Exposure to multiple metals from groundwater—a global crisis: Geology, climate change, health effects, testing, and mitigation

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.

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Erika Mitchell

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.

Seth Frisbie

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.

Bibudhendra Sarkar

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.

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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 drinking water 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, selenium^11
	Arsenic, manganese, uranium, iron^12
	Arsenic, nickel, iron^13
Taiwan	Arsenic, manganese, iron^14
Malaysia	Arsenic, manganese, uranium^15
Mekong River Delta (Cambodia and Vietnam)	Arsenic, manganese, cadmium, lead, nickel, selenium, barium^16
	Arsenic, manganese, lead, barium^17
	Arsenic, manganese, barium^18
	Arsenic, manganese, iron^19
	Arsenic, manganese^16,20
Bangladesh	Arsenic, manganese, uranium, boron^21
	Arsenic, manganese, nickel, chromium^10b
	Arsenic, manganese^22
India	Arsenic, lead, aluminium, cadmium^23
	Arsenic, manganese, iron^24
	Arsenic, iron^25
	Lead, iron^26
	Manganese, zinc^27
Iran	Arsenic, cadmium, selenium^28
Uganda	Manganese, uranium, cadmium, lead, nickel, barium, iron^29
Burkina Faso	Arsenic, manganese, molybdenum^7
Mali	Manganese, uranium^30
Ghana	Arsenic, manganese, iron^31
Finland	Arsenic,^32 uranium,^33 manganese, iron^34
Italy	Arsenic, vanadium^35
Greece	Arsenic, manganese, uranium^36
	Arsenic, manganese, antimony^37
Canada	Arsenic, manganese, iron^38
	Arsenic, uranium^39
United States	Arsenic, manganese, uranium, selenium, molybdenum, boron^40
	Arsenic, manganese, uranium, iron^41
	Arsenic, manganese^42
	Selenium, boron^43
Argentina	Arsenic, manganese, uranium, vanadium, iron, strontium, boron, molybdenum^44
	Arsenic, uranium, vanadium, selenium^45
	Arsenic, lithium, cesium, boron^46
	Arsenic, vanadium^2

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Table 2 Toxic effects of arsenic

Cancers	Skin cancer^60
	Lung cancer^61
	Bladder and urinary tract cancers^60a,62
	Digestive tract cancers^60a
	Liver cancer^63
	Prostate cancer^64
	Breast cancer^65
Skin conditions	Keratosis and pigment change^66
Liver disease	Enlargement of the liver, cirrhosis and fatty degeneration^11,66a,67
Lung disease	Pulmonary obstructive and restrictive effects, chronic cough and bronchitis^67,68
	Changes in mouse lung cells^69 and cultured human lung cells^70
Heart disease	Arteriosclerosis, myocardial infarction, ischemic heart disease, vascular constriction, and blackfoot disease^64a,71
	Hypertension^68d,72
Diabetes	Increased risk of diabetes^72b,73
Blood disorders	Anaemia or leucopoenia^68c
Kidney disease	Renal damage^74
Eye disease	Pterygium^75
	Cataracts^76
	Conjunctivitis^77
Immune effects	Reduced immune function^78
Reproductive effects	Endocrine disruption^79
	Decreased testosterone levels and increased rates of erectile dysfunction^80
	Aberrant morphology and decreased motility of sperm in rabbits^81
Neurological effects	Peripheral neuropathy of both sensory and motor neurons, causing numbness, loss of reflexes, and muscle weakness^2,66a,68d,82
	Learning disabilities in children and reduced intellectual function^83
Developmental effects	Adverse pregnancy outcomes: spontaneous abortion, stillbirth, and preterm delivery,^84 congenital malformations, and low birth weight^85
	Increased infant mortality^86
	Decreased weight, height, and lung capacities of children^87

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Table 3 Toxic effects of manganese

Neurological effects	Decreased brain function in domestic animals^102
	Neurological deficits in nonhuman primates^103
	Disruptions in dopamine, norepinephrin, and acetylcholinesterase levels^103
	Manganism, a condition characterized by a cock-like walk,^104 hyperirritability, violent acts, hallucinations, disturbances of libido, incoordination,^102 and ultimately, Parkinson-like symptoms including tremors and difficulties with balance^105
	Compulsive behaviours, emotional lability and hallucinations, and somatisation disorder^106
	Violent or criminal behaviour^107
	Hyperactivity in children, learning disabilities, and deficits in children’s manual dexterity and rapidity, short-term memory, and visual identification^56,108
	Amyotrophic lateral sclerosis^102
	Possible increased susceptibility to prion diseases^109
Liver disease	Liver damage and cirrhosis in rats^104
Kidney disease	Nephritis in rats^104
Reproductive effects	Degenerative changes in rat testes^104,110
Cardiovascular effects	Decreased heart muscle respiration in rats^111
Ear disorders	Hearing loss in mice^112
Developmental effects	Increased infant mortality, especially with concurrent pregnancy-induced iron deficiency anaemia^113

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Table 4 Toxic effects of uranium

Bone effects	Decreased bone formation^133
	Increased bone resorption^134
	Increased osteocalcin levels in men, particularly with current smokers^134
Kidney disease	Decreased kidney function^135
Cardiovascular effects	Increased blood pressure^136
Neurological effects	Changes in the brain cholinergic system in rats^137
Hormonal effects	Endocrine-disruptor^138
Reproductive effects	Disturbed follicogenesis, oocyte meiosis and oocyte morphology in mice^139
	Possible fertility problems and reproductive cancers^138

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Table 5 Toxic effects of lead

