arsenic round the world

Talanta 58 (2002) 201–235

Review

Arsenic round the world: a review

Badal Kumar Mandal, Kazuo T. Suzuki *Graduate School of Pharmaceutical Sciences, Chiba Uni�ersity, Chiba 263-8522, Japan

Received 7 December 2001; received in revised form 8 February 2002

Abstract

This review deals with environmental origin, occurrence, episodes, and impact on human health of arsenic. Arsenic,a metalloid occurs naturally, being the 20th most abundant element in the earth’s crust, and is a component of morethan 245 minerals. These are mostly ores containing sulfide, along with copper, nickel, lead, cobalt, or other metals.Arsenic and its compounds are mobile in the environment. Weathering of rocks converts arsenic sulfides to arsenictrioxide, which enters the arsenic cycle as dust or by dissolution in rain, rivers, or groundwater. So, groundwatercontamination by arsenic is a serious threat to mankind all over the world. It can also enter food chain causing widespread distribution throughout the plant and animal kingdoms. However, fish, fruits, and vegetables primarily containorganic arsenic, less than 10% of the arsenic in these foods exists in the inorganic form, although the arsenic contentof many foods (i.e. milk and dairy products, beef and pork, poultry, and cereals) is mainly inorganic, typically65–75%. A few recent studies report 85–95% inorganic arsenic in rice and vegetables, which suggest more studies forstandardisation. Humans are exposed to this toxic arsenic primarily from air, food, and water. Thousands andthousands of people are suffering from the toxic effects of arsenicals in many countries all over the world due tonatural groundwater contamination as well as industrial effluent and drainage problems. Arsenic, being a normalcomponent of human body is transported by the blood to different organs in the body, mainly in the form of MMAafter ingestion. It causes a variety of adverse health effects to humans after acute and chronic exposures such asdermal changes (pigmentation, hyperkeratoses, and ulceration), respiratory, pulmonary, cardiovascular, gastrointesti-nal, hematological, hepatic, renal, neurological, developmental, reproductive, immunologic, genotoxic, mutagenetic,and carcinogenic effects. Key research studies are needed for improving arsenic risk assessment at low exposure levelsurgently among all the arsenic research groups. © 2002 Elsevier Science B.V. All rights reserved.

Keywords: Arsenic; Chronic arsenic toxicity; Carcinogenic effects

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1. Introduction

Arsenic is a ubiquitous element that ranks 20thin abundance in the earth’s crust, 14th in the

seawater, and 12 in the human body [1]. Since itsisolation in 1250 A.D. by Albertus Magnus, thiselement has been a center of controversy in hu-man history. It has been used in medicine [2]. Notonly medicine, it has been used in various fieldsi.e. agriculture, livestock, electronics, industry andmetallurgy [3]. It is now well recognized that

* Corresponding author. Tel./fax: +81-43-290-2891E-mail address: [email protected] (K.T. Suzuki).

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B.K. Mandal, K.T. Suzuki / Talanta 58 (2002) 201–235202

consumption of arsenic, even at low levels, leadsto carcinogenesis.

2. Occurrence

The terrestrial abundance of arsenic is around1.5–3 mg kg−1. Source of arsenic in the envi-ronment includes natural and anthropogenic.

2.1. Natural sources

Long before man’s activities had any effect onthe balance of nature, arsenic was distributedubiquitously throughout earth crusts, soil, sedi-ments, water, air and living organisms.

2.1.1. Earth crustsArsenic is a rare crystal element comprising

about five hundred– thousandths of 1%(0.00005%) of the earth’s crust [4] and the aver-age concentration of arsenic in igneous and sedi-mentary rocks is 2 mg kg−1. In most rocks itranges from 0.5 to 2.5 mg kg−1 [5], thoughhigher concentrations were found in finer-grained argillaceous sediments and phosphorites.Arsenic is concentrated in some reducing marinesediment, which might contain up to 3000 mgkg−1. Arsenic might be co-precipitated with ironhydroxides and sulfides in sedimentary rocks.Iron deposits, sedimentary iron ores and man-ganese nodules were rich in arsenic. Arsenic con-tents in various geochemical materials werelisted in Table 1.

Arsenic naturally occurs in over 200 differentmineral forms, of which approximately 60% arearsenates, 20% sulfides and sulfosalts and theremaining 20% includes arsenides, arsenites, ox-ides, silicates and elemental arsenic (As) [14].But only certain of these are commonly encoun-tered in significant amounts (Table 2).

Arsenic in its most recoverable form is foundin various types of metalliferous deposits. Themajor deposits of this type are categorized intoseven major groups, which are listed in Table 3.It is common in iron pyrite, galena, chalcopyrite

and less common in sphalerite [16]. The mostcommon arsenic mineral is arsenopyrite.

2.1.2. Soil and sediment

2.1.2.1. SoilBackground �alues of arsenic. A�erage content

Table 1Arsenic concentrations of various terrestrial materials

Materials Arsenic (mg kg−1)

Igneous [6]Acidic

3.2–5.4Rhyolite (extrusive)0.18–15Granite (intrusive)

IntermediateLatite, andesite, trachyte 0.5–5.8(extrusive)Diorite, granodiorite, syenite 0.09–13.4(intrusive)

BasicBasalt (extrusive) 0.18–113

0.06–28Gabbro (intrusive)

UltrabasicPeridotite, dunite, serpentinite 0.3–15.8

Metamorphic rocks [6]Quartzite 2.2–7.6Slate/phyllite 0.5–143

0.0–18.5Schist/gneiss

Sedimentary rocks [7–9]Marine

Shale/claystone (nearshore) 4.0–25Shale/claystone (offshore) 3.0–490Carbonates 0.1–20.1Phosphorites 0.4–188

0.6–9Sandstone

Non-marineShales 3.0–12Claystone 3.0–10

Recent sediments (marine)3.2–60Muds [9]4.0–20Clays [9]�1.0Carbonate [10]

Stream/river [11] 5.0–4000 (mineralizedarea)

Lake [12] 2.0–300Soils [13] �0.1–97

B.K. Mandal, K.T. Suzuki / Talanta 58 (2002) 201–235 203

Table 2Major arsenic minerals occurring in nature [15]

Mineral OccurrenceComposition

Native arsenic Hydrothermal veinsAsGenerally one of the late Ag minerals in the sequence of primary depositionAg3AsS3Proustite

NiAs2Rammelsbergite Commonly in mesothermal vein deposits(Co,Fe)As2Safflorite Generally in mesothermal vein deposits

Occurs in hydrothermal veinsPbCuAsS3SeligmanniteCoAs2Smaltite –

Vein deposits and noritesNiAsNiccoliteAsSRealgar Vein deposits, often associated with orpiment, clays and limestones, also deposits

from hot springsOrpiment As2S3 Hydrothermal veins, hot springs, volcanic sublimation product

High-temperature deposits, metamorphic rocksCoAsSCobaltiteFeAsSArsenopyrite The most abundant As mineral, dominantly mineral veins

