 20 – 25 . Google Scholar Crossref Search ADS PubMed WorldCat W. H. Kojola , G. R. Brenniman and B. W. Carnow, A review of environmental characteristics and health effects of barium in public water supplies , Rev. Environ. Health , 1979 , 3 , 79 – 95 . Google Scholar PubMed OpenURL Placeholder Text WorldCat H. M. Perry , S. J. Kopp, E. F. Perry and M. W. Erlanger, Hypertension and associated cardiovascular abnormalities induced by chronic barium feeding , J. Toxicol. Environ. Health, Part A , 1989 , 28 , 373 – 388 . Google Scholar Crossref Search ADS WorldCat G. R. Brenniman , W. H. Kojola, P. S. Levy, B. W. Carnow and T. Namekata, High barium levels in public drinking water and its association with elevated blood pressure , Arch. Environ. Health , 1981 , 36 , 28 – 32 . Google Scholar Crossref Search ADS PubMed WorldCat R. G. Wones , B. L. Stadler and L. A. Frohman, Lack of effect of drinking water barium on cardiovascular risk factors , Environ. Health Perspect. , 1990 , 85 , 355 – 359 . Google Scholar PubMed OpenURL Placeholder Text WorldCat J. A. Zdanowicz , J. D. Featherstone, M. A. Espeland and M. E. Curzon, Inhibitory effect of barium on human caries prevalence , Community Dent. Oral Epidemiol. , 1987 , 15 , 6 – 9 . Google Scholar Crossref Search ADS PubMed WorldCat J. A. Zdanowicz , S. A. Mundorff, J. D. Featherstone and H. M. Proskin, Inhibitory effect of barium on caries formation in rats , Caries Res. , 1989 , 23 , 65 – 69 . Google Scholar Crossref Search ADS PubMed WorldCat D. O. Carpenter , K. Arcaro and D. C. Spink, Understanding the human health effects of chemical mixtures , Environ. Health Perspect. , 2002 , 110 ( Suppl 1 ), 25 – 42 . Google Scholar Crossref Search ADS PubMed WorldCat K. Kordas , B. Lönnerdal and R. J. Stoltzfus, Interactions between nutrition and environmental exposures: effects on health outcomes in women and children , J. Nutr. , 2007 , 137 , 2794 – 2797 . Google Scholar Crossref Search ADS PubMed WorldCat Z. Cheng , Y. Zheng, R. Mortlock and A. V. Geen, Rapid multi-element analysis of groundwater by high-resolution inductively coupled plasma mass spectrometry , Anal. Bioanal. Chem. , 2004 , 379 , 512 – 518 . Google Scholar Crossref Search ADS PubMed WorldCat M. Marlowe , J. Stellern, J. Errera and C. Moon, Main and interaction effects of metal pollutants on visual-motor performance , Arch. Environ. Health , 1985 , 40 , 221 – 225 . Google Scholar Crossref Search ADS PubMed WorldCat G. Samanta , R. Sharma, T. Roychowdhury and D. Chakraborti, Arsenic and other elements in hair, nails, and skin-scales of arsenic victims in West Bengal, India , Sci. Total Environ. , 2004 , 326 , 33 – 47 . Google Scholar Crossref Search ADS PubMed WorldCat L. Carrizales , I. Razo, J. L. Tellez-Hernández, R. Torres-Nerio, A. Torres, L. E. Batres, A. C. Cubillas and F. Díaz-Barriga, Exposure to arsenic and lead of children living near a copper-smelter in San Luis Potosi, Mexico: importance of soil contamination for exposure of children , Environ. Res. , 2006 , 101 , 1 – 10 . Google Scholar Crossref Search ADS PubMed WorldCat M. M. Diawara , J. S. Litt, D. Unis, N. Alfonso, L. Martínez, J. G. Crock, D. Smith and J. Carsella, Arsenic, cadmium, lead, and mercury in surface soils, Pueblo, Colorado: implications for population health risk , Environ. Geochem. Health , 2006 , 28 , 297 – 315 . Google Scholar Crossref Search ADS PubMed WorldCat C. G. Elinder , L. Friberg, B. Lind and M. Jawaid, Lead and cadmium levels in blood samples from the general population of Sweden , Environ. Res. , 1983 , 30 , 233 – 253 . Google Scholar Crossref Search ADS PubMed WorldCat A. Sukumar and R. Subramanian, Elements in hair and nails of residents from a village adjacent to New Delhi. Influence of place of occupation and smoking habits , Biol. Trace Elem. Res. , 1992 , 34 , 99 – 105 . Google Scholar Crossref Search ADS PubMed WorldCat N. Fréry , C. Nessmann, F. Girard, J. Lafond, T. Moreau, P. Blot, J. Lellouch and G. Huel, Environmental exposure to cadmium and human birthweight , Toxicology , 1993 , 79 , 109 – 118 . Google Scholar Crossref Search ADS PubMed WorldCat A. Sukumar and R. Subramanian, Relative element levels in the paired samples of scalp hair and fingernails of patients from New Delhi , Sci. Total Environ. , 2007 , 372 , 474 – 479 . Google Scholar Crossref Search ADS PubMed WorldCat D. Dhaware , A. Deshpande, R. N. Khandekar and R. Chowgule, Determination of toxic metals in Indian smokeless tobacco products , Scientific World Journal , 2009 , 9 , 1140 – 1147 . Google Scholar Crossref Search ADS PubMed WorldCat L. Järup and A. Akesson, Current status of cadmium as an environmental health problem , Toxicol. Appl. Pharmacol. , 2009 , 238 , 201 – 208 . Google Scholar Crossref Search ADS PubMed WorldCat P. A. Richter , E. E. Bishop, J. Wang and M. H. Swahn, Tobacco smoke exposure and levels of urinary metals in the U.S. youth and adult population: the National Health and Nutrition Examination Survey (NHANES) 1999–2004 , Int. J. Environ. Res. Public Health , 2009 , 6 , 1930 – 1946 . Google Scholar Crossref Search ADS PubMed WorldCat N. Lal , P. K. Sharma, K. K. Nagpaul, D. Behera and S. K. Malik, Radioactive uranium in various Indian tobaccos and consumable products (snuff, chutta, bidi and cigarette) , Int. J. Clin. Pharmacol. Ther. Toxicol. , 1987 , 25 , 36 – 37 . Google Scholar PubMed OpenURL Placeholder Text WorldCat A. K. Mitra , A. Haque, M. Islam and S. A. M. K. Bashar, Lead poisoning: an alarming public health problem in Bangladesh , Int. J. Environ. Res. Public Health , 2009 , 6 , 84 – 95 . Google Scholar Crossref Search ADS PubMed WorldCat H. Kreppel , J. Liu, Y. Liu, F. X. Reichl and C. D. Klaassen, Zinc-induced arsenite tolerance in mice , Fundam. Appl. Toxicol. , 1994 , 23 , 32 – 37 . Google Scholar Crossref Search ADS PubMed WorldCat O. Ramos , L. Carrizales, L. Yáñez, J. Mejía, L. Batres, D. Ortíz and F. Díaz-Barriga, Arsenic increased lipid peroxidation in rat tissues by a mechanism independent of glutathione levels , Environmental Health Perspectives , 1995 , 103 , 85 – 88 . Google Scholar PubMed OpenURL Placeholder Text WorldCat H. G. Petering , Some observations on the interaction of zinc, copper, and iron metabolism in lead and cadmium toxicity , Environ. Health Perspect. , 1978 , 25 , 141 – 145 . Google Scholar Crossref Search ADS PubMed WorldCat F. L. Cerklewski and R. M. Forbes, Influence of dietary zinc on lead toxicity in the rat , Journal of Nutrition , 1976 , 106 , 689 – 696 . Google Scholar Crossref Search ADS WorldCat P. R. Flanagan , J. Haist and L. S. Valberg, Comparative effects of iron deficiency induced by bleeding and a low-iron diet on the intestinal absorptive interactions of iron, cobalt, manganese, zinc, lead and cadmium , J. Nutr. , 1980 , 110 , 1754 – 1763 . Google Scholar Crossref Search ADS PubMed WorldCat L. L. Hopkins and K. Schwartz, Chromium(iii) binding to serum proteins, specifically siderophilin , Biochim. Biophys. Acta, Gen. Subj. , 1964 , 90 , 484 – 491 . Google Scholar Crossref Search ADS WorldCat C. J. Hahn and G. W. Evans, Absorption of trace metals in the zinc-deficient rat , Am. J. Physiol. , 1975 , 228 , 1020 – 1023 . Google Scholar Crossref Search ADS PubMed WorldCat C. T. Walsh , H. H. Sandstead, A. S. Prasad, P. M. Newberne and P. J. Fraker, Zinc: health effects and research priorities for the 1990s , Environmental Health Perspectives , 1994 , S2 , 5 – 46 . Google Scholar OpenURL Placeholder Text WorldCat F. T. Wieringa , J. Berger, M. A. Dijkhuizen, A. Hidayat, N. X. Ninh, B. Utomo, E. Wasantwisut and P. Winichagoon, Z. for the Seamtizi Study Group, Combined iron and zinc supplementation in infants improved iron and zinc status, but interactions reduced efficacy in a multicountry trial in southeast Asia , J. Nutr. , 2007 , 137 , 466 – 471 . Google Scholar Crossref Search ADS PubMed WorldCat J. E. Spallholz , L. M. Boylan and M. M. Rhaman, Environmental hypothesis: is poor dietary selenium intake an underlying factor for arsenicosis and cancer in Bangladesh and West Bengal, India? , Sci. Total Environ. , 2004 , 323 , 21 – 32 . Google Scholar Crossref Search ADS PubMed WorldCat W. J. Christian , C. Hopenhayn, J. A. Centeno and T. Todorov, Distribution of urinary selenium and arsenic among pregnant women exposed to arsenic in drinking water , Environ. Res. , 2006 , 100 , 115 – 122 . Google Scholar Crossref Search ADS PubMed WorldCat O. A. Levander and C. A. Baumann, Selenium metabolism. VI: Effect of arsenic on the excretion of selenium in the bile , Toxicol. Appl. Pharmacol. , 1966 , 9 , 106 – 115 . Google Scholar Crossref Search ADS PubMed WorldCat H. A. Schroeder , J. J. Balassa and I. H. Tipton, Essential trace metals in man: Manganese. A study in homeostasis , J. Chronic Dis. , 1966 , 19 , 545 – 571 . Google Scholar Crossref Search ADS PubMed WorldCat S. D. McDermott and C. Kies, in Nutritional Bioavailability of Manganese , ed. C. Kies, American Chemical Society , Washington, D.C. , 1987 , pp. 146 – 151 . Google Scholar Crossref Search ADS Google Preview WorldCat COPAC L. Davidsson , A. Cederblad, B. Lönnerdal and B. Sandström, The effect of individual dietary components on manganese absorption in humans , Am. J. Clin. Nutr. , 1991 , 54 , 1065 – 1070 . Google Scholar Crossref Search ADS PubMed WorldCat J. H. Freeland-Graves and P. H. Lin, Plasma uptake of manganese as affected by oral loads of manganese, calcium, milk, phosphorus, copper, and zinc , J. Am. Coll. Nutr. , 1991 , 10 , 38 – 43 . Google Scholar Crossref Search ADS PubMed WorldCat T. A. Lutz , A. Schroff and E. Scharrer, Effect of calcium and sugars on intestinal manganese absorption , Biol. Trace Elem. Res. , 1993 , 39 , 221 – 227 . Google Scholar Crossref Search ADS PubMed WorldCat M. E. Markowitz , M. Sinnett and J. F. Rosen, A randomized trial of calcium supplementation for childhood lead poisoning , Pediatrics , 2004 , 113 , 34 – 39 . Google Scholar Crossref Search ADS WorldCat R. A. Anderson , M. M. Polansky and N. A. Bryden, Stability and absorption of chromium and absorption of chromium histidinate complexes by humans , Biol. Trace Elem. Res. , 2004 , 101 , 211 – 218 . Google Scholar Crossref Search ADS PubMed WorldCat L. Hallberg , L. Rossander-Hultén, M. Brune and A. Gleerup, Calcium and iron absorption: mechanism of action and nutritional importance , Eur. J. Clin. Nutr. , 1992 , 46 , 317 – 327 . Google Scholar PubMed OpenURL Placeholder Text WorldCat A. Wise , Phytate and zinc bioavailability , Int. J. Food Sci. Nutr. , 1995 , 46 , 53 – 63 . Google Scholar Crossref Search ADS PubMed WorldCat M. Modi , R. K. Kaul, G. M. Kannan and S. J. S. Flora, Co-administration of zinc and n-acetylcysteine prevents arsenic-induced tissue oxidative stress in male rats , J. Trace Elem. Med. Biol. , 2006 , 20 , 197 – 204 . Google Scholar Crossref Search ADS PubMed WorldCat M. B. Zimmermann , S. Muthayya, D. Moretti, A. Kurpad and R. F. Hurrell, Iron fortification reduces blood lead levels in children in Bangalore, India , Pediatrics , 2006 , 117 , 2014 – 21 . Google Scholar Crossref Search ADS PubMed WorldCat M. Berglund , A. Åkesson, B. Nermell and M. Vahter, Intestinal absorption of dietary cadmium in women is dependent on body iron stores and fiber intake , Environ. Health Perspect. , 1994 , 102 , 1058 – 66 . Google Scholar Crossref Search ADS PubMed WorldCat R. A. Anderson , Chromium metabolism and its role in disease processes in man , Clin. Physiol. Biochem. , 1986 , 4 , 31 – 41 . Google Scholar PubMed OpenURL Placeholder Text WorldCat H. Spencer , L. Kramer, C. Norris and E. Wiatrowski, Effect of aluminum hydroxide on plasma fluoride and fluoride excretion during a high fluoride intake in man , Toxicol. Appl. Pharmacol. , 1981 , 58 , 140 – 141 . Google Scholar Crossref Search ADS PubMed WorldCat A. Trüpschuh , M. Anke, M. Müller, M. Illing-Günther and E. Hartmann, in Mengen und Spurenelemente , ed. M. Anke, W. Arnhold, H. Bergmann, R. Bitsch, W. Dorn, G. Flachowsky, M. Glei, B. Groppel, M. Grün, H. Gürtler, G. Jahreis, I. Lombeck, B. Luckas, D. Meißner, W. Merbach, M. Müller, R. Müller and H.