Neurological effects	Reduced children’s capacity to learn, even at very low levels of exposure^141
	Reduced cognitive function in older adults^142
	Degenerative dementia^143
Bone effects	Toxic systemic effects as lead is released from bones during pregnancy or menopause^144
	Dental caries and tooth loss in adults^145
Cardiovascular effects	Hypertension^146
	Ischemic heart disease^143
Kidney disease	Kidney damage in rats and humans^143,147
Liver disease	Liver damage in rats^147
Diabetes	Increased incidence of diabetes^146b
Reproductive disorders	Reduced fertility with paternal exposure^148
Eye disorders	Cataracts^149
Cancer	Bladder cancer^150

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Table 6 Effects of vanadium

Glucose balance and weight effects	Decreased fluid intake^161
	Weight loss in rats^162
	Lowered BMI in women^163
	Insulin mimicker, improved glucose tolerance^164
Bone effects	Increased bone growth^165
	Inhibited cancer metastasis in bone cells^166
Cardiovascular effects	Decreased heart rate in animals^167
	Lowered or increased blood pressure in animals and humans^167,168
	Increased total cholesterol levels in rats^169
	Increased triglyceride levels in impaired glucose tolerance patients^170
Reproductive effects	Impaired sperm morphology and motility in rabbits^81
	Reduced sperm count and fertility in mice^171
Neurological effects	Neurotoxic effects in dopaminergic neuronal cells^172
Kidney effects	Kidney damage in rats^162,168b
Immune effects	Reduced immune response in rats^162
Developmental effects	Adverse development in rats^162
	Necrotic death in neonatal cardiomyocytes in rats^173
Cancer	Increased chromosome mutations and DNA strand breaks in mammalian cells^174
	Reduced chromosome mutations in rats^175

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Fig. 1 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 phosphate fertilizers 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 versus oxidation-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 Graph of arsenic concentration (mg L⁻¹) versus oxidation-reduction potential in water from sampled Bangladeshi wells.^9a

Fig. 3 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 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 drinking water.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 methylate arsenic more efficiently than men,^90f,92 particularly during pregnancy.⁹³ Arsenic methylation efficiency in pregnant women was found to be resistant to effects of malnutrition.⁹³ Overweight women had highly efficient arsenic methylation 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 arsenic methylation 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 arsenic methylation 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 manganese excretion 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 drinking water, in each case, the youngest family member was the first to develop clinical symptoms of manganese poisoning.^108b,118

In a population-based study, 10-year-old Bangladeshi children whose drinking water 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 drinking water guidelines and US EPA RfDs for manganese are based solely on studies of adult exposures^109,120—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 hair^56b,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 manganese retention.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 drinking water, 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 drinking water.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 lead metabolism;¹⁵⁵ in particular, variants in genes associated with iron metabolism modify lead metabolism.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 drinking water. 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 drinking water. Chromium VI is carcinogenic but drinking water 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 drinking water 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 drinking water 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 drinking water 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 drinking water 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 drinking water, 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,^145,209e vanadium,¹⁷¹ arsenic,^209e uranium,²¹⁰ antimony,^209g or barium.^209g For these reasons, heavy metal interactions with drinking water contaminants including cadmium and other metals must be considered when populations exposed to metals through drinking water include smokers. Environmental lead exposure is also common in countries with metal-contaminated drinking water, 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 drinking water 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	↓ Arsenic^212
	↓ Lead^157,213
	↓ Manganese^214
	↓ chromium^215
	↓ Iron^216 and haemoglobin^217
Selenium	↓ Arsenic^218
	↓ Lead^157
Calcium	↓ Manganese^219
	↓ Lead^220
	↓ Chromium^221
	↓ Iron^222
	↓ Zinc^223
Iron	↓ Arsenic^69,195,224
	↓ Manganese^214
	↓ Lead^225
	↓ Cadmium^226
	↓ Chromium^215
	↓ Calcium^222
Chromium	↓ Lead^157
Vanadium	↓ Chromium^227
Barium	↑ Calcium^204b
Aluminium	↓ Fluoride^228
Arsenic	↓ Selenium^218a,c
Uranium	↓ Calcium^134
Nickel	↓ Manganese, zinc and magnesium^229
	↑ Iron^230
	↓ Calcium^231
	↓ Ascorbic acid^232
Manganese	↑ Cadmium^157
	↓ Iron^104,233
	↓ Zinc^214
	↓ Calcium^231
Lead	↓ Arsenic from bones^234
	↓ Zinc, iron and manganese from the brain^235
	↓ Zinc^213a
	↓ Selenium^157
Cadmium	↑ Nickel^236
	↓ Selenium^237
	↓ Iron^237,238
	↓ Zinc^214,239
	↓ Calcium^231,238,240

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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 absorption^214,249
	↑ Arsenic in liver^250
	↑ Lead absorption^104,157,214,237,251
	↑ Cadmium^104,214,237,252
	↑ Zinc^214
Zinc	↑ Lead^213a
	↑ Cadmium^237
Calcium	↑ Lead^157,253

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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 toxicity^157,213b,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 arsenic methylation 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 arsenic methylation. Smokers and chewers of betel quid were found to have reduced arsenic methylation efficiency;^92b smokers of bidis, hand-rolled cigarettes popular in South Asia, were found to methylate arsenic 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 toxicity^90c,d,289 and risk of skin lesions^{61b,90c,d,290} and lung, bladder and skin cancer is higher in smokers exposed to arsenic through drinking water than non-smokers or smokers who are not exposed to arsenic through drinking water.^{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 alone^287f,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 arsenic^68c may be particularly debilitating if there is co-exposure to manganese, which causes tremors and loss of balance^105a 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 drinking water 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 function^216,261,312 and is associated with increased levels of depression;³¹³ since nickel, lead, and cadmium exposure reduce zinc absorption and increase zinc excretion, 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.^157,253c 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 drinking water 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 drinking uranium-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 lead^146b 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 oestrogen signalling 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,d,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 zinc excretion 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 drinking water.