Hydrothermal veins(Cu,Fe)12As4S13TennantiteHydrothermal veinsEnargite Cu3AsS4

Secondary mineral formed by oxidation of arsenopyrite, native arsenic and otherAs2O3ArsenoliteAs minerals

Claudetite Secondary mineral formed by oxidation of realgar, arsenopyrite and other AsAs2O3

mineralsScorodite Secondary mineralFeAsO4·2H2OAnnabergite (Ni,Co)3(AsO4)2·8H2O Secondary mineral

Mg3(AsO4)2·8H2OHoernesite Secondary mineral, smelter wastes(Mn,Mg)4Al(AsO4) –Haematolite

(OH)8

Conichalcite Secondary mineralCaCu(AsO4)(OH)Secondary mineralZn2(OH)(AsO4)Adamite

Cu3AsDomeykite Found in vein and replacement deposits formed at moderate temperaturesFeAs2Loellingite Found in mesothermal vein deposits

Oxidation product of arsenopyrite and other As mineralsFe3(AsO4)2(OH)3·5H2OPharmacosiderite

of arsenic: The levels of arsenic in the soils ofvarious countries are said to range from 0.1 to 40mg kg−1 (mean 6 mg kg−1) [17], 1 to 50 mg kg−1

(mean 6 mg kg−1) [18] and mean 5 mg kg−1 [19],but varies considerably among geographic regions[20]. Arsenic is present in soils in higher concen-trations than those in rocks [21]. Uncontaminatedsoils usually contain 1–40 mg kg−1 of arsenic,with lowest concentrations in sandy soils andthose derived from granites, whereas larger con-centrations are found in alluvial and organic soils[5]. The contents of arsenic in the soils of variouscountries are shown in Table 4.

Factors influencing arsenic content in soil: Theprincipal factors influencing the concentration of

elements in soils are the parent rock and humanactivities. Factors such as climate, the organic andinorganic components of the soils and redox po-tential status also affect the level of arsenic insoils. Q model factor analysis, linear discriminantanalysis [35] and principal component analysis[36] indicate that the kind of parent rock is amuch more important factor affecting soil metalcontents than soil type. The arsenic contents ofburozem soil developed on granite, calcareousrock and basic rock are 7.48, 11.9 and 8.47 mgkg−1 [37]. The arsenic content is 10.3�8.5 mgkg−1 in Japanese paddy soils, 4.6�2 mg kg−1 inKorean soils and 9.1�6.7 mg kg−1 in soils fromThailand [38]. When rocks weather, arsenic may


mobilize as salts of arsenous and arsenic acids(H3AsO4) [39].

Arsenic in soil. Inorganic and organic forms:Arsenic occurs mainly as inorganic species butalso can bind to organic materials in soils. Underoxidizing conditions, in aerobic environments, ar-senates (iAsV) are the stable species and arestrongly sorbed onto clays, iron and manganeseoxides/hydroxides and organic matters. Arsenicprecipitates as ferric arsenate in soil horizons richin iron. Under reducing conditions arsenites(iAsIII) are the predominant arsenic compounds.Inorganic arsenic compounds can be methylatedby microorganisms, producing under oxidizingconditions, monomethylarsonic acid (MMA),dimethylarsinic acid (DMA) and trimethylarsineoxide (TMAsO) [24].

Under anaerobic conditions these can be re-duced to volatile and easily oxidized methylarsi-nes. The forms of arsenic present in soils dependon the type and amounts of sorbing components

of the soil, the pH and the redox potential. Arsen-ates of Fe and Al (AlAsO4, FeAsO4) are thedominant phases in acid soils and are less solublethan calcium arsenate (Ca3AsO4), which is themain chemical form in any alkaline and cal-careous soils [40]. The adsorbed arsenate fractionin soils is closely related to soil pH and redoxpotential (Eh). It also varied with soil type underthe same pH conditions, increasing in order fromsierozem to brown soil to chestnut soil [41].

Arsenic gets biomethylated (i.e. addition ofCH3 to arsenic through biological activity) in thesoil–water, sediment water interfaces through theactivity of bacteria (such as Escherichia coli,Fla�obacteriun sp, Methanobacterium sp) andfungi (such as Aspergillus glaucus, Candida humi-cola). In the course of biomethylation, iAsIII isoxidized to iAsV and CH3

+ is reduced to CH3− and

stable arsenic oxy-species was formed [42].Redox states of arsenic: Arsenic occurs fre-

quently in the pentavalent state as arsenate and in

Table 3Arsenic deposits of the world [15]

Average AsAs mineral(s) LocationType of depositsconc.(mg kg−1)

Enargite-bearing copper–zinc–lead 1000 (0.1%) United States, Argentina, Chile,Enargitedeposits Peru, Mexico, Republic of the

Philippines, Spain, Yugoslavia,USSR

Arsenical pyritic copper deposits United States, Sweden, Federal40,000 (4%)Arsenopyrite, tennantiteRepublic of Germany, Japan,France, USSR

Canada, Norway, Germany,25,000 (2.5%)Smaltite, domeykite, safflorite,Native silver and nickel–cobaltDemocratic Republic,rammelsbergite, cobaltite, niccolite,arsenide bearing deposits

loellingite, arsenopyrote, et al. Czechoslovakia

Unites States, Brazil, Canada,Arsenopyrite, loellingiteArsenical gold deposits �5000 (0.5%)Republic of South Africa, Australia,USSR

United States, People’s Republic of2000 (0.2%)Realgar, orpimentArsenic sulfide and arsenic sulfidegold deposits China

Arsenopyrite 2000 (0.2%)Arsenical tin deposits United States, Bolivia, Australia,Indonesia, Malaysia, Republic ofSouth Africa

Arsenopyrite 6000 (0.6%) United States, Canada, et al.Arsenical quartz, silver andlead–zinc deposits


Table 4Arsenic contents in the soils of various countries

Number of samples Range (mg kg−1)Country Mean (mg kg−1)Types of soil/sediment References

SedimentsWest Bengal, India 2235 10–196 [22]10 9.0–28Sediments 22.1Bangladesh [23]

All typesArgentina 20 0.8–22 5 [24]4095 0.01–626China 11.2All types [25]– 0.1–5All types 2France [26]2 2.5–4.6Germany 3.5Berlin region [27]20 1.8–60All types 20Italy [28]

All typesJapan 358 0.4–70 11 [28]97 1.2–38.2Paddy 9 [29]

All typesMexico 18 2–40 14 [30]South Africa 2 3.2–3.7 3 [31]

2 2–2.4 2.2Switzerland [32]52 1.0–20 7.5United States [33]Various states1215 1.6–72 7.5Tiller [34]

the trivalent state as arsenite in soil solution andboth oxidation states can be subjected to chemi-cally and microbiologically mediated oxidation,reduction and methylation reactions [43,44]. Thebiological availability and physiological and toxi-cological effects of arsenic depend on its chemicalform [45]. iAsIII is much more toxic, more solubleand more mobile than iAsV. Under the influenceof oxidizing factors, the H3AsO3 in soil can beconverted to H3AsO4. The theoretical oxidation–reduction potential of the system is 0.557 V at20 °C. Because the redox potential of soils de-pends on the redox potentials of all the reducingand oxidizing systems occurring in the soils, theserelationships are very complex and the redoxvalue for soils is not directly proportional to theiAsV to iAsIII ratio [19].