-J. Schneider, Verlag Harald Schubert , Leipzig , 1997 , pp. 699 – 705 . Google Scholar Google Preview OpenURL Placeholder Text WorldCat COPAC K. K. Das , S. N. Das and S. A. Dhundasi, Nickel, its adverse health effects & oxidative stress , Indian J. Med. Res. , 2008 , 128 , 412 – 425 . Google Scholar PubMed OpenURL Placeholder Text WorldCat J. Bingham-Smith , L. Smith, V. Pijuan, Y. Zhuang and Y. C. Chen, Transmembrane signals and protooncogene induction evoked by carcinogenic metals and prevented by zinc , Environmental Health Perspectives , 1994 , 102 , 181 – 189 . Google Scholar OpenURL Placeholder Text WorldCat K. Salnikow and K. S. Kasprzak, Ascorbate depletion: a critical step in nickel carcinogenesis? , Environ. Health Perspect. , 2005 , 113 , 577 – 584 . Google Scholar Crossref Search ADS PubMed WorldCat L. Rossander-Hultén , M. Brune, B. Sandström, B. Lonnerdal and L. Hallberg, Competitive inhibition of iron absorption by manganese and zinc in humans , Amer. J. Clin. Nutr. , 1991 , 54 , 152 – 156 . Google Scholar Crossref Search ADS WorldCat M. M. A. Boojar , F. Goodarzi and M. A. Basedaghat, Long-term follow-up of workplace and well water manganese effects on iron status indexes in manganese miners , Arch. Environ. Health , 2002 , 57 , 519 – 528 . Google Scholar Crossref Search ADS PubMed WorldCat D. G. Ellingsen , E. Haug, R. J. Ulvik and Y. Thomassen, Iron status in manganese alloy production workers , J. Appl. Toxicol. , 2003 , 23 , 239 – 247 . Google Scholar Crossref Search ADS PubMed WorldCat B. Elsenhans , G. Schmolke, K. Kolb, J. Stokes and W. Forth, Metal–metal interactions among dietary toxic and essential trace metals in the rat , Ecotoxicol. Environ. Saf. , 1987 , 14 , 275 – 287 . Google Scholar Crossref Search ADS PubMed WorldCat W. Mertz , C. O. Abernathy and S. S. Olin, Risk Assessment of Essential Elements , ILSI Press , Washington, D.C. , 1994 . Google Scholar Google Preview OpenURL Placeholder Text WorldCat COPAC Z. Li , J.-Y. Gu, X.-W. Wang, Q.-H. Fan, Y.-X. Geng, Z.-X. Jiao, Y.-P. Hou and W.-S. Wu, Effects of cadmium on absorption, excretion, and distribution of nickel in rats , Biol. Trace Elem. Res. , 2010 , 135 , 211 – 219 . Google Scholar Crossref Search ADS PubMed WorldCat M. Abdulla and J. Chmielnicka, New aspects on the distribution and metabolism of essential trace elements after dietary exposure to toxic metals , Biol. Trace Elem. Res. , 1990 , 23 , 25 – 53 . Google Scholar Crossref Search ADS WorldCat M. R. Fox , Nutritional influences on metal toxicity: cadmium as a model toxic element , Environ. Health Perspect. , 1979 , 29 , 95 – 104 . Google Scholar Crossref Search ADS PubMed WorldCat B. Lönnerdal , Dietary factors influencing zinc absorption , J. Nutr. , 2000 , 130 , 1378S – 1383S . Google Scholar Crossref Search ADS PubMed WorldCat T. Jin , G. Nordberg, T. Ye, M. Bo, H. Wang, G. Zhu, Q. Kong and A. Bernard, Osteoporosis and renal dysfunction in a general population exposed to cadmium in China , Environ. Res. , 2004 , 96 , 353 – 359 . Google Scholar Crossref Search ADS PubMed WorldCat M. Kippler , W. Goessler, B. Nermell, E. C. Ekström, B. Lönnerdal, S. E. Arifeen and M. Vahter, Factors influencing intestinal cadmium uptake in pregnant Bangladeshi women—a prospective cohort study , Environ. Res. , 2009 , 109 , 914 – 921 . Google Scholar Crossref Search ADS PubMed WorldCat P. Christian and K. P. West, Interactions between zinc and vitamin A: an update , Am. J. Clin. Nutr. , 1998 , 68 , 435S – 441S . Google Scholar Crossref Search ADS PubMed WorldCat K. T. Suzuki , H. Tamagawa, K. Takahashi and N. Shimojo, Pregnancy-induced mobilization of copper and zinc bound to renal metallothionein in cadmium loaded rats , Toxicology , 1990 , 60 , 199 – 210 . Google Scholar Crossref Search ADS PubMed WorldCat B. Teucher , M. Olivares and H. Cori, Enhancers of iron absorption: ascorbic acid and other organic acids , Int. J. Vitam. Nutr. Res. , 2004 , 74 , 403 – 419 . Google Scholar Crossref Search ADS PubMed WorldCat A. J. Roodenburg , C. E. West, R. Hovenier and A. C. Beynen, Supplemental vitamin A enhances the recovery from iron deficiency in rats with chronic vitamin A deficiency , Br. J. Nutr. , 1996 , 75 , 623 – 636 . Google Scholar Crossref Search ADS PubMed WorldCat S. Tuntipopipat , K. Judprasong, C. Zeder, E. Wasantwisut, P. Winichagoon, S. Charoenkiatkul, R. Hurrell and T. Walczyk, Chili, but not turmeric, inhibits iron absorption in young women from an iron-fortified composite meal , J. Nutr. , 2006 , 136 , 2970 – 2974 . Google Scholar Crossref Search ADS PubMed WorldCat I. M. Zijp , O. Korver and L. B. Tijburg, Effect of tea and other dietary factors on iron absorption , Crit. Rev. Food Sci. Nutr. , 2000 , 40 , 371 – 398 . Google Scholar Crossref Search ADS PubMed WorldCat R. A. Anderson in Trace Elements in Human and Animal Nutrition , ed. W. Mertz, Academic Press , San Diego, CA , 1994 , pp. 225 – 244 . Google Scholar Google Preview OpenURL Placeholder Text WorldCat COPAC C. Kies , K. D. Aldrich, J. M. Johnson, C. Creps, C. Kowalski and R. H. Wang, in Nutritional Bioavailability of Manganese , ed. C. Kies, American Chemical Society , Washington, DC , 1987 , pp. 136 – 145 . Google Scholar Crossref Search ADS Google Preview WorldCat COPAC M. Aschner , Manganese: brain transport and emerging research needs , Environ. Health Perspect. , 2000 , 108 ( Suppl 3 ), 429 – 432 . Google Scholar Crossref Search ADS PubMed WorldCat S. V. Chandra and G. S. Shukla, Role of iron deficiency in inducing susceptibility to manganese toxicity , Arch. Toxicol. , 1976 , 35 , 319 – 323 . Google Scholar Crossref Search ADS PubMed WorldCat A. Spencer , Whole blood manganese levels in pregnancy and the neonate , Nutrition , 1999 , 15 , 731 – 734 . Google Scholar Crossref Search ADS PubMed WorldCat S. L. Hansen , N. Trakooljul, H.-C. Liu, A. J. Moeser and J. W. Spears, Iron transporters are differentially regulated by dietary iron, and modifications are associated with changes in manganese metabolism in young pigs , J. Nutr. , 2009 , 139 , 1474 – 1479 . Google Scholar Crossref Search ADS PubMed WorldCat P. C. Paul , M. Misbahuddin, A. N. Ahmed, Z. F. Dewan and M. A. Mannan, Accumulation of arsenic in tissues of iron-deficient rats , Toxicol. Lett. , 2002 , 135 , 193 – 197 . Google Scholar Crossref Search ADS PubMed WorldCat S. Turgut , A. Polat, M. Inan, G. Turgot, G. Emmungil, M. Bican, T. Y. Karakus and O. Genc, Interaction between anemia and blood levels of iron, zinc, copper, cadmium and lead in children , Indian J. Pediatr. , 2007 , 74 , 827 – 830 . Google Scholar Crossref Search ADS PubMed WorldCat M. Piscator and S. E. Larsson, in Trace Element Metabolism in Animals-2 , ed. W. G. Hoekstra, H. E. Suttle, H. E. Ganther and W. Mertz, University Park Press , Baltimore , 1974 , p. 687 . Google Scholar Google Preview OpenURL Placeholder Text WorldCat COPAC E. Bárány , I. A. Bergdahl, L. E. Bratteby, T. Lundh, G. Samuelson, S. Skerfving and A. Oskarsson, Iron status influences trace element levels in human blood and serum , Environ. Res. , 2005 , 98 , 215 – 223 . Google Scholar Crossref Search ADS PubMed WorldCat M. Kippler , E.-C. Ekström, B. Lönnerdal, W. Goessler, A. Akesson, S. E. Arifeen, L.-A. Persson and M. Vahter, Influence of iron and zinc status on cadmium accumulation in Bangladeshi women , Toxicol. Appl. Pharmacol. , 2007 , 222 , 221 – 226 . Google Scholar Crossref Search ADS PubMed WorldCat J. Quarterman and J. N. Morrison, The effects of dietary calcium and phosphorus on the retention and excretion of lead in rats , Br. J. Nutr. , 1975 , 34 , 351 – 362 . Google Scholar Crossref Search ADS PubMed WorldCat J. C. Barton , M. E. Conrad, L. Harrison and S. Nuby, Effects of calcium on the absorption and retention of lead , J. Lab. Clin. Med. , 1978 , 91 , 366 – 376 . Google Scholar PubMed OpenURL Placeholder Text WorldCat R. A. Goyer , Nutrition and metal toxicity , Am. J. Clin. Nutr. , 1995 , 61 , 646S – 650S . Google Scholar Crossref Search ADS PubMed WorldCat I.-M. Olsson , I. Bensryd, T. Lundh, H. Ottosson, S. Skerfving and A. Oskarsson, Cadmium in blood and urine—impact of sex, age, dietary intake, iron status, and former smoking—association of renal effects , Environ. Health Perspect. , 2002 , 110 , 1185 – 1190 . Google Scholar Crossref Search ADS PubMed WorldCat M. Vahter , M. Berglund, A. Akesson and C. Lidén, Metals and women's health , Environ. Res. , 2002 , 88 , 145 – 155 . Google Scholar Crossref Search ADS PubMed WorldCat C. C. Bridges and R. K. Zalups, Molecular and ionic mimicry and the transport of toxic metals , Toxicol. Appl. Pharmacol. , 2005 , 204 , 274 – 308 . Google Scholar Crossref Search ADS PubMed WorldCat D. J. Svensgaard and R. C. Hertzberg, in Toxicology of Chemical Mixtures , ed. R. S. H. Yang, Academic Press , San Diego, CA , 1994 , pp. 599 – 640 . Google Scholar Crossref Search ADS Google Preview WorldCat COPAC D. S. Bae , C. Gennings, W. H. Carter, R. S. Yang and J. A. Campain, Toxicological interactions among arsenic, cadmium, chromium, and lead in human keratinocytes , Toxicol. Sci. , 2001 , 63 , 132 – 142 . Google Scholar Crossref Search ADS PubMed WorldCat D. Beyersmann , Interactions in metal carcinogenicity , Toxicol. Lett. , 1994 , 72 , 333 – 338 . Google Scholar Crossref Search ADS PubMed WorldCat J. P. Berry and P. Galle, Selenium–arsenic interaction in renal cells: role of lysosomes. Electron microprobe study , J. Submiscors. Cytol. Pathol. , 1994 , 26 , 203 – 210 . Google Scholar OpenURL Placeholder Text WorldCat S. Satarug , M. Nishijo, P. Ujjin, Y. Vanavanitkun, J. R. Baker and M. R. Moore, Evidence for concurrent effects of exposure to environmental cadmium and lead on hepatic CYP2A6 phenotype and renal function biomarkers in nonsmokers , Environ. Health Perspect. , 2004 , 112 , 1512 – 1518 . Google Scholar Crossref Search ADS PubMed WorldCat M. Valko , H. Morris and M. T. D. Cronin, Metals, toxicity and oxidative stress , Curr. Med. Chem. , 2005 , 12 , 1161 – 1208 . Google Scholar Crossref Search ADS PubMed WorldCat H. H. Sanstead , Understanding zinc: recent observations and interpretations , J. Lab. Clin. Med. , 1994 , 124 , 322 – 327 . Google Scholar PubMed OpenURL Placeholder Text WorldCat J. J. Chisholm , Heavy metal exposures: Toxicity from metal–metal interactions, and behavioral effects , Pediatrics , 1974 , 53 , 841 – 843 . Google Scholar PubMed OpenURL Placeholder Text WorldCat M. A. Peraza , F. Ayala-Fierro, D. S. Barber, E. Casarez and L. T. Rael, Effects of micronutrients on metal toxicity , Environ. Health Perspect. , 1998 , 106 ( Suppl 1 ), 203 – 216 . Google Scholar Crossref Search ADS PubMed WorldCat J. Pi , H. Yamauchi, Y. Kumagai, G. Sun, T. Yoshida, H. Aikawa, C. Hopenhayn-Rich and N. Shimojo, Evidence for induction of oxidative stress caused by chronic exposure of Chinese residents to arsenic contained in drinking water , Environ. Health Perspect. , 2002 , 110 , 331 – 336 . Google Scholar Crossref Search ADS PubMed WorldCat R. R. Engel , C. Hopenhayn-Rich, O. Receveur and A. H. Smith, Vascular effects of chronic arsenic exposure: a review , Epidemiol. Rev. , 1994 , 16 , 184 – 209 . Google Scholar Crossref Search ADS PubMed WorldCat X.-J. Qin , L. G. Hudson, W. Liu, W. Ding, K. L. Cooper and K. J. Liu, Dual actions involved in arsenite-induced oxidative DNA damage , Chem. Res. Toxicol. , 2008 , 21 , 1806 – 1813 . Google Scholar Crossref Search ADS PubMed WorldCat P. Sidhu , M. L. Garg and D. K. Dhawan, Protective role of zinc in nickel induced hepatotoxicity in rats , Chem.