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 damage^68c,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 drinking water is supplemented by exposure through food. Dietary exposure to manganese¹²³ and vanadium¹⁷¹ generally exceeds exposure through drinking water. This must be considered when calculating drinking water guidelines, since drinking water 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 drinking water 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 drinking water 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 products^261,356 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 water^157,364 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 drinking water 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 drinking water.^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 arsenic methylation efficiency and greater arsenic toxicity^71a,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 arsenic methylation reactions.^297,346h,376 Increased intake of B vitamins reduces arsenic toxicity^297,346h and people who consume diets with low amounts of niacin or folate were found to have reduced arsenic methylation efficiency.^374d Folate supplementation has been found to increase arsenic methylation 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 arsenic methylation ability and increase arsenic toxicity,^289b,61b 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 drinking water.

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 humans^{71a,263,374c,d,392} and good nutrition^347a,393 and higher BMI^90c 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 arsenic methylation 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 drinking water,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 drinking water.^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 drinking water 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 adults^{102,116,128,350} 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, drinking water 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 drinking water.^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 drinking water guidelines be re-examined in the light of recent research involving learning deficits caused by children's exposure to metals.^56,83b

Testing for multiple metals in water

The storage, preservation, and analysis of drinking water 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 drinking water 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 drinking water

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 drinking water 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 drinking water 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 filter^447a), 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 drinking water 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 drinking water 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, drinking water 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 drinking water 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