Gaseous states of arsenic: Extensive use wasmade of sodium and ammonium salts of MMAand DMA as non-selective, post-emergent, foliar-contact herbicides with the bioaccumulation ofthese arsenicals, as well as their reduction by soilmicroorganisms to the corresponding toxic andhighly volatile arsines [46,47]. Gaseous arseniccompounds are evolved by Penicillium bre�icaule,which is called arsenic fungi [48]. Certain strainsof Scopulariopsis fungi evolve an arsine gas fromagar solutions that contains inorganic arsenic [49].It is found that common fungi, yeasts and bacte-ria can methylate arsenic to MMA, DMA and

gaseous derivatives of arsenic [47,50] and the re-sulting methylated arsenic is widely distributed insoils [46,51]. From literature [52], it is found thatreduction to arsenic; not methylation to trimethy-larsine (TMA) is the primary mechanism forgaseous loss of arsenicals from soil.

Sediment. The natural level of arsenic in sedi-ments is usually below 10 mg kg−1, dry weight[53] and varies considerably all over the world.

2.1.3. WaterArsenic is found at low concentration in natural

water. The arsenic contents in groundwater ofdifferent countries are summarized in Table 5.The maximum permissible concentration of ar-senic in drinking water is 50 �g l−1 and recom-mended value is 10 �g l−1 by EPA and WHO[15,73]. The seawater ordinarily contains 0.001–0.008 mg l−1 of arsenic. The major chemical formin which arsenic appears to be thermodynamicallystable is arsenate ion. The ratio of iAsV to iAsIII

based on thermodynamic calculation should be1026:1 for oxygenated seawater at pH 8.1. Inreality, it is 0.1:1 to 10:1. This unexpected highiAsIII content is caused at least in part by biologi-cal reduction in seawater [74]. The arsenic specia-tion was performed on well water samples froman area around Alaska containing high levels ofarsenic [75] and 3 to 39% contained iAsIII and restwere iAsV. No methylated arsenic compounds


were detected. The concentration of arsenic inunpolluted fresh waters typically ranges from 1–10 �g l−1, rising to 100–5000 �g l−1 in areas ofsulfide mineralization and mining [76]. At moder-ate or high redox potentials arsenic can be stabi-lized as a series of pentavalent (arsenate)oxyanions, H3AsO4, H2AsO4

−, HAsO4−2 and

AsO4−3. However, under most reducing (acid and

mildly alkaline) conditions and lower redox po-tential, the trivalent arsenite species (H3AsO3) pre-dominate. As0 and As3− are rare in aquaticenvironments.

Complex organic arsenic compounds such as

tetramethylarsonium salts, arsenocholine, arseno-betaine, dimethyl(ribosyl)arsine oxides and ar-senic containing lipids are identified in the marineenvironment [39]. Only a very minor fraction ofthe total arsenic in the oceans remains in solutionin seawater, as the majority is sorbed on to sus-pended particulate materials.

The high levels of arsenic are in waters fromareas of thermal activity in New Zealand [77] upto 8.5 mg l−1. Geothermal water in Japan [78]contains 1.8–6.4 mg l−1 and neighboring streamsabout 0.002 mg l−1. Although normally ground-water does not contain methylated form of arsenic

Table 5Concentrations of arsenic in groundwater of the arsenic-affected countries

ConcentrationArsenic source ReferencesSampling periodLocation(�g l−1)a

68 (1–174)Deep groundwaterN.S. [54]Hungary[55]1993–1994 Well waters; natural origin 17–980 (range)South-west Finland

1 (median) [56]1977–1979New Jersey, USA Well waters1160 (maximum) [56]

Western USA [57]N.S. 48,000Geochemical environments(maximum)

Alluvial aquifers [58]1970– 16–62 (range)South-west USASouthern Iowa and western [59]N.S. Natural origin 34–490 (range)

Missouri, USAN.S.Northeastern Ohio, USA Natural origin �1–100 (range) [60]

Lagunera region, northern [61]N.S. Well waters 8–624 (range)Mexico

[62]Cordoba, Argentina �100Chile 470–770 (range) [63]Pampa, Cordoba, Argentina 2–15 m, 61°45�–63° W; 32°20�–35°00�SN.S. [64]100–3810 (range)

0.05–850 (range)1983 [65]Well watersKuitun-Usum, Xinjiang, PRChina

Shanxi, PR China 1988 0.03–1.41 (range)Well waters [65]Hsinchu, Taiwan N.S. Well waters [66]�0.7West Bengal, India 1989–1996 Arsenic-rich sediment [67]0.003–3700

(range)Calcutta, India 1990–1997 [68]Near pesticide production plant �50–23,080

(range)Well waters [69]1996–1997Bangladesh �10–�1000

(range)Shallow (alluvial) groundwater; mining [70]503.5 (1.25–5114)Nakhon Si Thammarat 1994

Province, Thailand activity1994 95.2 (1.25–1032) [70]Deep groundwater; mining activity

Fukuoka, Japan Natural origin 0.001–0.2931994 [71](range)

[72]1999–2000 Arsenic-rich sediment 159 (1–3050)Hanoi, Vietnam

NS, not stated.a Mean and ranges of total arsenic unless stated otherwise.


but lake and pond waters contain arsenite, arse-nate as well as methylated forms, i.e. MMA andDMA.

2.1.4. AirIn air, arsenic exists predominantly absorbed

on particulate matters, and is usually present as amixture of arsenite and arsenate, with the organicspecies being of negligible importance except inareas of arsenic pesticide application or bioticactivity [79].

The human exposure of arsenic through air isgenerally very low and normally arsenic concen-trations in air ranges from 0.4 to 30 ng m−3 [80].According to USEPA the estimated average na-tional exposure in the U.S. is at 6 ng As m−3.Absorption of inhaled arsenic ranges between 30and 85%, depending on the relative portions ofvapour and particulate matters. USEPA estimatesthat the general public will be exposed to a rangeof approximately 40–90 ng per day by inhalation[81]. The amount of arsenic inhaled per day isabout 50 ng or less (assuming that about 20 m3 ofair is inhaled per day) in unpolluted areas [82].The daily respiratory intake of arsenic is approxi-mately 120 ng of which 30 ng would be absorbed[83]. Typical arsenic levels for the European re-gion are currently quoted as being between 0.2and 1.5 ng m−3 in rural areas, 0.5 and 3 ng m−3

in urban areas and no more than 50 ng m−3 inindustrial areas [84].