-Biol. Interact. , 2004 , 150 , 199 – 209 . Google Scholar Crossref Search ADS PubMed WorldCat O. A. Levander , Metabolic interactions between metals and metalloids , Environ. Health Perspect. , 1978 , 25 , 77 – 80 . Google Scholar Crossref Search ADS PubMed WorldCat H. Babich , N. Martin-Alguacil and E. Borenfreund, Arsenic–selenium interactions determined with cultured fish cells , Toxicol. Lett. , 1989 , 45 , 157 – 164 . Google Scholar Crossref Search ADS PubMed WorldCat S. Biswas , G. Talukder and A. Sharma, Prevention of cytotoxic effects of arsenic by short-term dietary supplementation with selenium in mice in vivo , Mutat. Res., Genet. Toxicol. Environ. Mutagen. , 1999 , 441 , 155 – 160 . Google Scholar Crossref Search ADS WorldCat C. D. Davis , E. O. Uthus and J. W. Finley, Dietary selenium and arsenic affect DNA methylation in vitro in caco-2 cells and in vivo in rat liver and colon , J. Nutr. , 2000 , 130 , 2903 – 2909 . Google Scholar Crossref Search ADS PubMed WorldCat W. Wang , L. Yang, S. Hou, S. Tan and H. Li, Effects of selenium supplementation on arsenism: an intervention trial in Inner Mongolia , Environ. Geochem. Health , 2002 , 24 , 359 – 374 . Google Scholar Crossref Search ADS WorldCat S. L. Wagner , J. S. Maliner, W. E. Morton and R. S. Braman, Skin cancer and arsenical intoxication from well water , Arch. Dermatol. , 1979 , 115 , 1205 – 1207 . Google Scholar Crossref Search ADS PubMed WorldCat J. Gailer , Reactive selenium metabolites as targets of toxic metals/metalloids in mammals: a molecular toxicological perspective , Appl. Organomet. Chem. , 2002 , 16 , 701 – 707 . Google Scholar Crossref Search ADS WorldCat A. B. Kar , R. P. Das and B. Mukerji, Prevention of cadmium-induced changes in the gonads of rats by zinc and selenium. A study in antagonism between metals in the biological system , Proc. Natl. Inst. Sci. India, Part B Suppl. , 1960 , 26B , 40 . Google Scholar OpenURL Placeholder Text WorldCat A. N. Uddin , F. J. Burns and T. G. Rossman, Vitamin E and organoselenium prevent the cocarcinogenic activity of arsenite with solar UVR in mouse skin , Carcinogenesis , 2005 , 26 , 2179 – 2186 . Google Scholar Crossref Search ADS PubMed WorldCat F. L. Cerklewski and R. M. Forbes, Influence of dietary selenium on lead toxicity in the rat , J. Nutr. , 1976 , 106 , 778 – 783 . Google Scholar Crossref Search ADS PubMed WorldCat C. A. Northrop-Clewes and D. I. Thurnham, Monitoring micronutrients in cigarette smokers , Clin. Chim. Acta , 2007 , 377 , 14 – 38 . Google Scholar Crossref Search ADS PubMed WorldCat E. Marafante and M. Vahter, The effect of methyltransferase inhibition on the metabolism of [74As]arsenite in mice and rabbits , Chem.-Biol. Interact. , 1994 , 50 , 49 – 57 . Google Scholar Crossref Search ADS WorldCat M. Vahter , Mechanisms of arsenic biotransformation , Toxicology , 2002 , 181 , 211 – 217 . Google Scholar Crossref Search ADS PubMed WorldCat T. Hayakawa , Y. Kobayashi, X. Cui and S. Hirano, A new metabolic pathway of arsenite: arsenic–glutathione complexes are substrates for human arsenic methyltransferase Cyt19 , Arch. Toxicol. , 2005 , 79 , 183 – 191 . Google Scholar Crossref Search ADS PubMed WorldCat J. De Kimpe , R. Cornelis and R. Vanholder, In vitro methylation of arsenite by rabbit liver cytosol: effect of metal ions, metal chelating agents, methyltransferase inhibitors and uremic toxins , Drug Chem. Toxicol. , 1999 , 22 , 613 – 628 . Google Scholar Crossref Search ADS PubMed WorldCat K. H. Hong , C. L. Keen, Y. Mizuno, K. E. Johnston and T. Tamura, Effects of dietary zinc deficiency on homocysteine and folate metabolism in rats , J. Nutr. Biochem. , 2000 , 11 , 165 – 169 . Google Scholar Crossref Search ADS PubMed WorldCat F. S. Walton , S. B. Waters, S. L. Jolley, E. L. LeCluyse, D. J. thomas and M. Styblo, Selenium compounds modulate the activity of recombinant rat AsIII-methyltransferase and the methylation of arsenite by rat and human hepatocytes , Chem. Res. Toxicol. , 2003 , 16 , 261 – 265 . Google Scholar Crossref Search ADS PubMed WorldCat L. M. Fischer , K. A. daCosta, L. Kwock, P. W. Stewart, T. S. Lu, S. P. Stabler, R. H. Allen and S. H. Zeisel, Sex and menopausal status influence human dietary requirements for the nutrient choline , Am. J. Clin. Nutr. , 2007 , 85 , 1275 – 1285 . Google Scholar Crossref Search ADS PubMed WorldCat T. Gebel , Suppression of arsenic-induced chromosome mutagenicity by antimony , Mutat. Res., Genet. Toxicol. Environ. Mutagen. , 1998 , 412 , 213 – 218 . Google Scholar Crossref Search ADS WorldCat C. de Burbure , J.-P. Buchet, A. Leroyer, C. Nisse, J.-M. Haguenoer, A. Mutti, Z. Smerhovsky, M. Cikrt, M. Trzcinka-Ochocka, G. Razniewska, M. Jakubowski and A. Bernard, Renal and neurologic effects of cadmium, lead, mercury, and arsenic in children: evidence of early effects and multiple interactions at environmental exposure levels , Environ. Health Perspect. , 2006 , 114 , 584 – 590 . Google Scholar Crossref Search ADS PubMed WorldCat F. Hong , T. Jin and A. Zhang, Risk assessment on renal dysfunction caused by co-exposure to arsenic and cadmium using benchmark dose calculation in a Chinese population , BioMetals , 2004 , 17 , 573 – 580 . Google Scholar Crossref Search ADS PubMed WorldCat G. F. Nordberg , T. Jin, F. Hong, A. Zhang, J.-P. Buchet and A. M. Bernard, Biomarkers of cadmium and arsenic interactions , Toxicol. Appl. Pharmacol. , 2005 , 206 , 191 – 197 . Google Scholar Crossref Search ADS PubMed WorldCat S. C. Frost , R. A. Kohanski and M. D. Lane, Effect of phenylarsine oxide on insulin-dependent protein phosphorylation and glucose transport in 3T3-L1 adipocytes , J. Biol. Chem. , 1987 , 262 , 9872 – 9876 . Google Scholar PubMed OpenURL Placeholder Text WorldCat Z. Merali and R. L. Singhal, Protective effect of selenium on certain hepatotoxic and pancreotoxic manifestations of subacute cadmium administration , J. Pharmacol. Exp. Ther. , 1975 , 195 , 58 – 66 . Google Scholar PubMed OpenURL Placeholder Text WorldCat G. S. Shukla and S. V. Chandra, Effect of interation of Mn2+ with Zn2+, Hg2+ and Cd2+ on some neurochemicals in rat , Toxicol. Lett. , 1981 , 10 , 163 – 168 . Google Scholar Crossref Search ADS WorldCat T. Baba , T. Shimizu, Y.-I. Suzuki, M. Ogawara, K.-I. Isono, H. Koseki, H. Kurosawa and T. Shirasawa, Estrogen, insulin, and dietary signals cooperatively regulate longevity signals to enhance resistance to oxidative stress in mice , J. Biol. Chem. , 2005 , 280 , 16417 – 16426 . Google Scholar Crossref Search ADS PubMed WorldCat C. Byrne , S. D. Divekar, G. B. Storchan, D. A. Parodi and M. B. Martin, Cadmium—a metallohormone? , Toxicol. Appl. Pharmacol. , 2009 , 238 , 266 – 271 . Google Scholar Crossref Search ADS PubMed WorldCat S.-Y. Choe , S.-J. Kim, H.-G. Kim, J. H. Lee, Y. Choi, H. Lee and Y. Kim, Evaluation of estrogenicity of major heavy metals , Sci. Total Environ. , 2003 , 312 , 15 – 21 . Google Scholar Crossref Search ADS PubMed WorldCat J. H. Li and T. G. Rossman, Mechanism of comutagenesis of sodium arsenite with n-methyl-n-nitrosourea , Biol. Trace Elem. Res. , 1989 , 21 , 373 – 381 . Google Scholar Crossref Search ADS PubMed WorldCat T. C. Wang , J. S. Huang, V. C. Yang, H. J. Lan, C. J. Lin and K. Y. Jan, Delay of the excision of UV light-induced DNA adducts is involved in the coclastogenicity of UV light plus arsenite , Int. J. Radiat. Biol. , 1994 , 66 , 367 – 372 . Google Scholar Crossref Search ADS PubMed WorldCat M. J. Mass and L. Wang, Arsenic alters cytosine methylation patterns of the promoter of the tumor suppressor gene p53 in human lung cells: a model for a mechanism of carcinogenesis , Mutat. Res., Rev. Mutat. Res. , 1997 , 386 , 263 – 277 . Google Scholar Crossref Search ADS WorldCat A. Basu , J. Mahata, S. Gupta and A. K. Giri, Genetic toxicology of a paradoxical human carcinogen, arsenic: a review , Mutat. Res., Rev. Mutat. Res. , 2001 , 488 , 171 – 194 . Google Scholar Crossref Search ADS WorldCat S. H. Lamm , A. Engel, C. A. Penn, R. Chen and M. Feinleib, Arsenic cancer risk confounder in southwest Taiwan data set , Environ. Health Perspect. , 2006 , 114 , 1077 – 1082 . Google Scholar Crossref Search ADS PubMed WorldCat T. G. Rossman , A. N. Uddin and F. J. Burns, Evidence that arsenite acts as a cocarcinogen in skin cancer , Toxicol. Appl. Pharmacol. , 2004 , 198 , 394 – 404 . Google Scholar Crossref Search ADS PubMed WorldCat D. R. Germolec , J. Judson Spalding, H. S. Yu, J. S. Chen, P. P. Simeonova, P. C. Humble, A. Bruccoleri, G. A. Boorman, J. F. Foley, T. Yoshida and M. I. Luster, Arsenic enhancement of skin neoplasia by chronic stimulation of growth factors , Am. J. Pathol. , 1998 , 153 , 1175 – 1785 . Google Scholar Crossref Search ADS WorldCat F. J. Burns , A. N. Uddin, F. Wu, A. Nádas and T. G. Rossman, Arsenic-induced enhancement of ultraviolet radiation carcinogenesis in mouse skin: a dose-response study , Environ. Health Perspect. , 2004 , 112 , 599 – 603 . Google Scholar Crossref Search ADS PubMed WorldCat K. R. Mahaffey , S. G. Capar, B. C. Gladen and B. A. Fowler, Concurrent exposure to lead, cadmium, and arsenic. Effects on toxicity and tissue metal concentrations in the rat , J. Lab. Clin. Med. , 1981 , 98 , 463 – 481 . Google Scholar PubMed OpenURL Placeholder Text WorldCat C.-L. Chen , L.-I. Hsu, H.-Y. Chiou, Y.-M. Hsueh, S.-Y. Chen, M.-M. Wu and C.-J. Chen, B. D. S. Group, Ingested arsenic, cigarette smoking, lung cancer risk: a follow-up study in arseniasis-endemic areas in Taiwan , JAMA, J. Am. Med. Assoc. , 2004 , 292 , 2984 – 2990 . Google Scholar Crossref Search ADS WorldCat K. M. McCarty , E. A. Houseman, Q. Quamruzzaman, M. Rahman, G. Mahiuddin, T. Smith, L. Ryan and D. C. Christiani, The impact of diet and betel nut use on skin lesions associated with drinking-water arsenic in Pabna , Environ. Health Perspect. , 2006 , 114 , 334 – 340 . Google Scholar Crossref Search ADS PubMed WorldCat C.-L. Chen , H.-Y. Chiou, L.-I. Hsu, Y.-M. Hsueh, M.-M. Wu and C.-J. Chen, Ingested arsenic, characteristics of well water consumption and risk of different histological types of lung cancer in northeastern Taiwan , Environ. Res. , 2009 ,. Google Scholar OpenURL Placeholder Text WorldCat C. J. Chen , C. W. Chen, M. M. Wu and T. L. Kuo, Cancer potential in liver, lung, bladder and kidney due to ingested inorganic arsenic in drinking water , Br. J. Cancer , 1992 , 66 , 888 – 892 . Google Scholar Crossref Search ADS PubMed WorldCat M. N. Bates , A. H. Smith and K. P. Cantor, Case-control study of bladder cancer and arsenic in drinking water , Am. J. Epidemiol. , 1995 , 141 , 523 – 530 . Google Scholar Crossref Search ADS PubMed WorldCat P. Kurttio , E. Pukkala, H. Kahelin, A. Auvinen and J. Pekkanen, Arsenic concentrations in well water and risk of bladder and kidney cancer in Finland , Environ. Health Perspect. , 1999 , 107 , 705 – 710 . Google Scholar Crossref Search ADS PubMed WorldCat M. R. Karagas , T. D. Tosteson, J. S. Morris, E. Demidenko, L. A. Mott, J. Heaney and A. Schned, Incidence of transitional cell carcinoma of the bladder and arsenic exposure in New Hampshire , Cancer, Causes Control , 2004 , 15 , 465 – 472 . Google Scholar Crossref Search ADS WorldCat C. Ferreccio , C. Gonzalez, V. Milosavjlevic, G. Marshall, A. M. Sancha and A. H. Smith, Lung cancer and arsenic concentrations in drinking water in Chile , Epidemiology , 2000 , 11 , 673 – 679 . Google Scholar Crossref Search ADS PubMed WorldCat C. Steinmaus , Y. Yuan, M. N. Bates and A. H. Smith, Case-control study of bladder cancer and drinking water arsenic in the western United States , Am. J. Epidemiol. , 2003 , 158 , 1193 – 1201 . Google Scholar Crossref Search ADS PubMed WorldCat L. M. Knobeloch , K. M. Zierold and H. A. Anderson, Association of arsenic-contaminated drinking-water with prevalence of skin cancer in Wisconsin's Fox River Valley , J. Health Popul. Nutr. , 2006 , 24 , 206 – 213 . Google Scholar PubMed OpenURL Placeholder Text WorldCat A. Basu , P. Ghosh, J. K. Das, A. Banerjee, K. Ray and A. K. Giri, Micronuclei as biomarkers of carcinogen exposure in populations exposed to arsenic through drinking water in West Bengal, India: a comparative study in three cell types , Cancer Epidemiol. Biomarkers Prev. , 2004 , 13 , 820 – 827 . Google Scholar PubMed OpenURL Placeholder Text WorldCat A. S. Andrew , J. L. Burgess, M. M. Meza, E. Demidenko, M. G. Waugh, J. W. Hamilton and M. R. Karagas, Arsenic exposure is associated with decreased DNA repair in vitro and in individuals exposed to drinking water arsenic , Environ. Health Perspect. , 2006 , 114 , 1193 – 1198 . Google Scholar Crossref Search ADS PubMed WorldCat T. G. Rossman , A. N. Uddin, F. J. Burns and M. C. Bosland, Arsenite is a cocarcinogen with solar ultraviolet radiation for mouse skin: an animal model for arsenic carcinogenesis , Toxicol. Appl. Pharmacol. , 2001 , 176 , 64 – 71 . Google Scholar Crossref Search ADS PubMed WorldCat C.-H. Lee , C.-L. Yu, W.-T. Liao, Y.-H. Kao, C.-Y. Chai, G.-S. Chen and H.-S. Yu, Effects and interactions of low doses of arsenic and UVB on keratinocyte apoptosis , Chem. Res. Toxicol. , 2004 , 17 , 1199 – 1205 . Google Scholar Crossref Search ADS PubMed WorldCat P.-H. Chen , C.-C. E. Lan, M.-H. Chiou, M.-C. Hsieh and G.-S. Chen, Effects of arsenic and UVB on normal human cultured keratinocytes: impact on apoptosis and implication on photocarcinogenesis , Chem. Res. Toxicol. , 2005 , 18 , 139 – 144 . Google Scholar Crossref Search ADS PubMed WorldCat X.