1. S. Sambu and R. Wilson, Arsenic in food and water—a brief history, Toxicol. Ind. Health, 2008, 24, 217–226.
2. A. Ayerza, Arsenicismo regional endémico, Bol. Acad. Nac. Medicina., 1918, 1, 11–24.
3. 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.
4. 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.
5. Q. X. Huang Y and G. Wang, et al., A survey of endemic chronic arsenism, Acta Academiac Medicinae Xinjiang, 1983, 6, 91–96.
6. 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.
7. 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.
8. 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.
9. (a) 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; (b) 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.
10. (a) British Geological Survey Phase 1 groundwater studies of arsenic contamination in Bangladesh; British Geological Survey: Nottingham, 1999; (b) 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.
11. B. K. Mandal and K. T. Suzuki, Arsenic round the world: a review, Talanta, 2002, 58, 201–235.
12. 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.
13. J. Virkutyte and M. Sillanpää, Chemical evaluation of potable water in Eastern Qinghai Province, China: Human health aspects, Environment International, 2006, 32, 80–86.
14. 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.
15. 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.
16. 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.
17. 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.
18. 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.
19. 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.
20. 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.
21. (a) British Geological Survey Phase 2 groundwater studies of arsenic contamination in Bangladesh; British Geological Survey: Nottingham, 2001; (b) 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.
22. 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.
23. 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.
24. 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.
25. (a) 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; (b) 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.
26. (a) 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; (b) 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.
27. 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.
28. 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.
29. 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.
30. British Geological Survey Groundwater Quality: Mali; British Geological Survey: London, UK, 2002.
31. R. Buamah, Adsorptive Removal of Manganese, Arsenic and Iron From Groundwater, Wageningen University, Delft, The Netherlands, 2009.
32. 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.
33. (a) 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; (b) 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.
34. 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.
35. 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.
36. 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.
37. 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.
38. British Columbia Ministry of the Environment. British Columbia Ministry of the Environment, Surrey, B.C., 2010, vol. 2011.
39. (a) CBC News, in CBC News, Canada. CBC Radio-Canada: Toronto, ON, 2008; (b) Government of Nova Scotia. Government of Nova Scotia: Halifax, NS, 2010, vol. 2011.
40. F. N. Robertson, Arsenic in ground-water under oxidizing conditions, southwest United States, Environ. Geochem. Health, 1989, 11, 171–185.
41. (a) 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; (b) 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; (c) 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.
42. 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.
43. 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.
44. 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.
45. 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.
46. 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.
47. 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.
48. 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.
49. 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.
50. 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.
51. 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.
52. 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.
53. 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.
54. 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.
55. M. Rahman, International research on arsenic contamination and health, J. Health Popul. Nutr., 2006, 24, 123–128.
56. (a) 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; (b) 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.
57. 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.
58. (a) M. M. Sherif and V. P. singh, Effect of climate change on sea water intrusion in coastal aquifers, Hydrol. Processes, 1999, 13, 1277–1287; (b) 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.
59. J. Monan, Bangladesh: The strength to succeed, Oxfam, Oxford, 1995.
60. (a) 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; (b) 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.
61. (a) 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; (b) 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; (c) 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.
62. 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.
63. (a) 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; (b) 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; (c) J. Liu and M. P. Waalkes, Liver is a target of arsenic carcinogenesis, Toxicol. Sci., 2008, 105, 24–32.
64. (a) 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; (b) L. Benbrahim-Tallaa and M. P. Waalkes, Inorganic arsenic and human prostate cancer, Environ. Health Perspect., 2008, 116, 158–164.
65. 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.
66. (a) 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; (b) 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.
67. 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.
68. (a) 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; (b) 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; (c) 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; (d) 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; (e) 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; (f) 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.
69. 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.
70. 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.
71. (a) 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; (b) C.-H. Tseng, Blackfoot disease and arsenic: a never-ending story, J. Environ. Sci. Health C Environ. Carcinog Ecotoxicol. Rev., 2005, 23, 55–74; (c) H.-S. Yu, C.-H. Lee and G.-S. Chen, Peripheral vascular diseases resulting from chronic arsenical poisoning, J. Dermatol., 2002, 29, 123–130; (d) 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; (e) P. P. Simeonova and M. I. Luster, Arsenic and atherosclerosis, Toxicol. Appl. Pharmacol., 2004, 198, 444–449; (f) 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; (g) 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; (h) 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; (i) J. C. States, S. Srivastava, Y. Chen and A. Barchowsky, Arsenic and cardiovascular disease, Toxicol. Sci., 2009, 107, 312–323.
72. (a) 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; (b) 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.
73. (a) 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; (b) 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; (c) C.-H. Tseng, The potential biological mechanisms of arsenic-induced diabetes mellitus, Toxicol. Appl. Pharmacol., 2004, 197, 67–83; (d) 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; (e) 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; (f) 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.
74. 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.
75. 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.
76. 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.
77. 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.
78. (a) 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; (b) 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; (c) 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.
79. 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.
80. 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.
81. 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.
82. 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.
83. (a) 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; (b) 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; (c) 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.
84. (a) 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; (b) 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; (c) 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; (d) 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; (e) 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.
85. M. Vahter, Effects of arsenic on maternal and fetal health, Annu. Rev. Nutr., 2009, 29, 381–399.
86. 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.
87. 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.
88. (a) 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; (b) 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; (c) 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.
89. M. Vahter, Health effects of early life exposure to arsenic, Basic Clin. Pharmacol. Toxicol., 2008, 102, 204–211.
90. (a) 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; (b) 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; (c) 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; (d) 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; (e) 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; (f) 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.
91. 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.
92. (a) 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; (b) 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.
93. 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.