2.1.5. Li�ing organisms

2.1.5.1. Plants. Arsenic is an element, which isfound to be cumulative in living tissue, i.e. onceingested by any organism it is passed out of theorganism only very slowly if at all. The amount ofarsenic in a plant, then depends almost solely onthe amount of arsenic, it is exposed to. Its concen-tration varies from less than 0.01 to about 5 �gg−1 (dry weight basis) [85]. There appears to belittle chance that animals will be poisoned byconsuming plants which absorb arsenic residuesfrom contaminated soils, because plant injury oc-curs before toxic concentrations can appear [85].

2.1.5.2. Animals and human beings. As in planttissue, arsenic is cumulative in animal tissue, al-lowing for a wide variation in concentration dueto the variance in arsenic ingested in differentareas. Among marine animals, arsenic is found tobe accumulative to levels of from 0.005 to 0.3 mgkg−1 in coelenterates, some molluscs and crus-taceans [86]. Some shellfish may contain over 100�g g−1 of arsenic. The average arsenic content infreshwater fish is of 0.54 �g g−1 on the basis oftotal wet weight, but some values reach as high as77.0 �g g−1 in the liver oil of freshwater bass [87].

In mammals it is found that the arsenic accu-mulates in certain areas of the ectodermic tissue,primarily the hair and nails. The domestic animalsand human generally contain less than 0.3 �g g−1

on a wet weight basis [88]. The total human bodycontent varies between 3 and 4 mg and tends toincrease with age. With the exception of hair,nails and teeth, analyses reveal that most bodytissues contain less than 0.3–147 �g g−1 (dryweight) [15]. The absorption of arsenic in humanbody is high for anionic and soluble species andlow for insoluble species.

Inorganic arsenic has a special affinity for hairand other keratin-rich tissues [88]. The concentra-tions along the length of the hair show the expo-sure over a period of time [89]. The normalamount of arsenic in hair is about 0.08–0.25 �gg−1 with 1.0 �g g−1 being indication of thepresence of excess arsenic and poisoning [90]. Nailclippings from a patient with acute polyneuritisfrom arsenic poisoning contain arsenic at 20–130�g g−1 [91], where the normal arsenic concentra-tion in nail is 0.34�0.25 �g g−1 [92]. The arseniccontent of urine can vary normally from 5 to 40�g per day (total). Acute and sub acute poisoningwill produce an excess of 100 �g per day [90].

Great daily variation of arsenic exists and de-pends on the amount of arsenic in various foodstaffs. Higher organic arsenic compounds such asarsenobetaine and arsenocholine are found inmarine organisms, and they are very resistant tochemical degradation [93]. In general, it is foundthat organic arsenicals are more rapidly excretedthan inorganic forms and pentavalent arsenicalsare cleared faster than trivalent. The detailed ar-senic content of animals, human beings and plantsare given in literatures [73].


2.2. Anthropogenic sources

These exceed natural sources in the environ-ment by 3:1 [94]. Man in his utilization of naturalresources releases arsenic into the air, water andsoil. These emissions can ultimately affect residuelevels in plants and animals. Arsenic may accumu-late in soil through use of arsenical pesticides,application of fertilizers, dust from the burning offossil fuels, disposal of industrial and animalwastes [95,96].

2.2.1. Man made sourcesThe main arsenic producers were China, USSR,

France, Mexico, Germany, Peru, Namibia, Swe-den, and USA, and these countries accounted forabout 90% of the world production [97,98]. Dur-ing 1970s, about 80% of the consumption ofarsenic were for agriculture purpose. At present,agricultural use of arsenic is declining. Approxi-mately, 97% of the arsenic produced enters end-product manufacture in the form of white arsenicand remaining 3% as metal for metallurgic addi-tives, in special lead and copper alloys [98].

2.2.2. InsecticidesEarlier arsenic was widely used for preparation

of insecticides and pesticides. In 1955, the worldproduction of white arsenic was 37,000 tons. Ofthis quantity, 10,800 tons were produced in theU.S., while domestic consumption exceeded18,000 tons [99], most of it in the form of pesti-cides, such as lead arsenate, Ca3AsO4, copperacetoarsenite, Paris-Green (copper acetoarsenite),H3AsO4, MSMA (monosodium methanearson-ate), DSMA (disodium methanearsonate) and ca-codylic acid are used in cotton production aspesticides. The detailed production and uses ofother arsenical pesticides are mentioned in litera-tures [100–103].

2.2.3. HerbicidesThe inorganic arsenicals, primarily, sodium ar-

senite, were widely used since about 1890 as weedkillers, particularly as non-selective soil sterilants[103]. The literatures [103–105] document exten-sively on organic arsenical herbicides.

2.2.4. Desiccants and wood preser�ati�esArsenic acid is used extensively as a cotton

desiccant for many years. Two thousand and fivehundred tonnes of H3AsO4 were used as desic-cants on 1,222,000 acres (about 495,000 ha) ofU.S. cotton in 1964 [40].

The first wood preservative was Fluor–Chrome–Arsenic–Phenol (FCAP), which wasused as early 1918 in USA. The production,preparation, uses of principal wood preservativesare summarized by U.S. Department of Agricul-ture [106]. Earlier, Chromated Copper Arsenate(CCA) and Ammonical Copper Arsenate (ACA)in combination were used in 99% of the arsenicalwood preservatives [105]. Wolman salts and Os-mosalts, zinc and chromium arsenate are alsoused as wood preservative [101].

2.2.5. Feed additi�esMany arsenic compounds are used for feed

additives, such as H3AsO4, 3-nitro-4-hydroxyphenylarsonic acid, 4-nitrophenylarsonic acid etc.All substituted phenylarsonic acids were used forfeed additives under Food Additives Law of 1958[85].

2.3. Drugs

The medicinal virtues of arsenic are acclaimedfor nearly 2500 years. In Austria, the peasantsconsumed a large quantity of arsenic for softnessand cleanliness of the skin, to give the plumpnessto the figure, beauty and freshness to the com-plexion and also to improve the breathing prob-lem [107,108].

Common medicinal preparations, which con-tained arsenic, include Fowler’s solution (potas-sium arsenite), Donovan’s solution (arsenic andmercuric iodides), Asiatic pills (arsenic trioxideand black pepper), de Valagin’s solution (liquorarsenii chloridi), sodium cacodylate, ar-sphenamine (Salvarsan), neoarsphenamine, ox-ophenarsine hydrochloride (Mapharsen),arsthinol (Balarsen), acetarsone, tryparsamide andcarbarsone [99]. References [109–111] give de-tailed uses of arsenic compounds as drugs andmedicine.


2.4. Poison

Arsenic compounds are infamous as very po-tent poisons and are preferred to homicidal andsuicidal agents. Even the death of NapoleonBonaparte was suspected to be due to arsenicpoisoning [112].

3. Metabolisms and toxicity of arsenic

3.1. Metabolisms

Humans are exposed to many different formsof inorganic and organic arsenic species (arseni-cals) in food, water and other environmental me-dia. Each of the forms of arsenic has differentphysicochemical properties and bioavailabilityand therefore the study of the kinetics andmetabolism of arsenicals in animals and humansis a complex matter. Large interspecies differencescompared with other metals and metalloids alsocharacterize arsenic metabolism.