-J. Qin , L. G. Hudson, W. Liu, G. S. Timmins and K. J. Liu, Low concentration of arsenite exacerbates UVR-induced DNA strand breaks by inhibiting PARP-1 activity , Toxicol. Appl. Pharmacol. , 2008 , 232 , 41 – 50 . Google Scholar Crossref Search ADS PubMed WorldCat W. Ding , W. Liu, K. L. Cooper, X.-J. Qin, P. L. de Souza Bergo, L. G. Hudson and K. J. Liu, Inhibition of poly(ADP-ribose) polymerase-1 by arsenite interferes with repair of oxidative DNA damage. , J. Biol. Chem. , 2009 , 284 , 6809 – 6817 . Google Scholar Crossref Search ADS PubMed WorldCat F. J. Burns , T. Rossman, K. Vega, A. Uddin, S. Vogt, B. Lai and R. J. Reeder, Mechanism of selenium-induced inhibition of arsenic-enhanced UVR carcinogenesis in mice , Environ. Health Perspect. , 2008 , 116 , 703 – 708 . Google Scholar Crossref Search ADS PubMed WorldCat L. B. Zablotska , Y. Chen, J. H. Graziano, F. Parvez, A. van Geen, G. R. Howe and H. Ahsan, Protective effects of B vitamins and antioxidants on the risk of arsenic-related skin lesions in Bangladesh , Environ. Health Perspect. , 2008 , 116 , 1056 – 1062 . Google Scholar Crossref Search ADS PubMed WorldCat G. E. Arteel , L. Guo, T. Schlierf, J. I. Beier, J. P. Kaiser, T. S. Chen, M. Liu, D. J. Conklin, H. L. Miller, C. von Montfort and J. C. States, Subhepatotoxic exposure to arsenic enhances lipopolysaccharide-induced liver injury in mice , Toxicol. Appl. Pharmacol. , 2008 , 226 , 128 – 139 . Google Scholar Crossref Search ADS PubMed WorldCat A. N. Uddin , F. J. Burns, T. G. Rossman, H. Chen, T. Kluz and M. Costa, in skin of hairless mice , Toxicol. Appl. Pharmacol. , 2007 , 221 , 329 – 338 . Google Scholar Crossref Search ADS PubMed WorldCat S. Ivankovic and R. Preussman, Absence of toxic and carcinogenic effects after administration of high doses of chromic oxide pigment in subacute and long-term feeding experiments in rats , Food Cosmet. Toxicol. , 1975 , 13 , 347 – 351 . Google Scholar Crossref Search ADS PubMed WorldCat D. M. Stearns , J. P. S. Wise, S. R. Patierno and K. E. Wetterhahn, Chromium(iii) picolinate produces chromosome damage in Chinese hamster ovary cells , FASEB J. , 1995 , 9 , 1643 – 1649 . Google Scholar Crossref Search ADS PubMed WorldCat D. Bagchi , M. Bagchi, J. Balmoori, X. Ye and S. J. Stohs, Comparative induction of oxidative stress in cultured J774A.1 macrophage cells by chromium picolinate and chromium nicotinate , Res. Comm. Mol. Pathol, Pharmaco. , 1997 , 97 , 335 – 346 . Google Scholar OpenURL Placeholder Text WorldCat V. H. Ferm , The synteratogenic effect of lead and cadmium , Experientia , 1969 , 25 , 56 . Google Scholar Crossref Search ADS PubMed WorldCat ATSDR Interaction profile for: arsenic, cadmium, chromium, and lead ; US Department of Health and Human Services. Public Health Service. Agency for Toxic Substances and Disease Registry : Atlanta, GA , 2004 . H. Choudhury and A. Mudipalli, Potential considerations & concerns in the risk characterization for the interaction profiles of metals , Indian J. Med. Res. , 2008 , 128 , 462 – 483 . Google Scholar PubMed OpenURL Placeholder Text WorldCat Y. Kim , B.-N. Kim, Y.-C. Hong, M.-S. Shin, H.-J. Yoo, J.-W. Kim, S.-Y. Bhang and S.-C. Cho, Co-exposure to environmental lead and manganese affects the intelligence of school-aged children , NeuroToxicology , 2009 , 30 , 564 – 571 . Google Scholar Crossref Search ADS PubMed WorldCat T. Gebel , Arsenic and antimony: comparative approach on mechanistic toxicology , Chem.-Biol. Interact. , 1997 , 107 , 131 – 144 . Google Scholar Crossref Search ADS PubMed WorldCat A. G. Schauss , Comparative hair mineral analysis results of 21 elements in a random selected behaviorally normal 19–59 year old population and violent adult criminal offenders , International Journal of Biosocial and Medical Research , 1981 , 1 , 21 – 41 . Google Scholar OpenURL Placeholder Text WorldCat H. Hu , Knowledge of diagnosis and reproductive history among survivors of childhood plumbism , Am. J. Public Health , 1991 , 81 , 1070 – 1072 . Google Scholar Crossref Search ADS PubMed WorldCat K. M. Erikson , K. Thompson, J. Aschner and M. Aschner, Manganese neurotoxicity: a focus on the neonate , Pharmacol. Ther. , 2007 , 113 , 369 – 377 . Google Scholar Crossref Search ADS PubMed WorldCat J. G. Anderson , S. C. Fordahl, P. T. Cooney, T. L. Weaver, C. L. Colyer and K. M. Erikson, Extracellular norepinephrine, norepinephrine receptor and transporter protein and mRNA levels are differentially altered in the developing rat brain due to dietary iron deficiency and manganese exposure , Brain Res. , 2009 , 1281 , 1 – 14 . Google Scholar Crossref Search ADS PubMed WorldCat K. M. Jamil , A. S. Rahman, P. K. Bardhan, A. I. Khan, F. Chowdhury, S. A. Sarker, A. M. Khan and T. Ahmed, Micronutrients and anaemia , J. Health Popul. Nutr. , 2008 , 26 , 340 – 355 . Google Scholar PubMed OpenURL Placeholder Text WorldCat H. A. Ruff , M. E. Markowitz, P. E. Bijur and J. F. Rosen, Relationships among blood lead levels, iron deficiency, and cognitive development in two-year-old children , Environ. Health Perspect. , 1996 , 104 , 180 – 185 . Google Scholar PubMed OpenURL Placeholder Text WorldCat H. Sachdev , T. Gera and P. Nestel, Effect of iron supplementation on mental and motor development in children: systematic review of randomised controlled trials , Public Health Nutr. , 2005 , 8 , 117 – 132 . Google Scholar Crossref Search ADS PubMed WorldCat J. Y. Yager and D. S. Hartfield, Neurologic manifestations of iron deficiency in childhood , Pediatr. Neurol. , 2002 , 27 , 85 – 92 . Google Scholar Crossref Search ADS PubMed WorldCat E. S. Halas and M. J. Eberhardt, A behavioral review of trace element deficiencies in animals and humans , Nutr. Behav. , 1987 , 3 , 257 – 271 . Google Scholar OpenURL Placeholder Text WorldCat C. J. Frederickson , Neurobiology of zinc and zinc-containing neurons , Int. Rev. Neurobiol. , 1989 , 31 , 145 – 238 . Google Scholar Crossref Search ADS PubMed WorldCat R. Amani , S. Saeidi, Z. Nazari and S. Nematpour, Correlation Between Dietary Zinc Intakes and Its Serum Levels with Depression Scales in Young Female Students , Biol. Trace Elem. Res. , 2009 ,. Google Scholar OpenURL Placeholder Text WorldCat B. Rimland and G. E. Larson, Hair mineral analysis and behavior: an analysis of 51 studies , J. Learn. Disabil. , 1983 , 16 , 279 – 285 . Google Scholar Crossref Search ADS PubMed WorldCat S. Y. Tsai , H. Y. Chou, H. W. The, C. M. Chen and C. J. Chen, The effects of chronic arsenic exposure from drinking water on the neurobehavioral development in adolescence , NeuroToxicology , 2003 , 24 , 747 – 753 . Google Scholar Crossref Search ADS PubMed WorldCat R. O. Pihl and M. Parkes, Hair element content in learning disabled children , Science , 1977 , 198 , 204 – 206 . Google Scholar Crossref Search ADS PubMed WorldCat E. F. Madden and B. A. Fowler, Mechanisms of nephrotoxicity from metal combinations: a review , Drug Chem. Toxicol. , 2000 , 23 , 1 – 12 . Google Scholar Crossref Search ADS PubMed WorldCat O. Barbier , G. Jacquillet, M. Tauc, M. Cougnon and P. Poujeol, Effect of heavy metals on, and handling by, the kidney , Nephron Physiol. , 2005 , 99 , 105 – 110 . Google Scholar Crossref Search ADS WorldCat I. Saboli , Common mechanisms in nephropathy induced by toxic metals , Nephron Physiol. , 2006 , 104 , p107 – p114 . Google Scholar Crossref Search ADS PubMed WorldCat J. Liu , Y. Liu, S. M. Habeebu, M. P. Waalkes and C. D. Klaassen, Chronic combined exposure to cadmium and arsenic exacerbates nephrotoxicity, particularly in metallothionein-I/II null mice , Toxicology , 2000 , 147 , 157 – 166 . Google Scholar Crossref Search ADS PubMed WorldCat M. Föller , M. Sopjani, H. Mahmud and F. Lang, Vanadate-induced suicidal erythrocyte death , Kidney Blood Pressure Res. , 2008 , 31 , 87 – 93 . Google Scholar Crossref Search ADS WorldCat M. Donnadieu-Claraz , M. Bonnehorgne, B. Dhieux, C. Maubert, M. Cheynet, F. Paquet and P. Gourmelon, Chronic exposure to uranium leads to iron accumulation in rat kidney cells , Radiat. Res. , 2007 , 167 , 454 – 464 . Google Scholar Crossref Search ADS PubMed WorldCat P. Kurttio , A. Auvinen, L. Salonen, H. Saha, J. Pekkanen, I. Mäkeläinen, S. B. Väisänen, I. M. Penttilä and H. Komulainen, Renal effects of uranium in drinking water , Environ. Health Perspect. , 2002 , 110 , 337 – 342 . Google Scholar Crossref Search ADS PubMed WorldCat B. Fristedt , R. Lindqvist, A. Schutz and P. Ovrum, Survival in a case of acute chromic acid poisoning with acute renal failure treated by haemodialysis , Acta Med. Scand. , 1965 , 177 , 153 . Google Scholar Crossref Search ADS PubMed WorldCat World Health Organization (WHO) Principles and methods for the assessment of nephrotoxicity associated with exposure to chemicals , Environmental Health Criteria World Health Organization : Geneva , 1991 . J. Fadrowski , A. Navas-Acien, M. Tellez-Plaza, E. Guallar, V. Weaver and S. Furth, Blood lead level and kidney function in US adolescents , Arch. Intern. Med. , 2010 , 170 , 75 – 82 . Google Scholar Crossref Search ADS PubMed WorldCat I. o. M. Food and Nutrition Board in Dietary reference intakes for vitamin A, vitamin K, boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium, and zinc , National Academy Press , Washington, DC , 2001 , pp. 197 – 223 . Google Scholar Google Preview OpenURL Placeholder Text WorldCat COPAC A. S. Prasad , Essential and toxic trace elements in human health and disease , ed. A. S. Prasad and A. Alan R. Liss, New York , 1988 , pp. 3 – 53 . Google Scholar Google Preview OpenURL Placeholder Text WorldCat COPAC H. Malluche , Renal bone disease—an ongoing challenge to the nephrologist , Clin Nephrol , 1995 , 44 , S38 – S41 . Google Scholar PubMed OpenURL Placeholder Text WorldCat H. Malluche and M. C. Faugere, Renal bone disease 1990: an unmet challenge for the nephrologist , Kidney Int. , 1990 , 38 , 193 – 211 . Google Scholar Crossref Search ADS PubMed WorldCat T. Kido , K. Nogawa, R. Honda, I. Tsuritani, M. Ishizaki, Y. Yamada and H. Nakagawa, The association between renal dysfunction and osteopenia in environmental cadmium-exposed subjects , Environ. Res. , 1990 , 51 , 71 – 82 . Google Scholar Crossref Search ADS PubMed WorldCat K. Aoshima , J. Fan, Y. Cai, T. Katoh, H. Teranishi and M. Kasuya, Assessment of bone metabolism in cadmium-induced renal tubular dysfunction by measurements of biochemical markers , Toxicol. Lett. , 2003 , 136 , 183 – 192 . Google Scholar Crossref Search ADS PubMed WorldCat M. Ikeda , T. Ezaki, T. Tsukahara and J. Moriguchi, Dietary cadmium intake in polluted and non-polluted areas in Japan in the past and in the present , Int. Arch. Occup. Environ. Health , 2004 , 77 , 227 – 234 . Google Scholar Crossref Search ADS PubMed WorldCat D. M. Medeiros , A. Plattner, D. Jennings and B. Stoecker, Bone morphology, strength and density are compromised in iron-deficient rats and exacerbated by calcium restriction , J. Nutr. , 2002 , 132 , 3135 – 3141 . Google Scholar Crossref Search ADS PubMed WorldCat D. M. Medeiros , B. Stoecker, A. Plattner, D. Jennings and M. Haub, Iron deficiency negatively affects vertebrae and femurs of rats independently of energy intake and body weight , J. Nutr. , 2004 , 134 , 3061 – 3067 . Google Scholar Crossref Search ADS PubMed WorldCat M. Rahman , M. Tondel, S. A. Ahmad, I. A. Chowdhury, M. H. Faruquee and O. Axelson, Hypertension and arsenic exposure in Bangladesh , Hypertension , 1999 , 33 , 74 – 78 . Google Scholar Crossref Search ADS PubMed WorldCat M. S. Lubanski and P. A. McCullough, Kidney's role in hypertension , Minerva Cardioangiol , 2009 , 57 , 743 – 759 . Google Scholar PubMed OpenURL Placeholder Text WorldCat L. Järup , M. Berglund, C. G. Elinder, G. Nordberg and M. Vahter, Health effects of cadmium exposure—a review of the literature and a risk estimate , Scand. J. Work Environ. Health , 1998 , 24 ( Suppl 1 ), 1 – 51 . Google Scholar PubMed OpenURL Placeholder Text WorldCat J. Liu , Y. Xie, R. Cooper, D. M. K. Ducharme, R. Tennant, B. A. Diwan and M. P. Waalkes, Transplacental exposure to inorganic arsenic at a hepatocarcinogenic dose induces fetal gene expression changes in mice indicative of aberrant estrogen signaling and disrupted steroid metabolism , Toxicol. Appl. Pharmacol. , 2007 , 220 , 284 – 91 . Google Scholar Crossref Search ADS PubMed WorldCat S. V. Chandra , D. K. Saxena and M. Z. Hasan, Effect of zinc