94. 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.
95. 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.
96. (a) 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; (b) M. Vahter, Genetic polymorphism in the biotransformation of inorganic arsenic and its role in toxicity, Toxicol. Lett., 2000, 112–113, 209–217; (c) 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; (d) 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; (e) 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; (f) 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; (g) 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; (h) A. Hernández and R. Marcos, Genetic variations associated with interindividual sensitivity in the response to arsenic exposure, Pharmacogenomics, 2008, 9, 1113–1132; (i) 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.
97. 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.
98. 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.
99. 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.
100. 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.
101. (a) 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; (b) 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.
102. 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.
103. N. C. Burton and T. R. Guilarte, Manganese neurotoxicity: lessons learned from longitudinal studies in nonhuman primates, Environ. Health Perspect., 2009, 117, 325–332.
104. 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.
105. (a) 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; (b) D. G. Barceloux, Manganese, Clin. Toxicol., 1999, 37, 293–307; (c) 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; (d) 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; (e) 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.
106. 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.
107. (a) J. Cawte, Accounts of a mystery illness: The Groote Eylandt syndrome, Aust. NZ J. Psychiatry, 1984, 18, 179–187; (b) 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.
108. (a) P. J. Barlow, A pilot study on the metal levels in the hair of hyperactive children, Med. Hypotheses, 1983, 11, 309–318; (b) 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; (c) 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.
109. 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.
110. 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.
111. K. B. Miller, J. S. Caton and J. W. Finley, Manganese depresses rat heart muscle respiration, BioFactors, 2006, 28, 33–46.
112. 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.
113. 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.
114. 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.
115. 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.
116. 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.
117. P. J. Collipp, S. Y. Chen and S. Maitinsky, Manganese in infant formulas and learning disability, Ann. Nutr. Metab., 1983, 27, 488–494.
118. 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.
119. 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.
120. (a) 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; (b) 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; (c) 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.
121. 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.
122. A. Khalique, S. Ahmad, T. Anjum, M. Jaffar, M. H. Shah, N. Shaheen, S. R. Tariq and S. Manzoor, A comparative study based on gender and age dependence of selected metals in scalp hair, Environ. Monit. Assess., 2005, 104, 45–57.
123. 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.
124. J. W. Finley, Manganese absorption and retention by young women is associated with serum ferritin concentration, Am. J. Clin. Nutr., 1999, 70, 37–43.
125. 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.
126. (a) 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; (b) R. Bowler, D. Mergler, M. P. Sassine, F. Larribe and H. K. Hudnell, Neuropsychiatric effects of manganese on mood, Neurotoxicology, 1999, 20, 367–378.
127. 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.
128. H. K. Hudnell, Effects from environmental Mn exposures: a review of the evidence from non-occupational exposure studies, Neurotoxicology, 1999, 20, 379–397.
129. 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.
130. 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.
131. 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.
132. 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.
133. 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.
134. 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.
135. (a) 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; (b) 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.
136. 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.
137. 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.
138. 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.
139. (a) 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; (b) 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.
140. 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.
141. (a) 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; (b) 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; (c) 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; (d) 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; (e) D. C. Bellinger, Very low lead exposures and children's neurodevelopment, Curr. Opin. Pediatr., 2008, 20, 172–177; (f) 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; (g) 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; (h) 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; (i) 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; (j) 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; (k) 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; (l) 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.
142. 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.
143. A. Rosin, The long-term consequences of exposure to lead, Isr. Med. Assoc. J., 2009, 11, 689–694.
144. (a) M. Vahter, M. Berglund and A. Akesson, Toxic metals and the menopause, J. Br. Menopause Soc., 2004, 10, 60–64; (b) 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.
145. 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.
146. (a) 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; (b) 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.
147. 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.
148. D. C. Bellinger, Teratogen update: lead and pregnancy, Birth Defects Res., Part A, 2005, 73, 409–420.
149. 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.
150. 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.
151. 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.
152. 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.
153. D. C. Bellinger, Children's cognitive health: the influence of environmental chemical exposures, Altern. Ther. Health Med., 2007, 13, S140–S144.
154. 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.
155. 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.
156. (a) 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; (b) 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.
157. 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.
158. M. Loghman-Adham, Renal effects of environmental and occupational lead exposure, Environ. Health Perspect., 1997, 105, 928–938.
159. L. Coderre and A. K. Srivastava, Vanadium and the cardiovascular functions, Can. J. Physiol. Pharmacol., 2004, 82, 833–839.
160. J. L. Domingo, Vanadium and diabetes. What about vanadium toxicity?, Mol. Cell. Biochem., 2000, 203, 185–187.
161. 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.
162. ATSDR Draft toxicological profile for vanadium; US Department of Health and Human Services. Public Health Service. Agency for Toxic Substances and Disease Registry: 2009.
163. 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.
164. (a) 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; (b) P. Poucheret, S. Verma, M. D. Grynpas and J. H. McNeill, Vanadium and diabetes, Mol. Cell. Biochem., 1998, 188, 73–80; (c) 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.
165. D. A. Barrio and S. B. Etcheverry, Vanadium and bone development: putative signaling pathways, Can. J. Physiol. Pharmacol., 2006, 84, 677–686.
166. 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.
167. T. Akera, K. Temma and K. Takeda, Cardiac actions of vanadium, Fed. Proc., 1983, 42, 2984–2988.
168. (a) 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; (b) 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; (c) 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.
169. T. Vodichenska, [An experimental study of the atherogenic effect of vanadium in body uptake with drinking water], Probl. Khig., 1994, 1994, 32–40.
170. 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.
171. D. G. Barceloux, Vanadium. Journal of Toxicology: Clinical Toxicology, 1999, 37.
172. 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.
173. 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.
174. D. Beyersmann and A. Hartwig, Carcinogenic metal compounds: recent insight into molecular and cellular mechanisms, Arch. Toxicol., 2008, 82, 493–512.
175. 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.
176. 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.
177. 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.
178. E. Denkhaus and K. Salnikow, Nickel essentiality, toxicity, and carcinogenicity, Crit. Rev. Oncol. Hematol., 2002, 42, 35–56.
179. 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.
180. 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.
181. 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.
182. E. Szakmáry, V. Morvai, M. Náray and G. Ungváry, Haemodynamic effect of nickel chloride in pregnant rats, Acta Physiol. Hung., 1995, 83, 3–12.
183. 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.
184. 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.
185. C. Pellerin and S. M. Booker, Reflections on hexavalent chromium: health hazards of an industrial heavyweight, Environ. Health Perspect., 2000, 108, A402–A407.