Routes of arsenic intake in vivo considered arerespiratory for dust and fumes, and oral for ar-senic in water, beverages, soil, and food. Fewinvestigations of dermal absorption rates for ar-senicals are undertaken. The available datasetsindicate that absorption rates are generally low(�10%); however, for certain forms of arsenichigher rates may be observed [15]. Wester et al.[113] studied the percutaneous absorption ofH3AsO4 from water and soil. In rhesus monkeys,arsenic uptake ranges from 6 to 2%. The sameauthors also reported that human cadaver skinabsorbed approximately 1–2% of the adminis-tered dose over a 24-h period.

Both iAsIII and iAsV are found to cross theplacenta of laboratory animals [15,114,115]. Thisconclusion is substantiated by a more recent studyconducted by Concha et al. [116] who observedthat similar arsenic concentrations are found incord blood and maternal blood (�9 �g l−1) ofmaternal-infant pairs exposed to high arsenic-con-taining drinking water (�200 �g l−1). Olderstudies demonstrated that DMA was capable ofcrossing the placenta of rats [117] and that theorganoarsenical feed additive Roxarsone (3-nitro-

4-hydroxyphenylarsonic acid) accumulated in eggs[118]. However, more recent human or animaldata are not available to substantiate thesefindings.

The bioavailability of ingested inorganic arsenicwill vary depending on the matrix in which it isingested (i.e. be it food, water, beverages or soil),the solubility of the arsenical compound itself andthe presence of other food constituents and nutri-ents in the gastrointestinal tract. Tissue distribu-tions of arsenic depend on blood perfusion, tissuevolumes, diffusion coefficients, membrane charac-teristics, and tissue affinities. The fate of ingestedarsenic in vivo depends on: (1) oxidation andreduction reactions between iAsV and iAsIII in theplasma; and (2) consecutive methylation reactionsin the liver. Inorganic arsenic is methylated invivo in human. Arsenate is rapidly reduced toarsenite, which was afterwards partly methylated.The main site of methylation appears to be theliver, where arsenic methyltransferase enzymesmediate the methylation process with S-adenosyl-methionine as the methyl donor and GSH as anessential co-factor. Studies on humans suggestthat methylation may begin to be limiting at doseof about 0.2–1 mg kg−1 (0.003–0.015 mg Askg−1 per day) [119]. Raie [120] compared tissuearsenic levels in infants (aged 1 day to 5 months)and adults from Glasgow, Scotland using NAA.Mean levels of arsenic (mg kg−1 or �g g−1 dryweight) in liver, lung and spleen in infants versusadults are 0.0099 versus 0.048, 0.007 versus 0.044,and 0.0049 versus 0.015, respectively. These datasuggest that arsenic accumulates in tissues withage, a finding that is wholly consistent with obser-vations in laboratory animals [121].

In most animal studies DMA is the mainmetabolite, while in human the urinary excretionconsists under normal conditions, i.e. without ex-cessive ingestion of inorganic arsenic—of about20% inorganic arsenic, 20% MMA and 60%DMA. Inorganic arsenic gets methylated toMMA and DMA in vivo and during circulationin plasma MMA is partly absorbed and this ab-sorbed MMA is further methylated to DMA,while DMA is excreted mainly in an unchangedform [122,123]. The very recent studies [124,125]informed that both MMAV and DMAV were re-


duced to their trivalent analogues monomethylar-sonous acid (MMAIII) and dimethylarsinous acid(DMAIII), respectively and excreted throughurine. Arsenobetaine is absorbed and excretes un-changed [126,127]. Similar studies are unavailablefor other organoarsenicals. Studies with radioac-tively labeled (As74) arsenate in human show that38% of the dose is excreted in the urine within 48h and 58% of the total within 5 days [128]. In thesubjects who ingested 500 �g As in the form ofarsenite, 33% of the dose was excreted in the urinewithin 48 h and 45% within 4 days [123]. It isestimated that about 60–70% of the daily-ingestedinorganic arsenic is excreted in the urine [129].About 76% of the organic arsenic ingested withflounder is excreted in the urine within 8 days[130]. However, in a later study, Marafante et al.[131] reported that 3.5% of a single oral dose ofDMA (0.1 mg As kg−1) was eliminated in urineas TMAO within 3 days. No metabolism studiesare identified in which humans specifically con-sumed TMA or TMAO alone rather than inseafood. Yamauchi et al. [132] calculated the bio-logical half-lives following oral administration oforganoarsenicals to hamsters from multiple stud-ies conducted in their laboratory. They reportedhalf-lives of 7.4 h for MMA, 5.6 h for DMA, 5.3h for TMAO, 3.7 h for TMA and 6.1 h forarsenobetaine. No studies are identified that ad-dressed the issue of biliary excretion or otherroutes of elimination for organoarsenicals inhumans.

Although arsenic is excreted via other routesthan via urine and feces (e.g. in sweat), theseroutes of excretion are generally minor [15]. Sincearsenic can accumulate in keratin-containing tis-sues [133], skin, hair and nails can also be consid-ered as potentially minor excretory routes. Botholder [15] and recent studies indicate that arseniccan be excreted in human milk, although thelevels are low [134,135].

The three most commonly employed biomark-ers used to identify or quantify arsenic exposureare total arsenic in hair or nails, blood arsenic,and total or speciated metabolites of arsenic inurine. Because arsenic (as the trivalent form) ac-cumulated in keratin-rich tissues such as skin, hairand nails [133]), arsenic levels in hair and nails areused as indicators of past arsenic exposure.

Normally inorganic arsenic is very quicklycleared from human blood. For this reason bloodarsenic is used only as an indicator of very recentand/or relatively high level exposure, for example,in poisoning cases [136] or in cases of chronicstable exposure (i.e. from drinking water). Studiesshow that in general blood arsenic does not corre-late well with arsenic exposure in drinking water,particularly at low levels.

In common with other biomarkers of arsenicexposure, arsenic levels in urine may result frominhalation exposure as well as ingestion fromfood, water and soils [137] and as such provided ameasure of the total absorbed dose. However,since arsenic is rapidly metabolized and excretedinto the urine, levels in urine are best suited toindicate recent arsenic exposure. Total arsenic,inorganic arsenic and the sum of arsenic metabo-lites (inorganic arsenic+MMA+DMA) in urineare all used as biomarkers of recent arsenic expo-sure. In many older studies, total urinary arsenicis used as a biomarker of recent arsenic exposure.This approach becomes increasingly uncommonbecause certain organoarsenicals (for example, thepractically non-toxic compound arsenobetaine)present in substantial amounts in certain food-stuffs are excreted mainly unchanged in urine[138–140]. Since consumption of seafood (e.g.marine fishes, crustaceans, bivalves, seaweeds) byhuman volunteers is associated with increased to-tal urinary arsenic excretion [141] assessment ofinorganic arsenic exposure using total urinary ar-senic under these conditions will result in overesti-mation of inorganic arsenic exposure.