on manganese induced testicular injury in rats , Ind. Health , 1975 , 13 , 51 – 56 . Google Scholar Crossref Search ADS WorldCat M. Takiguchi and S. i. Yoshihara, New aspects of cadmium as endocrine disruptor , Environ Sci , 2006 , 13 , 107 – 116 . Google Scholar PubMed OpenURL Placeholder Text WorldCat W. H. Watson and J. D. Yager, Arsenic: extension of its endocrine disruption potential to interference with estrogen receptor-mediated signaling , Toxicol. Sci. , 2007 , 98 , 1 – 4 . Google Scholar Crossref Search ADS PubMed WorldCat G. S. Prins , Endocrine disruptors and prostate cancer risk , Endocr. Relat. Cancer , 2008 , 15 , 649 – 656 . Google Scholar Crossref Search ADS PubMed WorldCat J. D. Meeker , M. G. Rossano, B. Protas, M. P. Diamond, E. Puscheck, D. Daly, N. Paneth and J. J. Wirth, Cadmium, lead, and other metals in relation to semen quality: human evidence for molybdenum as a male reproductive toxicant , Environ. Health Perspect. , 2008 , 116 , 1473 – 1479 . Google Scholar Crossref Search ADS PubMed WorldCat A. H. Milton , A. H. Smith, A. Rahman, Z. Hasan, U. Kulsum, K. Dear, M. Rakibuddin and A. Ali, Chronic arsenic exposure and adverse preganancy outcomes in Bangladesh , Epidemiology , 2005 , 16 , 82 – 86 . Google Scholar Crossref Search ADS PubMed WorldCat N. W. Flodin , Micronutrient supplements: toxicity and drug interactions , Prog. Food Nutr. Sci. , 1990 , 14 , 277 – 331 . Google Scholar PubMed OpenURL Placeholder Text WorldCat B. Haglund , K. Ryckenberg, O. Selinus and G. Dahlquist, Evidence of a relationship between childhood-onset type I diabetes and low groundwater concentration of zinc , Diabetes Care , 1996 , 19 , 873 – 875 . Google Scholar Crossref Search ADS PubMed WorldCat R. R. Bell , J. L. Early, V. K. Nonavinakere and Z. Mallory, Effect of cadmium on blood glucose level in the rat , Toxicol. Lett. , 1990 , 54 , 199 – 205 . Google Scholar Crossref Search ADS PubMed WorldCat A. W. Dobson , K. M. Erikson and M. Aschner, Manganese neurotoxicity , Ann. N. Y. Acad. Sci. , 2004 , 1012 , 115 – 128 . Google Scholar Crossref Search ADS PubMed WorldCat N. Hasgekar , J. P. Beck, H. Dunkelberg, K. I. Hirsch-Ernst and T. W. Gebel, Influence of antimonite, selenite, and mercury on the toxicity of arsenite in primary rat hepatocytes , Biol. Trace Elem. Res. , 2006 , 111 , 167 – 83 . Google Scholar Crossref Search ADS PubMed WorldCat M. S. Bhuiyan and K. Fukunaga, Cardioprotection by vanadium compounds targeting Akt-mediated signaling , J. Pharmacol. Sci. , 2009 , 110 , 1 – 13 . Google Scholar Crossref Search ADS PubMed WorldCat L. Yáñez , L. Carrizales, M. T. Zanatta, J. J. Mejía, L. Batres and F. Díaz-Barriga, Arsenic-cadmium interaction in rats: toxic effects in the heart and tissue metal shifts , Toxicology , 1991 , 67 , 227 – 234 . Google Scholar Crossref Search ADS PubMed WorldCat A. A. Meharg , E. Lombi, P. N. Williams, K. G. Scheckel, J. Feldmann, A. Raab, Y. Zhu and R. Islam, Speciation and Localization of Arsenic in White and Brown Rice , Environ. Sci. Technol. , 2008 , 42 , 1051 – 1057 . Google Scholar Crossref Search ADS PubMed WorldCat P. N. Williams , A. H. Price, A. Raab, A. Hossain, J. Feldmann and A. A. Meharg, Variation in arsenic speciation and concentration in paddy rice related to dietary exposure , Environ. Sci. Technol. , 2005 , 39 , 5531 – 5540 . Google Scholar Crossref Search ADS PubMed WorldCat T. Roychowdhury , H. Tokunaga and M. Ando, Survey of arsenic and other heavy metals in food composites and drinking water and estimation of dietary intake by the villagers from an arsenic-affected area of West Bengal, India , Sci. Total Environ. , 2003 , 308 , 15 – 35 . Google Scholar Crossref Search ADS PubMed WorldCat R. Ortega , S. H. Frisbie, D. Alber, G. Devès, B. Stanik, D. Maynard and B. Sarkar, Presented in part at Nineteenth Annaul Conference on Contaminated Soils , University of Massachusetts , Amherst, MA, Yea . Google Scholar Google Preview OpenURL Placeholder Text WorldCat COPAC S. W. A. Rmalli , P. I. Haris, C. F. Harrington and M. Ayub, A survey of arsenic in foodstuffs on sale in the United Kingdom and imported from Bangladesh , Sci. Total Environ. , 2005 , 337 , 23 – 30 . Google Scholar Crossref Search ADS PubMed WorldCat A. Heikens , G. M. Panaullah and A. A. Meharg, Arsenic behaviour from groundwater and soil to crops: impacts on agriculture and food safety , Rev. Environ. Contam. Toxicol. , 2007 , 189 , 43 – 87 . Google Scholar PubMed OpenURL Placeholder Text WorldCat F. Queirolo , S. Stegen, M. F. Restovic, M. Paz, P. Ostapczuk, M. J. Schwuger and L. Muñoz, Total arsenic level, lead, and cadmium in vegetables cultivated at the Andean villages of northern Chile , Sci. Total Environ. , 2000 , 255 , 75 – 84 . Google Scholar Crossref Search ADS PubMed WorldCat N. M. Smith , R. Lee, D. T. Heitkemper, K. D. Cafferky, A. Haque and A. K. Henderson, Inorganic arsenic in cooked rice and vegetables from Bangladeshi households , Sci. Total Environ. , 2006 , 370 , 294 – 301 . Google Scholar Crossref Search ADS PubMed WorldCat T. Uchino , T. Roychowdhury, M. Ando and H. Tokunaga, Intake of arsenic from water, food composites and excretion through urine, hair from a studied population in West Bengal, India , Food Chem. Toxicol. , 2006 , 44 , 455 – 461 . Google Scholar Crossref Search ADS PubMed WorldCat M. L. Kile , E. A. Houseman, C. V. Breton, T. Smith, Q. Quamruzzaman, M. Rahman, G. Mahiuddin and D. C. Christiani, Dietary arsenic exposure in bangladesh , Environ. Health Perspect. , 2007 , 115 , 889 – 893 . Google Scholar Crossref Search ADS PubMed WorldCat B. K. Mandal , K. T. Suzuki and K. Anzai, Impact of arsenic in foodstuffs on the people living in the arsenic-affected areas of West Bengal, India , J. Environ. Sci. Health A Tox. Hazard Subst. Environ. Eng. , 2007 , 42 , 1741 – 1752 . Google Scholar Crossref Search ADS PubMed WorldCat A. A. Carbonell-Barrachina , A. J. Signes-Pastor, L. Vázquez-Araújo, F. Burló and B. Sengupta, Presence of arsenic in agricultural products from arsenic-endemic areas and strategies to reduce arsenic intake in rural villages , Mol. Nutr. Food Res. , 2009 , 53 , 531 – 541 . Google Scholar Crossref Search ADS PubMed WorldCat M. M. Rahman , G. Owens and R. Naidu, Arsenic levels in rice grain and assessment of daily dietary intake of arsenic from rice in arsenic-contaminated regions of Bangladesh—implications to groundwater irrigation , Environ. Geochem. Health , 2009 , 31 ( Suppl 1 ), 179 – 187 . Google Scholar Crossref Search ADS PubMed WorldCat T. Roychowdhury , T. Uchino, H. Tokunaga and M. Ando, Survey of arsenic in food composites from an arsenic-affected area of West Bengal, India , Food Chem. Toxicol. , 2002 , 40 , 1611 – 1621 . Google Scholar Crossref Search ADS PubMed WorldCat M. L. Kile , E. A. Houseman, C. V. Breton, Q. Quamruzzaman, M. Rahman, G. Mahiuddin and D. C. Christiani, Association between total ingested arsenic and toenail arsenic concentrations , J. Environ. Sci. Health A Tox. Hazard Subst. Environ. Eng. , 2007 , 42 , 1827 – 1834 . Google Scholar Crossref Search ADS PubMed WorldCat C. D. Kozul , A. P. Nomikos, T. H. Hampton, L. A. Warnke, J. A. Gosse, J. C. Davey, J. E. Thorpe, B. P. Jackson, M. A. Ihnat and J. W. Hamilton, Laboratory diet profoundly alters gene expression and confounds genomic analysis in mouse liver and lung , Chem.-Biol. Interact. , 2008 , 173 , 129 – 140 . Google Scholar Crossref Search ADS PubMed WorldCat J. A. T. Pennington , B. E. Young, D. B. Wilson, R. D. Johnson and J. E. Vanderveen, Mineral content of foods and total diets: the selected minerals in foods survey, 1982–1984 , J. Am. Diet. Assoc. , 1986 , 86 , 876 – 891 . Google Scholar PubMed OpenURL Placeholder Text WorldCat S. F. Velazquez and J. T. Du, in Risk Assessment of Essential elements , ed. W. Mertz, C. O. Abernathy and S. S. Olin, ILSI Press , Washington, D.C. , 1994 , pp. 253 – 266 . Google Scholar Google Preview OpenURL Placeholder Text WorldCat COPAC K. Ljung and M. Vahter, Time to re-evaluate the guideline value for manganese in drinking water? , Environ. Health Perspect. , 2007 , 115 , 1533 – 1538 . Google Scholar Crossref Search ADS PubMed WorldCat R. W. Wenlock , D. H. Buss and E. J. Dixon, Trace nutrients. 2. Manganese in British food , Br. J. Nutr. , 1979 , 41 , 253 – 261 . Google Scholar Crossref Search ADS PubMed WorldCat ATSDR Toxicological profile for cadmium ; Agency for Toxic Substances and Disease Registry : Atlanta, GA , 1999 . R. W. Simmons , P. Pongsakul, D. Saiyasitpanich and S. Klinphoklap, Elevated levels of cadmium and zinc in paddy soils and elevated levels of cadmium in rice grain downstream of a zinc mineralized area in Thailand: implications for public health , Environ. Geochem. Health , 2005 , 27 , 501 – 511 . Google Scholar Crossref Search ADS PubMed WorldCat I. Mariam , S. Iqbal and S. A. Nagra, Distribution of some trace and macrominerals in beef, mutton and poultry , International Journal of Agriculture and Biology , 2004 , 6 , 816 – 820 . Google Scholar OpenURL Placeholder Text WorldCat D. Santhi , V. B. Balakrishnan, A. Kalaikanna and K. T. Radhakrishnan, Presence of heavy metals in pork products in Chennai (India) , Am. J. Food Technol. , 2008 , 3 , 192 – 199 . Google Scholar Crossref Search ADS WorldCat S. O. Welsh and R. M. Marston, Zinc levels of the US food supply 1909–1980 , Food Technol. , 1982 , 36 , 70 – 76 . Google Scholar OpenURL Placeholder Text WorldCat D. G. Barceloux , Zinc , Clin. Toxicol. , 1999 , 37 , 279 – 292 . Google Scholar OpenURL Placeholder Text WorldCat M. B. Kristensen , O. Hels, C. M. Morberg, J. Marving, S. Bügel and I. Tetens, Total zinc absorption in young women, but not fractional zinc absorption, differs between vegetarian and meat-based diets with equal phytic acid content , Br. J. Nutr. , 2006 , 95 , 963 – 967 . Google Scholar Crossref Search ADS PubMed WorldCat A. L. Rauma and H. Mykkänen, Antioxidant status in vegetarians versus omnivores , Nutrition , 2000 , 16 , 111 – 119 . Google Scholar Crossref Search ADS PubMed WorldCat T. Roychowdhury , T. Uchino, H. Tokunaga and M. Ando, Arsenic and other heavy metals in soils from an arsenic-affected area of West Bengal, India , Chemosphere , 2002 , 49 , 605 – 618 . Google Scholar Crossref Search ADS PubMed WorldCat M. J. Abedin , M. S. Cresser, A. A. Meharg, J. Feldmann and J. Cotter-Howells, Arsenic accumulation and metabolism in rice (Oryza sativa L.) , Environ. Sci. Technol. , 2002 , 36 , 962 – 968 . Google Scholar Crossref Search ADS PubMed WorldCat M. G. M. Alam , E. T. Snow and A. Tanaka, Arsenic and heavy metal contamination of vegetables grown in Samta village, Bangladesh , Sci. Total Environ. , 2003 , 308 , 83 – 96 . Google Scholar Crossref Search ADS PubMed WorldCat J. M. Duxbury , A. B. Mayer, J. G. Lauren and N. Hassan, Food chain aspects of arsenic contamination in Bangladesh: effects on quality and productivity of rice , J. Environ. Sci. Health A Tox. Hazard Subst. Environ. Eng. , 2003 , 38 , 61 – 69 . Google Scholar Crossref Search ADS PubMed WorldCat A. A. Meharg and M. Rahman, Arsenic contamination of Bangladesh paddy field soils: implications for rice contribution to arsenic consumption , Environ. Sci. Technol. , 2003 , 37 , 229 – 234 . Google Scholar Crossref Search ADS PubMed WorldCat S. Norra , Z. A. Berner, P. Agarwala, F. Wagner, D. Chandrasekharam and D. Stuben, with As rich groundwater on soil and crops: a geochemical case study in West Bengal Delta Plain, India , Appl. Geochem. , 2005 , 20 , 1890 – 1906 . Google Scholar Crossref Search ADS WorldCat S. M. I. Huq , J. C. Joardar, S. Parvin, R. Correll and R. Naidu, Arsenic contamination in food-chain: transfer of arsenic into food materials through groundwater irrigation , J. Health Popul. Nutr. , 2006 , 24 , 305 – 316 . Google Scholar PubMed OpenURL Placeholder Text WorldCat M. B. Arain , T. G. Kazi, J. A. Baig, M. K. Jamali, H. I. Afridi, N. Jalbani, R. A. Sarfraz, A. Q. Shah and G. A. Khandro, Respiratory effects in people exposed to arsenic via the drinking water and tobacco smoking in southern part of Pakistan , Sci. Total Environ. , 2009 , 407 , 5524 – 5530 . Google Scholar Crossref Search ADS PubMed WorldCat P. Saipan and S. Ruangwises, Health risk assessment of inorganic arsenic intake of Ronphibun residents via duplicate diet study , J. Med. Assoc. Thai. , 2009 , 92 , 849 – 855 . Google Scholar PubMed OpenURL