186. 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.
187. (a) 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; (b) 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.
188. (a) 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; (b) A. Levina and P. A. Lay, Chemical properties and toxicity of chromium(III) nutritional supplements, Chem. Res. Toxicol., 2008, 21, 563–571.
189. (a) 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; (b) 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.
190. 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.
191. 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.
192. 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.
193. 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.
194. G. Papanikolaou and K. Pantopoulos, Iron metabolism and toxicity, Toxicol. Appl. Pharmacol., 2005, 202, 199–211.
195. 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.
196. 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.
197. (a) G. J. Brewer, Risks of copper and iron toxicity during aging in humans, Chem. Res. Toxicol., 2010, 23, 319–326; (b) 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.
198. 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.
199. 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.
200. A. Loh, M. Hadziahmetovic and J. L. Dunaief, Iron homeostasis and eye disease, Biochim. Biophys. Acta, Gen. Subj., 2009, 1790, 637–649.
201. 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.
202. 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.
203. 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.
204. (a) 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; (b) 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.
205. (a) 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; (b) 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.
206. (a) 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; (b) 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.
207. 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.
208. (a) 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; (b) 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; (c) 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; (d) 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.
209. (a) 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; (b) 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; (c) 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; (d) 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; (e) 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; (f) L. Järup and A. Akesson, Current status of cadmium as an environmental health problem, Toxicol. Appl. Pharmacol., 2009, 238, 201–208; (g) 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.
210. 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.
211. 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.
212. (a) 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; (b) 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.
213. (a) 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; (b) F. L. Cerklewski and R. M. Forbes, Influence of dietary zinc on lead toxicity in the rat, Journal of Nutrition, 1976, 106, 689–696.
214. 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.
215. (a) L. L. Hopkins and K. Schwartz, Chromium(III) binding to serum proteins, specifically siderophilin, Biochim. Biophys. Acta, Gen. Subj., 1964, 90, 484–491; (b) C. J. Hahn and G. W. Evans, Absorption of trace metals in the zinc-deficient rat, Am. J. Physiol., 1975, 228, 1020–1023.
216. 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.
217. 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.
218. (a) 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; (b) 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; (c) 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.
219. (a) 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; (b) S. D. McDermott and C. Kies, in Nutritional Bioavailability of Manganese, ed. C. Kies, American Chemical Society,Washington, D.C., 1987, pp. 146–151; (c) 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; (d) 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; (e) 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.
220. M. E. Markowitz, M. Sinnett and J. F. Rosen, A randomized trial of calcium supplementation for childhood lead poisoning, Pediatrics, 2004, 113, 34–39.
221. 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.
222. 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.
223. A. Wise, Phytate and zinc bioavailability, Int. J. Food Sci. Nutr., 1995, 46, 53–63.
224. 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.
225. 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.
226. 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.
227. R. A. Anderson, Chromium metabolism and its role in disease processes in man, Clin. Physiol. Biochem., 1986, 4, 31–41.
228. 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.
229. 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.
230. 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.
231. 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.
232. K. Salnikow and K. S. Kasprzak, Ascorbate depletion: a critical step in nickel carcinogenesis?, Environ. Health Perspect., 2005, 113, 577–584.
233. (a) 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; (b) 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; (c) 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.
234. 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.
235. W. Mertz, C. O. Abernathy and S. S. Olin, Risk Assessment of Essential Elements, ILSI Press, Washington, D.C., 1994.
236. 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.
237. 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.
238. M. R. Fox, Nutritional influences on metal toxicity: cadmium as a model toxic element, Environ. Health Perspect., 1979, 29, 95–104.
239. B. Lönnerdal, Dietary factors influencing zinc absorption, J. Nutr., 2000, 130, 1378S–1383S.
240. (a) 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; (b) 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.
241. P. Christian and K. P. West, Interactions between zinc and vitamin A: an update, Am. J. Clin. Nutr., 1998, 68, 435S–441S.
242. 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.
243. 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.
244. 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.
245. 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.
246. 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.
247. R. A. Anderson, in Trace Elements in Human and Animal Nutrition, ed. W. Mertz, Academic Press, San Diego, CA, 1994, pp. 225–244.
248. 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.
249. (a) M. Aschner, Manganese: brain transport and emerging research needs, Environ. Health Perspect., 2000, 108(Suppl 3), 429–432; (b) S. V. Chandra and G. S. Shukla, Role of iron deficiency in inducing susceptibility to manganese toxicity, Arch. Toxicol., 1976, 35, 319–323; (c) A. Spencer, Whole blood manganese levels in pregnancy and the neonate, Nutrition, 1999, 15, 731–734; (d) 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.
250. 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.
251. 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.
252. (a) 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; (b) 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; (c) 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.
253. (a) 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; (b) 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; (c) R. A. Goyer, Nutrition and metal toxicity, Am. J. Clin. Nutr., 1995, 61, 646S–650S.
254. (a) 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; (b) M. Vahter, M. Berglund, A. Akesson and C. Lidén, Metals and women's health, Environ. Res., 2002, 88, 145–155.
255. C. C. Bridges and R. K. Zalups, Molecular and ionic mimicry and the transport of toxic metals, Toxicol. Appl. Pharmacol., 2005, 204, 274–308.
256. 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.
257. 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.
258. D. Beyersmann, Interactions in metal carcinogenicity, Toxicol. Lett., 1994, 72, 333–338.
259. (a) 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; (b) 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.
260. M. Valko, H. Morris and M. T. D. Cronin, Metals, toxicity and oxidative stress, Curr. Med. Chem., 2005, 12, 1161–1208.
261. H. H. Sanstead, Understanding zinc: recent observations and interpretations, J. Lab. Clin. Med., 1994, 124, 322–327.
262. J. J. Chisholm, Heavy metal exposures: Toxicity from metal–metal interactions, and behavioral effects, Pediatrics, 1974, 53, 841–843.
263. 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.
264. 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.
265. 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.
266. 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.
267. 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.
268. O. A. Levander, Metabolic interactions between metals and metalloids, Environ. Health Perspect., 1978, 25, 77–80.
269. (a) H. Babich, N. Martin-Alguacil and E. Borenfreund, Arsenic–selenium interactions determined with cultured fish cells, Toxicol. Lett., 1989, 45, 157–164; (b) 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; (c) 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; (d) 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.
270. 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.
271. J. Gailer, Reactive selenium metabolites as targets of toxic metals/metalloids in mammals: a molecular toxicological perspective, Appl. Organomet. Chem., 2002, 16, 701–707.
272. (a) 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; (b) 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.
273. F. L. Cerklewski and R. M. Forbes, Influence of dietary selenium on lead toxicity in the rat, J. Nutr., 1976, 106, 778–783.
274. C. A. Northrop-Clewes and D. I. Thurnham, Monitoring micronutrients in cigarette smokers, Clin. Chim. Acta, 2007, 377, 14–38.