To avoid the potential for over-estimation ofinorganic arsenic exposure inherent in using totalurinary arsenic, most studies now measure speci-ated metabolites in urine, and used either inor-ganic arsenic or the sum of arsenic metabolites(inorganic arsenic+MMA+DMA) as an indexof arsenic exposure. However, this can give mis-leading results unless a careful diet history istaken and/or seafood consumption is prohibitedfor at least 3 days prior to urine collection. Thereare two reasons for this. First, some seafoodscontain the arsenic metabolites MMA and DMA,particularly DMA, in fairly high amounts. Sec-ondly, arsenosugars present in seaweeds and some


bivalves are extensively metabolized to DMA (ei-ther by the body itself or the gut microbiota),which is then excreted in urine [15,142,143]

3.2. Toxicity

The chemical forms and oxidation states ofarsenic are more important as regards to toxicity.Toxicity also depends on other factors such asphysical state, gas, solution, or powder particlesize, the rate of absorption into cells, the rate ofelimination, the nature of chemical substituents inthe toxic compound, and, of course, the pre-exist-ing state of the patient. The toxicity of arsenicalsdecrease in the order, arsines� iAsIII�arsenox-ides (org AsIII)� iAsV�arsonium compounds�As [87,144]. Recently Vega et al. [145] reports thetoxicity order of arsenicals as iAsIII�monomethylarsine oxide (MMAOIII)�DMAIIIGS�DMAV�MMAV� iAsV. While it isgenerally accepted that methylation is the princi-pal detoxification pathway, recent studies havesuggested that methylated metabolites may bepartly responsible for the adverse effects associ-ated with arsenic exposure [145].

Studies in laboratory animals have demon-strated that the toxicity of arsenic is dependent onits form and its oxidation states. It is generallyrecognized that the soluble inorganic arsenicalsare more toxic than the organic ones, and theiAsIII are more toxic than iAsV [63,146]. A fewreports [147,148] documented that at low to mod-erate exposure levels, the long-term distributionpattern of arsenic is rather independent on expo-sure form, iAsIII or iAsV in rabbits and marmosetmonkeys. But Maeda [146] reported that iAsV isless toxic than iAsIII to both animal and humansbut can be toxic to plants. Although there are afew literatures [15,63,149–151] on chronic andacute arsenic toxicity, the species-specific epidemi-ological studies on chronic arsenic toxicity in ar-senic endemic areas are literally nil. In thearsenic-affected areas of West Bengal, India Chat-terjee et al. [152] reported that the most toxicspecies, iAsIII, is present in groundwater at about50% of the total arsenic level. In the arsenic-af-fected areas of Bangladesh the modal proportionof iAsIII appears to be between 50 and 60% of the

total arsenic [153]. In the arsenic-affected areas ofTaiwan, Chen et al. [154] reported that the aver-age arsenic, predominately iAsIII, concentration inthree wells was 671�149 �g l−1 in the black footdisease (BFD) area. The ratio of iAsIII to iAsV

was 2.6:1. But no above-mentioned studies docu-mented any species-specific toxicity of arsenic intheir publications on chronic arsenic toxicity. So,more studies on species-specific toxicity of arsenicare necessary to elucidate species-specific chronictoxicity of arsenic in the endemic arsenic-affectedareas.

In reality, use of new analytical methods thatdetermine the oxidation states of arsenic in themetabolites of inorganic arsenic (iAs) in the popu-lation-based studies are likely to provide newinsights into the linkage between exposure,metabolism, and toxicity [124,125,155–158]. Al-though studies on species-specific chronic toxicityof arsenic in the endemic arsenic-affected areasare not available several recent documents ofspecies-specific toxicity of arsenic on animal andhuman cell lines suggest that trivalent arsenicalsare more toxic than pentavalent arsenicals. Be-cause ingested iAs is extensively metabolized inhumans, chronic exposure to iAs results inchronic exposure to methylated and dimethylatedarsenicals. MMAIII, a biotransformant of inor-ganic arsenic, is up to 26 times more toxic thaninorganic arsenite in Chang human hepatocytes[159]. According to Lin et al. [160], MMAIII isover 100 times more potent than iAsIII as an invitro inhibitor of thioredoxin reductase. So, for-mation of MMAIII appears to represent toxifica-tion of both iAsV and iAsIII. Also, in vitro studieshave shown that MMAIII and DMAIII, like iAsIII,can form GSH complexes, and that these are atleast as toxic as iAsIII [161,162]. Another recent invitro study showed that MMAIII was more cyto-toxic to human cells (hepatocytes, epidermal ker-atinocytes, and bronchial epithelial cells),compared to iAsIII and iAsV [162]. The authorsconcluded that high methylation capacity did notprotect these cells from the acute toxicity of triva-lent arsenicals. Recently Vega et al. [163] reportedthat trivalent arsenicals induced an increase in cellproliferation, but pentavalent arsenicals did not,in an in vitro experiment with human epidermal


keratinicytes. Another very recent in vitro studyassessed the induction of DNA damage by methy-lated trivalent arsenicals (MMAIII and DMAIII) inhuman peripheral lymphocytes using single-cellgel (SCG, ‘comet’) assay [164]. On the basis of theslopes of the concentration–response curve forthe tail moment in the SCG assay, MMAIII andDMAIII were 77 and 386 times more potent thaniAsIII, respectively. The authors concluded thatthey (MMAIII and DMAIII) were considered to bedirect-acting forms of arsenic that were genotoxic,though they were not, necessarily, the onlygenotoxic species of arsenic that could exist.

The most common toxic mode of an element isthe inactivation of enzyme systems, which servesas biological catalyst [69]. The iAsV does not reactdirectly with the active sites of enzymes [165]. Itfirst reduces to iAsIII in vivo before exerting its

toxic effect [166,167]. Aposhian postulated thatthe binding of trivalent arsenic to non-essentialsulfhydryl groups in cells might represent an im-portant route for arsenic detoxification [168].

Trivalent arsenic interferes with enzymes bybonding to �SH and �OH groups, especially whenthere are two adjacent HS-groups in the enzyme.

The enzymes, which generated cellular energy inthe citric acid cycle, are adversely affected. Theinhibitory action is based on inactivation of pyru-vate dehydrogenase by complexation with iAsIII,whereby the generation of adenosine-5-triphos-phate (ATP) is prevented. The enzyme systemcomprises of several enzymes and cofactors, oneprotein molecule of enzyme having one lipoicacid. In the presence of iAsIII, it replaces the twohydrogen atoms from the thiol groups and at-taches with a sulfur molecule and forms a dihy-drolipoylarsenite chelate complex, which preventsthe reoxidation of the dihydrolipoyl group that isnecessary for continued enzymatic activity, andthis pivotal enzyme steps blocked. As a result, theamount of pyruvate in the blood increases, energyproduction is reduced, and finally the cell dam-ages slowly [169,170]. The reactions are shownbelow.