Placeholder Text WorldCat R. A. Karim , S. M. Hossain, M. M. H. Miah, K. Nehar and M. S. H. Mubin, Arsenic and heavy metal concentrations in surface soils and vegetables of Feni district in Bangladesh , Environ. Monit. Assess. , 2008 , 145 , 417 – 425 . Google Scholar Crossref Search ADS PubMed WorldCat J. R. Peralta-Videa , M. L. Lopez, M. Narayan, G. Saupe and J. Gardea-Torresdey, The biochemistry of environmental heavy metal uptake by plants: implications for the food chain , Int. J. Biochem. Cell Biol. , 2009 , 41 , 1665 – 1677 . Google Scholar Crossref Search ADS PubMed WorldCat P. Zaprjanova , L. Dospatliev, V. Angelova and K. Ivanov, Correlation between soil characteristics and lead and cadmium content in the aboveground biomass of Virginia tobacco , Environ. Monit. Assess. , 2010 , 163 , 253 – 261 . Google Scholar Crossref Search ADS PubMed WorldCat N. Waegeneers , H. D. Steur, L. D. Temmerman, S. V. Steenwinkel, X. Gellynck and J. Viaene, Transfer of soil contaminants to home-produced eggs and preventitive measures to reduce contamination , Sci. Total Environ. , 2009 , 407 , 4438 – 4446 . Google Scholar Crossref Search ADS PubMed WorldCat V. Devesa , D. Vélez and R. Montoro, Effect of thermal treatments on arsenic species contents in food , Food Chem. Toxicol. , 2008 , 46 , 1 – 8 . Google Scholar Crossref Search ADS PubMed WorldCat M. Bae , C. Watanabe, T. Inaoka, M. Sekiyama, N. Sudo, M. H. Bokul and R. Ohtsuka, Arsenic in cooked rice in Bangladesh , Lancet , 2002 , 360 , 1839 – 1840 . Google Scholar Crossref Search ADS PubMed WorldCat M. M. Rahman , B. K. Mandal, T. R. Chowdhury, M. K. Sengupta, U. K. Chowdhury, D. Lodh, C. R. Chanda, G. K. Basu, S. C. Mukherjee, K. C. Saha and D. Chakraborti, Arsenic groundwater contamination and sufferings of people in North 24-Parganas, one of the nine arsenic affected districts of West Bengal, India , J. Environ. Sci. Health A Tox. Hazard Subst. Environ. Eng. , 2003 , 38 , 25 – 59 . Google Scholar Crossref Search ADS PubMed WorldCat O. P. Díaz , I. Leyton, O. Muñoz, N. Nuñez, V. Devesa, M. A. Suñer, V. Dinoraz and R. Montoro, Contribution of water, bread, and vegetables (raw and cooked) to dietary intake of inorganic arsenic in a rural village of northern Chile , J. Agric. Food Chem. , 2004 , 52 , 1773 – 1779 . Google Scholar Crossref Search ADS PubMed WorldCat D. G. Barceloux , Nickel , Clin. Toxicol. , 1999 , 37 , 239 – 258 . Google Scholar OpenURL Placeholder Text WorldCat M. Ajmal , A. Khan, A. A. Nomani and S. Ahmed, Heavy metals: leaching from glazed surfaces of tea mugs , Sci. Total Environ. , 1997 , 207 , 49 – 54 . Google Scholar Crossref Search ADS PubMed WorldCat R. Raghunath and K. S. Nambi, Lead leaching from pressure cookers , Sci. Total Environ. , 1998 , 224 , 143 – 148 . Google Scholar Crossref Search ADS PubMed WorldCat P. K. Sinha , S. Mandal and D. Kundu, Leaching of lead and cadmium from glass dinnerware , J. Environ. Sci. Eng. , 2007 , 49 , 58 – 61 . Google Scholar PubMed OpenURL Placeholder Text WorldCat N. Shivapurkar and L. A. Poirer, Tissue levels of S-adenosylmethio-nine and S-adenosylhomocysteine in rats fed methyl-deficient, amino acid-defined diets for one to five weeks , Carcinogenesis , 1983 , 4 , 1051 – 1057 . Google Scholar Crossref Search ADS PubMed WorldCat J. Kristiansen , J. M. Christensen, B. S. Iversen and E. Sabbioni, Toxic trace element reference levels in blood and urine: influence of gender and lifestyle factors , Sci. Total Environ. , 1997 , 204 , 147 – 160 . Google Scholar Crossref Search ADS PubMed WorldCat P. L. Goering , H. V. Aposhian, M. J. Mass, M. Cebrian, B. D. Beck and M. P. Waalkes, The enigma of arsenic carcinogenesis: role of metabolism , Toxicol. Sci. , 1999 , 49 , 5 – 14 . Google Scholar Crossref Search ADS PubMed WorldCat S. R. Mitra , D. N. G. Mazumder, A. Basu, G. Block, R. Haque, S. Samanta, N. Ghosh, M. M. H. Smith, O. S. von Ehrenstein and A. H. Smith, Nutritional factors and susceptibility to arsenic-caused skin lesions in West Bengal, India , Environ. Health Perspect. , 2004 , 112 , 1104 – 1109 . Google Scholar Crossref Search ADS PubMed WorldCat C. Steinmaus , K. Carrigan, D. Kalman, R. Atallah, Y. Yuan and A. H. Smith, Dietary intake and arsenic methylation in a U.S. population , Environ. Health Perspect. , 2005 , 113 , 1153 – 1159 . Google Scholar Crossref Search ADS PubMed WorldCat O. A. Levander , Lead toxicity and nutritional deficiencies , Environ. Health Perspect. , 1979 , 29 , 115 – 125 . Google Scholar Crossref Search ADS PubMed WorldCat M. V. Gamble , X. Liu, H. Ahsan, R. Pislner, V. Ilievski, V. Slavkovich, F. Parvez, D. Levy, P. Factor-Litvak and J. Graziano, Folate, homocysteine, and arsenic metabolism in arsenic-exposed individuals in Bangladesh , Environ. Health Perspect. , 2005 , 113 , 1683 – 1688 . Google Scholar Crossref Search ADS PubMed WorldCat M. V. Gamble , X. Liu, H. Ahsan, J. R. Pilsner, V. Ilievski, V. Slavkovich, F. Parvez, Y. Chen, D. Levy, P. Factor-Litvak and J. H. Graziano, Folate and arsenic metabolism: a double-blind, placebo-controlled folic acid-supplementation trial in Bangladesh , Am. J. Clin. Nutr. , 2006 , 84 , 1093 – 1101 . Google Scholar Crossref Search ADS PubMed WorldCat M. V. Gamble , X. Liu, V. Slavkovich, J. R. Pilsner, V. Ilievski, P. Factor-Litvak, D. Levy, S. Alam, M. Islam, F. Parvez, H. Ahsan and J. H. Graziano, Folic acid supplementation lowers blood arsenic , Am. J. Clin. Nutr. , 2007 , 86 , 1202 – 1209 . Google Scholar Crossref Search ADS PubMed WorldCat M. L. Kile and A. G. Ronnenberg, Can folate intake reduce arsenic toxicity? , Nutr. Rev. , 2008 , 66 , 349 – 353 . Google Scholar Crossref Search ADS PubMed WorldCat Y.-K. Huang , Y.-S. Pu, C.-J. Chung, H.-S. Shiue, M.-H. Yang, C.-J. Chen and Y.-M. Hsueh, Plasma folate level, urinary arsenic methylation profiles, and urothelial carcinoma susceptibility , Food Chem. Toxicol. , 2008 , 46 , 929 – 938 . Google Scholar Crossref Search ADS PubMed WorldCat J. R. Pilsner , X. Liu, H. Ahsan, V. Ilievski, V. Slavkovich, D. Levy, P. Factor-Litvak, J. H. Graziano and M. V. Gamble, Folate deficiency, hyperhomocysteinemia, low urinary creatinine, and hypomethylation of leukocyte DNA are risk factors for arsenic-induced skin lesions , Environ. Health Perspect. , 2009 , 117 , 254 – 260 . Google Scholar Crossref Search ADS PubMed WorldCat P. N. Baker , S. J. Wheeler, T. A. Sanders, J. E. Thomas, C. J. Hutchinson, K. Clarke, J. L. Berry, R. L. Jones, P. T. Seed and L. Poston, A prospective study of micronutrient status in adolescent pregnancy , Am. J. Clin. Nutr. , 2009 , 89 , 1114 – 1124 . Google Scholar Crossref Search ADS PubMed WorldCat A. Alberg , The influence of cigarette smoking on circulating concentrations of antioxidant micronutrients , Toxicology , 2002 , 180 , 121 – 137 . Google Scholar Crossref Search ADS PubMed WorldCat S. K. Bashar and A. K. Mitra, Effect of smoking on vitamin A, vitamin E, and other trace elements in patients with cardiovascular disease in Bangladesh: a cross-sectional study , Nutr. J. , 2004 , 3 , 18 . Google Scholar Crossref Search ADS PubMed WorldCat P. Wallström , E. Wirfält, P. H. Lahmann, B. Gullberg, L. Janzon and G. Berglund, Serum concentrations of beta-carotene and alpha-tocopherol are associated with diet, smoking, and general and central adiposity , Am. J. Clin. Nutr. , 2001 , 73 , 777 – 785 . Google Scholar Crossref Search ADS PubMed WorldCat O. Müller and M. Krawinkel, Malnutrition and health in developing countries , Can. Med. Assoc. J. , 2005 , 173 , 279 – 286 . Google Scholar Crossref Search ADS WorldCat F. Ahmed , Vitamin A deficiency in Bangladesh: a review and recommendations for improvement , Public Health Nutr. , 1999 , 2 , 1 – 14 . Google Scholar Crossref Search ADS PubMed WorldCat F. Ahmed , Anaemia in Bangladesh: a review of prevalence and aetiology , Public Health Nutr. , 2000 , 3 , 385 – 393 . Google Scholar Crossref Search ADS PubMed WorldCat F. Ahmed , M. R. Khan, C. P. Banu, M. R. Qazi and M. Akhtaruzzaman, The coexistence of other micronutrient deficiencies in anaemic adolescent schoolgirls in rural Bangladesh , Eur. J. Clin. Nutr. , 2008 , 62 , 365 – 372 . Google Scholar Crossref Search ADS PubMed WorldCat V. Persson , F. Ahmed, M. Gebre-Medhin and T. Greiner, Relationships between vitamin A, iron status and helminthiasis in Bangladeshi school children , Public Health Nutr. , 2000 , 3 , 83 – 89 . Google Scholar Crossref Search ADS PubMed WorldCat M. Z. Islam , C. Lamberg-Allardt, M. A. Bhuyan and Q. Salamatullah, Iron status of premenopausal women in two regions of Bangladesh: prevalence of deficiency in high and low socio-economic groups , Eur. J. Clin. Nutr. , 2001 , 55 , 598 – 604 . Google Scholar Crossref Search ADS PubMed WorldCat S. M. Z. Hyder , L.-A. Persson, M. Chowdhury, B. O. Lönnerdal and E.-C. Ekström, Anaemia and iron deficiency during pregnancy in rural Bangladesh , Public Health Nutr. , 2004 , 7 , 1065 – 1070 . Google Scholar Crossref Search ADS PubMed WorldCat A. S. G. Faruque , A. I. Khan, M. A. Malek, S. Huq, M. A. Wahed, M. A. Salam, G. J. Fuchs and M. A. Khaled, Childhood anemia and vitamin a deficiency in rural Bangladesh , Southeast Asian J. Trop Med. Public Health , 2006 , 37 , 771 – 777 . Google Scholar PubMed OpenURL Placeholder Text WorldCat A. Khambalia , D. L. O'Connor and S. Zlotkin, Periconceptional iron and folate status is inadequate among married, nulliparous women in rural Bangladesh , J. Nutr. , 2009 , 139 , 1179 – 1184 . Google Scholar Crossref Search ADS PubMed WorldCat M. H. Or-Rashid , U. F. Khatun, Y. Yoshida, S. Morita, N. Chowdhury and J. Sakamoto, Iron and iodine deficiencies among under-2 children, adolescent girls, and pregnant women of Bangladesh: association with common diseases , Nagoya J. Med. Sci. , 2009 , 71 , 39 – 49 . Google Scholar PubMed OpenURL Placeholder Text WorldCat A. Misra , N. K. Vikram, R. M. Pandey, M. Dwivedi, F. U. Ahmad, K. Luthra, K. Jain, N. Khanna, J. R. Devi, R. Sharma and R. Guleria, Hyperhomocysteinemia and low intakes of folic acid and vitamin B12 in urban North India , Eur. J. Nutr. , 2002 , 41 , 68 – 77 . Google Scholar Crossref Search ADS PubMed WorldCat P. Pathak , U. Kapil, S. K. Kapoor, R. Saxena, A. Kumar, N. Gupta, S. N. Dwivedi, R. Singh and P. Singh, Prevalence of multiple micronutrient deficiencies amongst pregnant women in a rural area of Haryana , Indian J. Pediatr. , 2004 , 71 , 1007 – 1014 . Google Scholar Crossref Search ADS PubMed WorldCat P. Pathak , U. Kapil, C. S. Yajnik, S. K. Kapoor, S. N. Dwivedi and R. Singh, Iron, folate, and vitamin B12 stores among pregnant women in a rural area of Haryana State, India , Food Nutr. Bull. , 2007 , 28 , 435 – 438 . Google Scholar Crossref Search ADS PubMed WorldCat T. Jiang , P. Christian, S. K. Khatry, L. Wu and K. P. West, Micronutrient deficiencies in early pregnancy are common, concurrent, and vary by season among rural Nepali pregnant women , J. Nutr. , 2005 , 135 , 1106 – 1112 . Google Scholar Crossref Search ADS PubMed WorldCat V. P. Anderson , S. Jack, D. Monchy, N. Hem, P. Hok, K. B. Bailey and R. S. Gibson, Co-existing micronutrient deficiencies among stunted Cambodian infants and toddlers , Asia Pac. J. Clin. Nutr. , 2008 , 17 , 72 – 79 . Google Scholar PubMed OpenURL Placeholder Text WorldCat N. V. Nhien , N. C. Khan, N. X. Ninh, P. V. Huan, L. T. Hop, N. T. Lam, F. Ota, T. Yabutani, V. Q. Hoa, J. Motonaka, T. Nishikawa and Y. Nakaya, Micronutrient deficiencies and anemia among preschool children in rural Vietnam , Asia Pac. J. Clin. Nutr. , 2008 , 17 , 48 – 55 . Google Scholar PubMed OpenURL Placeholder Text WorldCat R. A. Thurlow , P. Winichagoon, T. Pongcharoen, S. Gowachirapant, A. Boonpraderm, M. S. Manger, K. B. Bailey, E. Wasantwisut and R. S. Gibson, Risk of zinc, iodine, and other micronutrient deficiences among school children in North East Thailand , Eur. J. Clin. Nutr. , 2006 , 60 , 623 – 632 . Google Scholar Crossref Search ADS PubMed WorldCat R. L. Lander , T. Enkhjargal, J. Batjargal, K. B. Bailey, S. Diouf, T. J. Green, C. M. Skeaff and R. S. Gibson, Multiple micronutrient deficiencies persist during early childhood in Mongolia , Asia Pac. J. Clin. Nutr. , 2008 , 17 , 429 – 440 . Google Scholar PubMed OpenURL Placeholder Text WorldCat P. Galan , F. E. Viteri, S. Bertrais, S. Czernichow, H. Faure, J. Arnaud, D. Ruffieux, S. Chenal, N. Arnault, A. Favier, A. M. Roussel