275. (a) 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; (b) M. Vahter, Mechanisms of arsenic biotransformation, Toxicology, 2002, 181, 211–217; (c) 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.
276. (a) 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; (b) 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; (c) 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.
277. 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.
278. T. Gebel, Suppression of arsenic-induced chromosome mutagenicity by antimony, Mutat. Res., Genet. Toxicol. Environ. Mutagen., 1998, 412, 213–218.
279. 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.
280. (a) 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; (b) 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.
281. 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.
282. 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.
283. 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.
284. 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.
285. 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.
286. 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.
287. (a) 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; (b) 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; (c) 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; (d) 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; (e) 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; (f) 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; (g) 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; (h) 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.
288. 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.
289. (a) 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; (b) 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.
290. 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.
291. (a) 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; (b) 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; (c) 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; (d) 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; (e) 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; (f) 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; (g) 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.
292. 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.
293. 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.
294. 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.
295. (a) 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; (b) 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; (c) 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; (d) 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.
296. 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.
297. 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.
298. 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.
299. A. N. Uddin, F. J. Burns, T. G. Rossman, H. Chen, T. Kluz and M. Costa, Dietary chromium and nickel enhance UV-carcinogenesis in skin of hairless mice, Toxicol. Appl. Pharmacol., 2007, 221, 329–338.
300. 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.
301. (a) 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; (b) 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.
302. V. H. Ferm, The synteratogenic effect of lead and cadmium, Experientia, 1969, 25, 56.
303. 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.
304. 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.
305. 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.
306. T. Gebel, Arsenic and antimony: comparative approach on mechanistic toxicology, Chem.-Biol. Interact., 1997, 107, 131–144.
307. (a) 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; (b) H. Hu, Knowledge of diagnosis and reproductive history among survivors of childhood plumbism, Am. J. Public Health, 1991, 81, 1070–1072.
308. K. M. Erikson, K. Thompson, J. Aschner and M. Aschner, Manganese neurotoxicity: a focus on the neonate, Pharmacol. Ther., 2007, 113, 369–377.
309. 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.
310. 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.
311. (a) 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; (b) 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; (c) J. Y. Yager and D. S. Hartfield, Neurologic manifestations of iron deficiency in childhood, Pediatr. Neurol., 2002, 27, 85–92.
312. (a) E. S. Halas and M. J. Eberhardt, A behavioral review of trace element deficiencies in animals and humans, Nutr. Behav., 1987, 3, 257–271; (b) C. J. Frederickson, Neurobiology of zinc and zinc-containing neurons, Int. Rev. Neurobiol., 1989, 31, 145–238.
313. 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.
314. (a) B. Rimland and G. E. Larson, Hair mineral analysis and behavior: an analysis of 51 studies, J. Learn. Disabil., 1983, 16, 279–285; (b) 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.
315. R. O. Pihl and M. Parkes, Hair element content in learning disabled children, Science, 1977, 198, 204–206.
316. (a) E. F. Madden and B. A. Fowler, Mechanisms of nephrotoxicity from metal combinations: a review, Drug Chem. Toxicol., 2000, 23, 1–12; (b) 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; (c) I. Saboli, Common mechanisms in nephropathy induced by toxic metals, Nephron Physiol., 2006, 104, p107–p114.
317. 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.
318. M. Föller, M. Sopjani, H. Mahmud and F. Lang, Vanadate-induced suicidal erythrocyte death, Kidney Blood Pressure Res., 2008, 31, 87–93.
319. 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.
320. 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.
321. (a) 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; (b) 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; (c) 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.
322. 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.
323. 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.
324. (a) H. Malluche, Renal bone disease—an ongoing challenge to the nephrologist, Clin Nephrol, 1995, 44, S38–S41; (b) H. Malluche and M. C. Faugere, Renal bone disease 1990: an unmet challenge for the nephrologist, Kidney Int., 1990, 38, 193–211.
325. (a) 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; (b) 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.
326. 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.
327. (a) 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; (b) 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.
328. 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.
329. M. S. Lubanski and P. A. McCullough, Kidney's role in hypertension, Minerva Cardioangiol, 2009, 57, 743–759.
330. 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.
331. 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.
332. 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.
333. (a) M. Takiguchi and S. i. Yoshihara, New aspects of cadmium as endocrine disruptor, Environ Sci, 2006, 13, 107–116; (b) 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.
334. G. S. Prins, Endocrine disruptors and prostate cancer risk, Endocr. Relat. Cancer, 2008, 15, 649–656.
335. 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.
336. 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.
337. N. W. Flodin, Micronutrient supplements: toxicity and drug interactions, Prog. Food Nutr. Sci., 1990, 14, 277–331.
338. 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.
339. 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.
340. A. W. Dobson, K. M. Erikson and M. Aschner, Manganese neurotoxicity, Ann. N. Y. Acad. Sci., 2004, 1012, 115–128.
341. 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.
342. M. S. Bhuiyan and K. Fukunaga, Cardioprotection by vanadium compounds targeting Akt-mediated signaling, J. Pharmacol. Sci., 2009, 110, 1–13.
343. 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.
344. 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.
345. 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.
346. (a) 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; (b) 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; (c) 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; (d) 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; (e) 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; (f) 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; (g) 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; (h) 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; (i) 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; (j) 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; (k) 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.
347. (a) 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; (b) 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.
348. 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.
349. 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.
350. 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.
351. K. Ljung and M. Vahter, Time to re-evaluate the guideline value for manganese in drinking water?, Environ. Health Perspect., 2007, 115, 1533–1538.
352. R. W. Wenlock, D. H. Buss and E. J. Dixon, Trace nutrients. 2. Manganese in British food, Br. J. Nutr., 1979, 41, 253–261.
353. ATSDR Toxicological profile for cadmium; Agency for Toxic Substances and Disease Registry: Atlanta, GA, 1999.
354. 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.
355. (a) 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; (b) 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.
356. S. O. Welsh and R. M. Marston, Zinc levels of the US food supply 1909–1980, Food Technol., 1982, 36, 70–76.
357. D. G. Barceloux, Zinc, Clin. Toxicol., 1999, 37, 279–292.
358. (a) 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; (b) A. L. Rauma and H. Mykkänen, Antioxidant status in vegetarians versus omnivores, Nutrition, 2000, 16, 111–119.
359. 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.
360. (a) 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; (b) 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; (c) 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; (d) 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; (e) S. Norra, Z. A. Berner, P. Agarwala, F. Wagner, D. Chandrasekharam and D. Stuben, Impact of irrigation with As rich groundwater on soil and crops: a geochemical case study in West Bengal Delta Plain, India, Appl. Geochem., 2005, 20, 1890–1906; (f) 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.