The strong bond between iAsIII and sulfur maybe the reason why arsenic accumulates in thekeratin tissues hair and nail. Peters proposed thattrivalent arsenic form a stable ringed structurewith vicinal dithilols of keratin in hair [171]. Ar-senic inhibits enzymes, such as the pyruvate ox-


idase, S-aminoacid oxidase, choline oxidase andtransaminase. Although iAsIII is regarded themore toxic form of the element, iAsV as arsenatecan be disruptive by competing with phosphate.For example, arsenate uncouples oxidative phos-phorylation. Oxidative phosphorylation is theprocess by which ATP is produced, while at thesame time reduced nicotinamide adenine dinucle-otide (NADPH) is oxidized [172].

3ADP+3H3PO4�3ATP+3H2O

NADPH+H++1/2O2�NADP++H2O

The arsenate disrupts this process by producingan arsenate ester of ADP, which is unstable andundergone hydrolysis non-enzymatically. Thisprocess was termed as arsenolysis [168]. Hence theenergy metabolism is inhibited and glucose-6-arse-nate is produced rather than glucose-6-phosphate.Arsenate may also replace the phosphorous inDNA [173] and this appears to inhibit the DNArepair mechanism. Such an action may explain theclastogenicity of arsenic, because an arsenodiesterbond will most likely be weaker than the normalphosphodiester bond. However, no direct evi-dence is located to show that arsenate is incorpo-rated into DNA.

In environments where phosphate concentra-tions are high, arsenate toxicity to biota is gener-ally reduced. Arsenic-contaminated environmentsare characterized by limited species abundanceand diversity. If levels of arsenate are highenough, only species, which exhibited resistance,may be present [15].

Arsenic and selenium are antagonistic to eachother in the body, and each counteracts the toxic-ity of the other. However, arsenic may also inter-fere with the essential role of selenium in humanmetabolism [174]. Arsenic inhibits the action ofselenium, which causes the apparent deficiency ofglutathione peroxidase system—a selenium de-pendent enzyme. The more detail information ofarsenic interaction with selenium is given by Elderet al. [137,165].

Arsenic induced increases in metallothionein(MT) levels [175]. Although it is not knownwhether arsenic can be detoxified by MT, a lowmolecular weight cysteine-rich, metal binding

protein. Zinc-induced increases in MT, however,does not seem to be responsible for the protectionagainst arsenic lethality in mice pretreated withzinc. Although the mechanism for this toleranceto arsenic toxicity is not known, zinc pretreatmentis associated with increased elimination of arsenic[176].

Chronic exposure to inorganic arsenic may giverise to several health effects including effects onthe gastrointestinal tract, respiratory tract, skin,liver, cardiovascular system, hematopoietic sys-tem, nervous system etc. The earliest reports dateback to the latter part of the 19th century whenthe onset of skin effects (including pigmentationchanges, hyperkerotosis and skin cancers) werelinked to the consumption of arsenic in medicinesand drinking water [15]. There is also no pub-lished information concerning toxicological effectsin human exposed orally to organoarsenicals. Thehealth effects of arsenic exposure to various inter-nal and external organs are summarized asfollows.

3.2.1. Respiratory effectsHumans exposed to inorganic arsenic naturally

and occupationally experience laryngitis, tracheaebronchitis, rhinitis, pharyngitis, shortness ofbreath, chest sounds (crepitations and/orrhonchi), nasal congestion and perforation of thenasal septum [119,177–180].

3.2.2. Pulmonary effectsThe possible role of chronic arsenic ingestion in

the genesis of non-malignant pulmonary disease issuggested in a few cases due to chronically ex-posed to increased concentrations of arsenic indrinking water. Borgono et al. [181] reported that38.8% of 144 subjects with ‘abnormal skin pig-mentation’ complained of chronic cough, com-pared with 3.1% of 36 subjects with normal skinin a cohort study of 180 residents of Antofagasta,Chile with arsenic contaminated drinking water(0.80 mg l−1). In a study of arsenic in drinkingwater in West Bengal, India, Guha Mazumder etal. [182] noted a complaint of cough in 89 (57%)of 156 patients with arsenical hyperpigmentation.Lung-function tests performed on 17 of thosepatients showed features of restrictive lung disease


in nine (53%) and combined obstructive and re-strictive disease in seven (41%) [182].

3.2.3. Cardio�ascular effectsBoth the heart and peripheral arterial tree com-

monly manifest effects of arsenic toxicity such ascardiovascular abnormalities, Raynaud’s disease,myocardial infarction, myocardial depolarization,cardiac arrhythmias, thickening of blood vesselsand their occlusion and BFD. Studies from Tai-wan was clearly demonstrated that exposure toarsenic via drinking water is associated with BFD,with significant exposure–response relationshipsrelating both the duration and level of exposureto observed effects [15], which is characterized bya progressive loss of circulation in the hands andfeet, which ultimately leads to severely painfulgangrene formation of the extremities (particu-larly the toes and feet), often necessitating ampu-tation of the limb [119,172,183]. Zaldivar [184]reported several cases of myocardial infarctionand arterial thickening in children who consumedwater containing 0.60 mg As l−1. The extremeform and high prevalence of BFD found in Tai-wan is not observed in other regions. It is proba-ble therefore, that other factors, such asmalnutrition or concurrent exposures, are playinga role in the pathophysiology of the disease [15].In contrast, there is only limited evidence for anassociation between arsenic exposure and cere-brovascular diseases. A few Taiwanese studiesshow an elevated risk of death from cerebrovascu-lar disease with increasing arsenic exposure, mostnotably that of Chiou et al. [118]. Furthermore,studies from other countries provide only verylimited support for the Taiwanese findings [15].Chen et al. [185] suggested that long-term arsenicexposure might induce hypertension in humans.Rahaman et al. [186] also reported induced hyper-tension among arsenic-affected people inBangladesh.

3.2.4. Gastrointestinal effectsThe efficiency of absorption of inorganic arseni-

cals from the gastrointestinal tract depends ontheir water solubility. Several gastrointestinalsymptoms are common and salient features ofarsenic intoxication due to ingestion of heavy

doses of arsenic. Sub-acute arsenic poisoningfrom lesser doses of arsenic may manifest as drymouth and throat, heartburn, nausea, abdominalpains and cramps, and moderate diarrhea.Chronic low dose arsenic ingestion may be with-out symptomatic gastrointestinal irritation or mayproduce a mild esophagitis, gastritis, or colitiswith respective upper and lower abdominal dis-comfort [119]. Anorexia, malabsorption andweight loss may be present [187].