and S. Hercberg, Serum concentrations of beta-carotene, vitamins C and E, zinc and selenium are influenced by sex, age, diet, smoking status, alcohol consumption and corpulence in a general French adult population , Eur. J. Clin. Nutr. , 2005 , 59 , 1181 – 1190 . Google Scholar Crossref Search ADS PubMed WorldCat T. G. Kazi , S. K. Wadhwa, H. I. Afridi, N. Kazi, G. A. Kandhro, J. A. Baig, A. Q. Shah, N. F. Kolachi and M. B. Arain, Interaction of cadmium and zinc in biological samples of smokers and chewing tobacco female mouth cancer patients , J. Hazard. Mater. , 2010 , 176 , 985 – 991 . Google Scholar Crossref Search ADS PubMed WorldCat Y. M. Hseuh , C. S. Cheng, M. M. Wu, T. L. Kuo and C. J. Chen, Multiple risk factors associatecd with arsenic-induced skin cancers: effects of chronic liver disease and malnutrition , Br. J. Cancer , 1995 , 71 , 109 – 114 . Google Scholar Crossref Search ADS PubMed WorldCat J. I. Anetor , H. Wanibuchi and S. Fukushima, Arsenic exposure and its health effects and risk of cancer in developing countries: micronutrients as host defence , Asian Pac. J. Cancer Prev. , 2007 , 8 , 13 – 23 . Google Scholar PubMed OpenURL Placeholder Text WorldCat U. K. Chowdhury , M. M. Rahman, M. K. Sengupta, D. Lodh, C. R. Chanda, S. Roy, Q. Quamruzzaman, H. Tokunaga, M. Ando and D. Chakraborti, Pattern of excretion of arsenic compounds [arsenite, arsenate, MMA(V), DMA(V)] in urine of children compared to adults from an arsenic exposed area in Bangladesh , J. Environ. Sci. Health A Tox. Hazard Subst. Environ. Eng. , 2003 , 38 , 87 – 113 . Google Scholar Crossref Search ADS PubMed WorldCat J. Calderon , M. E. Navarro, M. E. Jimenez-Capdeville, M. A. Santos-Diaz, A. Golden, I. Rodriguez-Leyva, V. H. Borja-Aburto and F. Diaz-Barriga, Exposure to arsenic and lead and neuropsychological development in Mexican children , Environ. Res. , 2001 , 85 , 69 – 76 . Google Scholar Crossref Search ADS PubMed WorldCat G. V. Iyengar and H. Kawamura, Dietary intakes of seven elements of importance in radiological protection by Asian population: comparison with ICRP data , Health Phys. , 2004 , 86 , 557 – 564 . Google Scholar Crossref Search ADS PubMed WorldCat A. Jain , B. K. Agrawal, M. Varma and A. A. Jadhav, Antioxidant status and smoking habits: relationship with diet , Singapore Med. J. , 2009 , 50 , 624 – 627 . Google Scholar PubMed OpenURL Placeholder Text WorldCat S. Wani , Ahmad, F. Ahmad, S. A. Zargar, A. Pervaiz and H. Tak, Prevalence of intestinal parasites and associated risk factors among schoolchildren in Srinagar City, Kashmir, India , J. Parasitol. , 2007 , 93 , 1541 – 1543 . Google Scholar Crossref Search ADS PubMed WorldCat S. A. Sarker , L. Davidsson, H. Mahmud, T. Walczyk, R. F. Hurrell, N. Gyr and G. J. Fuchs, Helicobacter pylori infection, iron absorption, and gastric acid secretion in Bangladeshi children , Am. J. Clin. Nutr. , 2004 , 80 , 149 – 153 . Google Scholar Crossref Search ADS PubMed WorldCat E. I. Brima , R. O. Jenkins, P. R. Lythgoe, A. G. Gault, D. A. Polya and P. I. Haris, Effect of fasting on the pattern of urinary arsenic excretion , J. Environ. Monit. , 2007 , 9 , 98 – 103 . Google Scholar Crossref Search ADS PubMed WorldCat D. Brugge , J. L. de Lemos and B. Oldmixon, Exposure pathways and health effects associated with chemical and radiological toxicity of natural uranium: a review , Reviews on Environmental Health , 2005 , 20 , 177 – 193 . Google Scholar Crossref Search ADS PubMed WorldCat R. W. Leggett and J. D. Harrison, Fractional absorption of ingested uranium in humans , Health Phys. , 1995 , 68 , 484 – 498 . Google Scholar Crossref Search ADS PubMed WorldCat M. Z. Islam , C. Lamberg-Allardt, M. Kärkkäinen and S. M. K. Ali, Dietary calcium intake in premenopausal Bangladeshi women: do socio-economic or physiological factors play a role? , Eur. J. Clin. Nutr. , 2003 , 57 , 674 – 680 . Google Scholar Crossref Search ADS PubMed WorldCat J. E. D. de Oliveira , J. B. Ferreira, V. P. Vasconcellos and J. S. Marchini, Drinking water as an iron carrier to control anemia in preschool children in a day-care center , J. Am. Coll. Nutr. , 1994 , 13 , 198 – 202 . Google Scholar Crossref Search ADS PubMed WorldCat M. Z. Islam , C. Lamberg-Allardt, M. Kärkkäinen, T. Outila, Q. Salamatullah and A. A. Shamim, Vitamin D deficiency: a concern in premenopausal Bangladeshi women of two socio-economic groups in rural and urban region , Eur. J. Clin. Nutr. , 2002 , 56 , 51 – 56 . Google Scholar Crossref Search ADS PubMed WorldCat Bangladesh Bureau of Statistics Local Estimation of Poverty and Malnutrition in Bangladesh ; United Nations World Food Program : 2004 . S. M. Ahmed , A. Adams, A. M. Chowdhury and A. Bhuiya, Chronic energy deficiency in women from rural Bangladesh: some socioeconomic determinants , J. Biosoc. Sci. , 1998 , 30 , 349 – 358 . Google Scholar Crossref Search ADS PubMed WorldCat Y. Balarajan and E. Villamor, Nationally representative surveys show recent increases in the prevalence of overweight and obesity among women of reproductive age in Bangladesh, Nepal, and India , J. Nutr. , 2009 , 139 , 2139 – 2144 . Google Scholar Crossref Search ADS PubMed WorldCat M. Z. Islam , M. Akhtaruzzaman and C. Lamberg-Allardt, Nutritional status of women in Bangladesh: comparison of energy intake and nutritional status of a low income rural group with a high income urban group , Asia Pac. J. Clin. Nutr. , 2004 , 13 , 61 – 68 . Google Scholar PubMed OpenURL Placeholder Text WorldCat B. L. Pierce , T. Kalra, M. Argos, F. Parvez, Y. Chen, T. Islam, A. Ahmed, R. Hasan, M. Rakibuz-Zaman, J. Graziano, P. J. Rathouz and H. Ahsan, A prospective study of body mass index and mortality in Bangladesh , Int. J. Epidemiol. , 2009 ,. Google Scholar OpenURL Placeholder Text WorldCat S. Shafique , N. Akhter, G. Stallkamp, S. de Pee, D. Panagides and M. W. Bloem, Trends of under- and overweight among rural and urban poor women indicate the double burden of malnutrition in Bangladesh , Int. J. Epidemiol. , 2007 , 36 , 449 – 457 . Google Scholar Crossref Search ADS PubMed WorldCat D. N. Guha Mazumder , R. Haque, N. Ghosh, B. K. De, A. Santra and D. Chakraborty, Arsenic levels in drinking water and the prevalence of skin lesions in West Bengal, India , Int. J. Epidemiol. , 1998 , 27 , 871 – 877 . Google Scholar Crossref Search ADS PubMed WorldCat M. S. Pednekar , P. C. Gupta, H. C. Shukla and J. R. Hebert, Association between tobacco use and body mass index in urban Indian population: implications for public health in India , BMC Public Health , 2006 , 6 , 70 . Google Scholar Crossref Search ADS PubMed WorldCat T. Rastogi , P. Jha, K. S. Reddy, D. Prabhakaran, D. Spiegelman, M. J. Stampfer, W. C. Willett and A. Ascherio, Bidi and cigarette smoking and risk of acute myocardial infarction among males in urban India , Tob. Control , 2005 , 14 , 356 – 358 . Google Scholar Crossref Search ADS PubMed WorldCat H. C. Shukla , P. C. Gupta, H. C. Mehta and J. R. Hebert, Descriptive epidemiology of body mass index of an urban adult population in western India , J. Epidemiol. Community Health , 2002 , 56 , 876 – 880 . Google Scholar Crossref Search ADS PubMed WorldCat S. V. Subramanian and G. D. Smith, Patterns, distribution, and determinants of under- and overnutrition: a population-based study of women in India , Am. J. Clin. Nutr. , 2006 , 84 , 633 – 640 . Google Scholar Crossref Search ADS PubMed WorldCat G. A. Wasserman , X. Liu, P. Factor-Litvak, J. M. Gardner and J. H. Graziano, Developmental impacts of heavy metals and undernutrition , Basic Clin. Pharmacol. Toxicol. , 2008 , 102 , 212 – 217 . Google Scholar Crossref Search ADS PubMed WorldCat C. Watanabe , T. Matsui, T. Inaoka, T. Kadono, K. Miyazaki, M.-J. Bae, T. Ono, R. Ohtsuka and A. T. M. M. H. Bokul, Dermatological and nutritional/growth effects among children living in arsenic-contaminated communities in rural Bangladesh , J. Environ. Sci. Health A Tox. Hazard Subst. Environ. Eng. , 2007 , 42 , 1835 – 1841 . Google Scholar Crossref Search ADS PubMed WorldCat M. Argos , F. Parvez, Y. Chen, A. Z. M. I. Hussain, H. Momotaj, G. R. Howe, J. H. Graziano and H. Ahsan, Socioeconomic status and risk for arsenic-related skin lesions in Bangladesh , Am. J. Public Health , 2007 , 97 , 825 – 831 . Google Scholar Crossref Search ADS PubMed WorldCat J. Brinkel , M. H. Khan and A. Kraemer, A systematic review of arsenic exposure and its social and mental health effects with special reference to Bangladesh , Int. J. Environ. Res. Public Health , 2009 , 6 , 1609 – 1619 . Google Scholar Crossref Search ADS PubMed WorldCat A. Hadi and R. Parveen, Arsenicosis in Bangladesh: prevalence and socio-economic correlates , Public Health , 2004 , 118 , 559 – 564 . Google Scholar Crossref Search ADS PubMed WorldCat R. A. Lynch , D. T. Boatright and S. K. Moss, Lead-contaminated imported tamarind candy and children's blood lead levels , Public Health Rep. , 2000 , 115 , 537 – 543 . Google Scholar Crossref Search ADS PubMed WorldCat J. F. Kauffman , B. J. Westenberger, J. D. Robertson, J. Guthrie, A. Jacobs and S. K. Cummins, Lead in pharmaceutical products and dietary supplements , Regul. Toxicol. Pharmacol. , 2007 , 48 , 128 – 134 . Google Scholar Crossref Search ADS PubMed WorldCat W. R. Mindak , J. Cheng, B. J. Canas and P. M. Bolger, Lead in women's and children's vitamins , J. Agric. Food Chem. , 2008 , 56 , 6892 – 6896 . Google Scholar Crossref Search ADS PubMed WorldCat J. K. Nduka and O. E. Orisakwe, Heavy metal hazards of pediatric syrup administration in Nigeria: a look at chromium, nickel and manganese , Int. J. Environ. Res. Public Health , 2009 , 6 , 1972 – 1979 . Google Scholar Crossref Search ADS PubMed WorldCat G. B. van der Voet , A. Sarafanov, T. I. Todorov, J. A. Centeno, W. B. Jonas, J. A. Ives and F. G. Mullick, Clinical and analytical toxicology of dietary supplements: a case study and a review of the literature , Biol. Trace Elem. Res. , 2008 , 125 , 1 – 12 . Google Scholar Crossref Search ADS PubMed WorldCat A. A. Abou-Arab and M. A. A. Donia, Heavy metals in Egyptian spices and medicinal plants and the effect of processing on their levels , J. Agric. Food Chem. , 2000 , 48 , 2300 – 2304 . Google Scholar Crossref Search ADS PubMed WorldCat S. Dey , A. Saxena, A. Dan and D. Swarup, Indian medicinal herb: a source of lead and cadmium for humans and animals , Arch. Environ. Occup. Health , 2009 , 64 , 164 – 167 . Google Scholar Crossref Search ADS PubMed WorldCat J. G. Ayenimo , A. M. Yusuf, A. S. Adekunle and O. W. Makinde, Heavy metal exposure from personal care products , Bull. Environ. Contam. Toxicol. , 2010 , 84 , 8 – 14 . Google Scholar Crossref Search ADS PubMed WorldCat N. Z. Janjua , E. Delzell, R. R. Larson, S. Meleth, E. K. Kabagambe, S. Kristensen and N. Sathiakumar, Maternal nutritional status during pregnancy and surma use determine cord lead levels in Karachi, Pakistan , Environ. Res. , 2008 , 108 , 69 – 79 . Google Scholar Crossref Search ADS PubMed WorldCat C. Parry and J. Eaton, Kohl: a lead-hazardous eye makeup from the Third World to the First World , Environ. Health Perspect. , 1991 , 94 , 121 – 123 . Google Scholar PubMed OpenURL Placeholder Text WorldCat S. Oshikawa , A. Geater, V. Chongsuvivatwong and D. Chakraborti, Arsenic contamination of Ronphibun residents associated with uses of arsenic-contaminated shallow-well water other than drinking , J. Environ. Sci. Health A Tox. Hazard Subst. Environ. Eng. , 2007 , 42 , 1753 – 1761 . Google Scholar Crossref Search ADS PubMed WorldCat B. A. Fowler and M. J. Sexton, in Heavy Metals in the Environment , ed. B. Sarkar, Marcel Dekker, Inc. , New York , 2002 , pp. 631 – 645 . Google Scholar Google Preview OpenURL Placeholder Text WorldCat COPAC M. Vahter , of inorganic arsenic in different mammalian species and population groups , Sci. Prog. , 1999 , 82 ( Pt 1 ), 69 – 88 . Google Scholar Crossref Search ADS PubMed WorldCat D. S. Paul , A. Hernández-Zavala, F. S. Walton, B. M. Adair, J. Dedina, T. Matousek and M. Stýblo, Examination of the effects of arsenic on glucose homeostasis in cell culture and animal studies: development of a mouse model for arsenic-induced diabetes , Toxicol. Appl. Pharmacol. , 2007 , 222 , 305 – 314 . Google Scholar Crossref Search ADS PubMed WorldCat World Health Organization (WHO) Manganese in drinking water. Background document for development of WHO Guide for drinking water quality ; World Health Organization : 1994 . W. Mertz , Risk assessment of essential trace elements: new approaches to setting recommended dietary allowances and safety limits , Nutr. Rev. , 1995 , 53 , 179 – 185 . Google Scholar Crossref Search ADS PubMed WorldCat C. F. Wilkinson , G. R. Christoph, E. Julien, J. M. Kelley, J. Kronenberg, J. McCarthy and R. Reiss, Assessing the risks of exposures to multiple chemicals with a common mechanism of toxicity: how to cumulate? , Regul. Toxicol. Pharmacol. , 2000 , 31 , 30 – 43 . Google Scholar Crossref Search ADS PubMed WorldCat M. A. Callahan and K. Sexton, If cumulative risk assessment is the answer , Environ. Health Perspect. , 2007 , 115 , 799 – 806 . Google Scholar Crossref Search ADS PubMed WorldCat A. Kortenkamp , M. Faust, M. Scholze and T. Backhaus, Low-level exposure to multiple chemicals: reason for human health concerns? , Environ. Health Perspect. , 2007 , 115 ( Suppl 1 ), 106 – 114 . Google Scholar Crossref Search ADS PubMed WorldCat E. A. C. Hubal , J. Moya and S. G. Selevan, A lifestage approach to assessing children's exposure , Birth Defects Res., Part B , 2008 , 83 , 522 – 529 . Google Scholar Crossref Search ADS WorldCat J. I. Levy , Is epidemiology the key to cumulative risk assessment? , Risk Anal. , 2008 , 28 , 1507 – 1513 . Google Scholar Crossref Search ADS PubMed WorldCat G. Rice , M. MacDonell, R. C. Hertzberg, L. Teuschler, K. Picel, J. Butler, Y.