361. 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.
362. 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.
363. 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.
364. 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.
365. 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.
366. 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.
367. V. Devesa, D. Vélez and R. Montoro, Effect of thermal treatments on arsenic species contents in food, Food Chem. Toxicol., 2008, 46, 1–8.
368. 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.
369. 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.
370. 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.
371. D. G. Barceloux, Nickel, Clin. Toxicol., 1999, 37, 239–258.
372. (a) 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; (b) R. Raghunath and K. S. Nambi, Lead leaching from pressure cookers, Sci. Total Environ., 1998, 224, 143–148; (c) P. K. Sinha, S. Mandal and D. Kundu, Leaching of lead and cadmium from glass dinnerware, J. Environ. Sci. Eng., 2007, 49, 58–61.
373. 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.
374. (a) 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; (b) 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; (c) 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; (d) 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.
375. O. A. Levander, Lead toxicity and nutritional deficiencies, Environ. Health Perspect., 1979, 29, 115–125.
376. 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.
377. (a) 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; (b) 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; (c) M. L. Kile and A. G. Ronnenberg, Can folate intake reduce arsenic toxicity?, Nutr. Rev., 2008, 66, 349–353.
378. 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.
379. 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.
380. 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.
381. (a) A. Alberg, The influence of cigarette smoking on circulating concentrations of antioxidant micronutrients, Toxicology, 2002, 180, 121–137; (b) 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; (c) 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.
382. O. Müller and M. Krawinkel, Malnutrition and health in developing countries, Can. Med. Assoc. J., 2005, 173, 279–286.
383. (a) F. Ahmed, Vitamin A deficiency in Bangladesh: a review and recommendations for improvement, Public Health Nutr., 1999, 2, 1–14; (b) F. Ahmed, Anaemia in Bangladesh: a review of prevalence and aetiology, Public Health Nutr., 2000, 3, 385–393; (c) 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; (d) 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; (e) 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; (f) 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; (g) 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; (h) 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; (i) 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.
384. (a) 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; (b) 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; (c) 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.
385. 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.
386. 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.
387. 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.
388. 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.
389. 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.
390. 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.
391. 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.
392. 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.
393. 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.
394. 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.
395. 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.
396. 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.
397. 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.
398. 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.
399. 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.
400. 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.
401. (a) 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; (b) R. W. Leggett and J. D. Harrison, Fractional absorption of ingested uranium in humans, Health Phys., 1995, 68, 484–498.
402. 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.
403. 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.
404. 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.
405. Bangladesh Bureau of Statistics Local Estimation of Poverty and Malnutrition in Bangladesh; United Nations World Food Program: 2004.
406. (a) 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; (b) 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; (c) 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; (d) 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; (e) 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.
407. 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.
408. (a) 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; (b) 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; (c) 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.
409. 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.
410. 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.
411. 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.
412. (a) 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; (b) 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; (c) A. Hadi and R. Parveen, Arsenicosis in Bangladesh: prevalence and socio-economic correlates, Public Health, 2004, 118, 559–564.
413. 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.
414. (a) 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; (b) 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.
415. 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.
416. 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.
417. (a) 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; (b) 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.
418. (a) 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; (b) 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; (c) 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.
419. 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.
420. 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.
421. (a) M. Vahter, Methylation of inorganic arsenic in different mammalian species and population groups, Sci. Prog., 1999, 82(Pt 1), 69–88; (b) 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.
422. World Health Organization (WHO) Manganese in drinking water. Background document for development of WHO Guide for drinking water quality; World Health Organization: 1994.
423. W. Mertz, Risk assessment of essential trace elements: new approaches to setting recommended dietary allowances and safety limits, Nutr. Rev., 1995, 53, 179–185.
424. 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.
425. (a) M. A. Callahan and K. Sexton, If cumulative risk assessment is the answer, Environ. Health Perspect., 2007, 115, 799–806; (b) 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; (c) 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; (d) J. I. Levy, Is epidemiology the key to cumulative risk assessment?, Risk Anal., 2008, 28, 1507–1513; (e) 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; (f) 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.
426. (a) G. W. Chance, Environmental contaminants and children's health: Cause for concern, time for action, Paediatr Child Health, 2001, 6, 731–743; (b) 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.
427. 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.
428. 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.
429. (a) 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; (b) R. O. Wright and A. Baccarelli, Metals and neurotoxicology, J. Nutr., 2007, 137, 2809–2812.
430. (a) 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; (b) M. P. Waalkes, J. Liu, J. M. Ward and B. A. Diwan, Enhanced urinary bladder and liver carcinogenesis in male CD1 mice exposed to transplacental inorganic arsenic and postnatal diethylstilbestrol or tamoxifen, Toxicol. Appl. Pharmacol., 2006, 215, 295–305.
431. 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.
432. 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.
433. 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.
434. 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.
435. D. N. G. Mazumder, Effect of drinking arsenic contaminated water in children, Indian Pediatr, 2007, 44, 925–927.
436. American Public Health Association, Standard Method for the Examination of Water and Wastewater, American Public Health Association, 21 edn, 2005.
437. K. R. Neubauer, R. E. Wolf, 2004.
438. (a) 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; (b) 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.
439. (a) 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; (b) 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.
440. 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.
441. 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.
442. (a) 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; (b) 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; (c) 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.
443. 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.
444. 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.
445. 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.
446. 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.
447. (a) 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; (b) M. F. Ahmed .
448. D. Mohan and C. U. Pittman, Arsenic removal from water/wastewater using adsorbents—A critical review, J. Hazard. Mater., 2007, 142, 1–53.
449. G. L. Amy, H.-W. Chen, A. Drizo and P. Brandhuber, Adsorbent Treatment Technologies for Arsenic Removal, Awwa Research Foundation, Denver, CO, 2005.
450. 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.

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