-S. Chang and H. Hartmann, An approach for assessing human exposures to chemical mixtures in the environment , Toxicol. Appl. Pharmacol. , 2008 , 233 , 126 – 136 . Google Scholar Crossref Search ADS PubMed WorldCat S. J. Ryker and M. J. Small, Combining occurrence and toxicity information to identify priorities for drinking-water mixture research , Risk Anal. , 2008 , 28 , 653 – 666 . Google Scholar Crossref Search ADS PubMed WorldCat G. W. Chance , Environmental contaminants and children's health: Cause for concern, time for action , Paediatr Child Health , 2001 , 6 , 731 – 743 . Google Scholar Crossref Search ADS PubMed WorldCat C. Watanabe , T. Inaoka, T. Matsui, K. Ishigaki, N. Murayama and R. Ohtsuka, Effects of arsenic on younger generations , J. Environ. Sci. Health A Tox. Hazard Subst. Environ. Eng. , 2003 , 38 , 129 – 139 . Google Scholar Crossref Search ADS PubMed WorldCat E. A. C. Hubal , L. S. Sheldon, J. M. Burke, T. R. McCurdy, M. R. Berry, M. L. Rigas, V. G. Zartarian and N. C. Freeman, Children's exposure assessment: a review of factors influencing Children's exposure, and the data available to characterize and assess that exposure , Environ. Health Perspect. , 2000 , 108 , 475 – 486 . Google Scholar Crossref Search ADS WorldCat G. Daston , E. Faustman, G. Ginsberg, P. Fenner-Crisp, S. Olin, B. Sonawane, J. Bruckner, W. Breslin and T. J. McLaughlin, A framework for assessing risks to children from exposure to environmental agents , Environ. Health Perspect. , 2004 , 112 , 238 – 256 . Google Scholar Crossref Search ADS PubMed WorldCat D. Rice and S. J. Barone, Critical periods of vulnerability for the developing nervous system: evidence from humans and animal models , Environ. Health Perspect. , 2007 , 108 , 511S – 533S . Google Scholar OpenURL Placeholder Text WorldCat R. O. Wright and A. Baccarelli, Metals and neurotoxicology , J. Nutr. , 2007 , 137 , 2809 – 2812 . Google Scholar Crossref Search ADS PubMed WorldCat J. Liu , Y. Xie, J. M. Ward, B. A. Diwan and M. P. Waalkes, Toxicogenomic analysis of aberrant gene expression in liver tumors and nontumorous livers of adult mice exposed in utero to inorganic arsenic , Toxicol. Sci. , 2004 , 77 , 249 – 257 . Google Scholar Crossref Search ADS PubMed WorldCat M. P. Waalkes , J. Liu, J. M. Ward and B. A. Diwan, and liver carcinogenesis in male CD1 mice exposed to transplacental inorganic arsenic and postnatal diethylstilbestrol or tamoxifen , Toxicol. Appl. Pharmacol. , 2006 , 215 , 295 – 305 . Google Scholar Crossref Search ADS PubMed WorldCat A. Makri , M. Goveia, J. Balbus and R. Parkin, Children's susceptibility to chemicals: a review by developmental stage , J. Toxicol. Environ. Health B Crit. Rev. , 2004 , 7 , 417 – 435 . Google Scholar Crossref Search ADS PubMed WorldCat J. A. Moreno , E. C. Yeomans, K. M. Streifel, B. L. Brattin, R. J. Taylor and R. B. Tjalkens, Age-dependent susceptibility to manganese-induced neurological dysfunction , Toxicol. Sci. , 2009 , 112 , 394 – 404 . Google Scholar Crossref Search ADS PubMed WorldCat J. M. Borgoño , P. Vicent, H. Venturino and A. Infante, Arsenic in the drinking water of the city of Antofagasta: epidemiological and clinical study before and after the installation of a treatment plant , Environ. Health Perspect. , 1977 , 19 , 103 – 105 . Google Scholar PubMed OpenURL Placeholder Text WorldCat G. Concha , B. Nermell and M. V. Vahter, Metabolism of inorganic arsenic in children with chronic high arsenic exposure in northern Argentina , Environ. Health Perspect. , 1998 , 106 , 355 – 359 . Google Scholar Crossref Search ADS PubMed WorldCat D. N. G. Mazumder , Effect of drinking arsenic contaminated water in children , Indian Pediatr , 2007 , 44 , 925 – 927 . Google Scholar PubMed OpenURL Placeholder Text WorldCat American Public Health Association , Standard Method for the Examination of Water and Wastewater , American Public Health Association , 21 edn, 2005 . K. R. Neubauer , R. E. Wolf, 2004 . A. van Geen , K. M. Ahmed, A. A. Seddique and M. Shamsudduha, Community wells to mitigate the arsenic crisis in Bangladesh , Bull. World Health Organ. , 2003 , 81 , 632 – 638 . Google Scholar PubMed OpenURL Placeholder Text WorldCat N. Shibasaki , P. Lei and A. Kamata, Evaluation of deep groundwater development for arsenic mitigation in western Bangladesh , J. Environ. Sci. Health A Tox. Hazard Subst. Environ. Eng. , 2007 , 42 , 1919 – 1932 . Google Scholar Crossref Search ADS PubMed WorldCat S. H. Frisbie , E. J. Mitchell, A. Z. Yusuf, M. Y. Siddiq, R. E. Sanchez, R. Ortega, D. M. Maynard and B. Sarkar, The development and use of an innovative laboratory method for measuring arsenic in drinking water from western Bangladesh , Environ. Health Perspect. , 2005 , 113 , 1196 – 1204 . Google Scholar Crossref Search ADS PubMed WorldCat F. Parvez , Y. Chen, M. Argos, A. Z. M. I. Hussain, H. Momotaj, R. Dhar, A. van Geen, J. H. Graziano and H. Ahsan, Prevalence of arsenic exposure from drinking water and awareness of its health risks in a Bangladeshi population: results from a large population-based study , Environ. Health Perspect. , 2006 , 114 , 355 – 359 . Google Scholar Crossref Search ADS PubMed WorldCat M. M. Hira-Smith , Y. Yuan, X. Savarimuthu, J. Liaw, A. Hira, C. Green, T. Hore, P. Chakraborty, O. S. von Ehrenstein and A. H. Smith, Arsenic concentrations and bacterial contamination in a pilot shallow dugwell program in West Bengal, India , J. Environ. Sci. Health A Tox. Hazard Subst. Environ. Eng. , 2007 , 42 , 89 – 95 . Google Scholar Crossref Search ADS PubMed WorldCat K. M. Lokuge , W. Smith, B. Caldwell, K. Dear and A. H. Milton, The effect of arsenic mitigation interventions on disease burden in Bangladesh , Environ. Health Perspect. , 2004 , 112 , 1172 – 1177 . Google Scholar Crossref Search ADS PubMed WorldCat M. R. Islam , P. W. Lahermo, R. Salminen, S. Rojstaczer and V. Peuraniemi, Lake and reservoir water quality affects by metals leaching from tropical soils , Environ. Geol. , 2000 , 39 , 1083 – 1089 . Google Scholar Crossref Search ADS WorldCat M. R. Islam , R. Salminen and P. W. Lahermo, Arsenic and other toxic elemental contamination of groundwater, surface water and soil in Bangladesh and its possible effects on human health , Environ. Geochem. Health , 2000 , 22 , 33 – 53 . Google Scholar Crossref Search ADS WorldCat H. B. Bennett , A. Shantz, G. Shin, M. L. Sampson and J. S. Meschke, Characterisation of the water quality from open and rope-pump shallow wells in rural Cambodia , Water Sci. Technol. , 2010 , 61 , 473 – 479 . Google Scholar Crossref Search ADS PubMed WorldCat K. Gopal , S. S. Tripathy, J. L. Bersillon and S. P. Dubey, Chlorination byproducts, their toxicodynamics and removal from drinking water , J. Hazard. Mater. , 2007 , 140 , 1 – 6 . Google Scholar Crossref Search ADS PubMed WorldCat A. Mukherjee , A. Fryar and P. D. Howell, Regional hydrostratigraphy and groundwater flow modeling in the arenic-affected areas of the western Bengal basin, West Bengla, India , Hydrogeol. J. , 2007 , 15 , 1397 – 1418 . Google Scholar Crossref Search ADS WorldCat S. J. Hug , O. X. Leupin and M. Berg, Bangladesh and Vietnam: different groundwater compositions require different approaches to arsenic mitigation , Environ. Sci. Technol. , 2008 , 42 , 6318 – 6323 . Google Scholar Crossref Search ADS PubMed WorldCat L. Wang and J. Huang, in Arsenic in the Environment. Part II: Human Health and Ecosystem Effects , ed. J. O. Nriagu, Wiley , New York , 1994 , pp. 159 – 172 . Google Scholar Google Preview OpenURL Placeholder Text WorldCat COPAC D. Sutherland , P. M. Swash, A. C. Macqueen, L. E. McWilliam, D. J. Ross and S. C. Wood, A field based evaluation of household arsenic removal technologies for the treatment of drinking water , Environ. Technol. , 2002 , 23 , 1385 – 1403 . Google Scholar Crossref Search ADS PubMed WorldCat M. F. Ahmed . D. Mohan and C. U. Pittman, Arsenic removal from water/wastewater using adsorbents—A critical review , J. Hazard. Mater. , 2007 , 142 , 1 – 53 . Google Scholar Crossref Search ADS PubMed WorldCat G. L. Amy , H.-W. Chen, A. Drizo and P. Brandhuber, Adsorbent Treatment Technologies for Arsenic Removal , Awwa Research Foundation , Denver, CO , 2005 . Google Scholar Google Preview OpenURL Placeholder Text WorldCat COPAC M. A. Hossain , M. K. Sengupta, S. Ahamed, M. M. Rahman, D. Mondal, D. Lodh, B. Das, B. Nayak, B. K. Roy, A. Mukherjee and D. Chakraborti, Ineffectiveness and poor reliability of arsenic removal plants in West Bengal, India , Environ. Sci. Technol. , 2005 , 39 , 4300 – 4306 . Google Scholar Crossref Search ADS PubMed WorldCat Open in new tabDownload slide Erika Mitchell has worked as a researcher with Better Life Laboratories, a non-profit research and training institute in Vermont, since getting her PhD at Cornell University in 1993. She has been a part of an international team of volunteer scientists in Bangladesh since 1998, mapping the extent of arsenic and other toxic metals in the groundwater and developing methods for groundwater testing. She has strong interests in societal factors involving diet and nutrition, and societal responses to proposed technological solutions for groundwater remediation. Open in new tabDownload slide Dr Seth H. Frisbie is an environmental and analytical chemist at Norwich University, and the president of a nonprofit corporation, Better Life Laboratories, Inc. He received his doctoral and master's degrees from Cornell University. He has studied drinking water for over 30 years. He has worked on drinking water and public health in Bangladesh and other developing countries since 1997. Open in new tabDownload slide Bibudhendra Sarkar received his PhD in biochemistry from the University of Southern California and did his further studies in protein chemistry in Cambridge University and quantum biochemistry in the Université de Paris-Sorbonne. At the University of Toronto and the Hospital for Sick Children, he established his research career in metal-caused diseases. He became full professor in 1978, department head of Structural Biology and Biochemistry 1990–2002 and director of the Advanced Protein Technology Center 1998–2002. Since 1997 he has been leading a team of international volunteer scientists researching the health crisis caused by multiple metals contamination of drinking water in South Asia. Erika Mitchell and Seth Frisbie are members of this team. © The Royal Society of Chemistry 2011 This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model) © The Royal Society of Chemistry 2011
TI - Exposure to multiple metals from groundwater—a global crisis: Geology, climate change, health effects, testing, and mitigation
JF - Metallomics
DO - 10.1039/c1mt00052g
DA - 2011-08-30
UR - https://www.deepdyve.com/lp/oxford-university-press/exposure-to-multiple-metals-from-groundwater-a-global-crisis-geology-LfM0RF5m0f
SP - 874
EP - 908
VL - 3
IS - 9
DP - DeepDyve
ER -