3.2.5. Hematological effectsThe hematopoietic system is also affected by

both short- and long-term arsenic exposure. Ane-mia (normochromic normocytic, aplastic andmegaloblastic) and leukopenia (granulocytopenia,thrombocytopenia, myeloid, myelodysplasia) arecommon effects of poisoning and is reported asresulting from acute [188], intermediate [189] andchronic oral exposures [190,191]. These effectsmay be due to direct hemolytic or cytotoxic ef-fects on the blood cells and a suppression oferythropoiesis [192]. No such effects are noticed inhumans exposed chronically to 0.07 mg As kg−1

per day or less. Relatively high doses of arsenicare reported to cause bone marrow depression inhuman [193]. Winski and Carter [194] recentlyexamined the effect of inorganic arsenite and arse-nate on human erythrocyte morphology in an invitro model. They estimated that human erythro-cytes are at least 1000 times more sensitive toarsenate than arsenite. Recent one study docu-ments that DMA is taken up by RBCs in theform of DMAIII, and that the uptake and effluxrates are dependent on the animal species, theefflux arsenic being DMAV [195].

The mechanism of hemolysis involves depletionof intracellular GSH, resulting in oxidation ofsulfhydryl groups in the hemocyanin from Fe2+

to Fe3+ in mice and rats. Hemoglobin combineswith arsenic, which reduces oxygen uptake bycells and therapy prevents hatching [149].

3.2.6. Hepatic effectsSince the liver tends to accumulate arsenic with

repeated exposures, hepatic involvement is re-ported most commonly as a complication ofchronic exposures over periods of months or years


[194]. Chronic arsenic induced hepatic changesinclude cirrhosis, portal hypertension without cir-rhosis, fatty degeneration and primary hepaticneoplasia. Patients may come to medical attentionwith bleeding esophageal varices, ascites, jaundice,or simply an enlarged tender liver, mitochondrialdamage, impaired mitochondrial functions, andporphyrin metabolism [119,197–199], congestion,fatty infiltration, cholangitis, cholecystitis andacute yellow atrophy [200], and swollen and ten-der liver [92,201,202]. The analysis of blood some-times shown elevated levels of hepatic enzymes[203], hepatic fatty infiltration and cirrhosis of theliver in patients who used Fowler’s solution [204].There is no evidence of hepatic dysfunction ofseveral workers exposed to arsenic dust by inhala-tion [205].

3.2.7. Renal effectsLike the liver, the kidneys will accumulate inor-

ganic arsenic in the presence of repeated expo-sures. The kidneys are the major route of arsenicexcretion, as well as a major site of conversion ofpentavalent arsenic [188,206]. In humans, the kid-neys seem to be less sensitive to arsenic than mostother organ systems. The effects of organoarseni-cals on the human renal system are not reported.Sites of arsenic damage in the kidney includescapillaries, tubules and glomeruli, which leaded tohematuria and proteinuria [196], oliguria, shockand dehydration with a real risk of renal failure[207], cortical necrosis [208], and cancer [209].

3.2.8. Dermal effectsChronic exposures to arsenic by either ingestion

or inhalation will produce a variety of skin in-signia of arsenic toxicity (i.e. diffused and spottedmelanosis, leucomelanosis, keratosis, hyperkerato-sis, dorsum, Bowen’s disease, and cancer). Skindisorders are documented in several epidemiologi-cal studies in which people consumed drinkingwater that contained arsenic at the doses of 0.01–0.1 mg As kg−1 per day or more [63,150,151,210–216], no dermal or other effects as a result ofexposure to chronic doses of 0.003–0.01 mg Askg−1 per day [217,218]. Hyperpigmentation mayoccur, particularly in body areas where the skintends to be a little darker [219]. The initial ery-

thromatous flush from arsenic may phase into anactinic keratosis, a hyperkeratosis of palms andsoles, papillomatosis, recurrent episodes of pru-ritic urticaria, or even generalized pruritis withouta visible rash [220], basal cell carcinoma orsquamous cell carcinoma, which are histologicallyindistinguishable from analogous non-arsenic tu-mors [119], and fingernails and toenails withtransverse white indentations called ‘Mees’ or‘Aldrich-Mees’ lines [221].

3.2.9. Neurological effectsSeveral studies indicate that ingestion of inor-

ganic arsenic can result in neural injury. Acutehigh exposure (1 mg As kg−1 per day or more)often causes encephalopathy with symptoms asheadache, lethargy, mental confusion, hallucina-tion, seizures and coma [222]. Intermediate andchronic exposures (0.05–0.5 mg As kg−1 per day)cause symmetrical peripheral neuropathy, whichbegins as numbness in the hands and feet but latermay develop into a painful ‘pins and needles’sensation [223], wrist or ankle drop [224], asym-metric bilateral phrenic nerve [225], and periph-eral neuropathy of both sensory and motorneurons causing numbness, loss of reflexes, andmuscle weakness [226,227].

3.2.10. De�elopmental effectsIt is not well established whether ingestion of

inorganic arsenic can cause developmental abnor-malities in humans. No overall association be-tween arsenic in drinking water and congenitalheart defects is found in a case-control study inBoston [228], although an association with coarc-tation of the aorta is noted.

Some researchers find that babies born towomen exposed to arsenic dusts during pregnancyhas a higher than expected incidence of congenitalmalformations [229,230], below average birthweight [231]. The incidence of spontaneous abor-tion in women who lived near a copper smelter inSweden tends to decrease as a function of distance[231], and in Eastern Massachusetts [232]. A cou-ple of studies reported an increased number ofmiscarriages among women who worked in thesemiconductor industry, which caused arsine[233,234].


3.2.11. Reproducti�e effectsFor over 50 years, it is known that inorganic

arsenic readily crosses the placental barrier andaffects fetal development [235]. Organic arsenicalsdo not seem to cross the placenta so readily andare stored in the placenta [236]. There is an exten-sive documentation of experimental induction ofmalformations in a variety of species [235] withincreased fetal, neonatal and postnatal mortali-ties, and elevations in low birth weights, sponta-neous abortions, still-birth, pre-eclampsia andcongenital malformations.

A series of ecological studies involving workersand their families living in the vicinity of theRonnskar copper smelter in Sweden, for example,reported an increase in the prevalence of low birthweight infants [231], higher rates of spontaneousabortions, elevations in congenital malformationsamong female employees and in women livingclose to the smelter relative to women living fur-ther a field [230], and higher frequency of preg-nancy complications, mortality rates at birth andlow birth weights near a Bulgarian coppersmelter, relative to countrywide rates [237].

3.2.12. Immunologic effectsThe effects on the immune system of inhalation

exposure to arsenic are not well studies. No ab-normalities are detected in the serum levels ofimmunoglobulin of workers exposed to arsenic ina coal burning power plant [238]. At low doses ofarsenite (2×10−6 M) and arsenate (5×10−6 M),phytohemagglutinin (PHA)-induced stimulationof cultured human lymphocytes is increased 49%with arsenite and 19% with arsenate, but at highdoses of arsenite (1.9×10−5 M) and arsenate(6×10−4 M), PHA-induced stimulation is com-pletely inhibited [239] with an impairment of im-mune response. It is also supported by other study[240].

In a follow-up study, Gonsebatt et al. [241]compared lymphocyte-replicating ability in 33 in-dividuals consuming drinking water with a meanarsenic concentration of 37 �g l−1. The peripheralblood lymphocyte count of the arsenic-exposedsubjects is slightly increased relative to the con-trols (3.1�1.0×106 versus 2.6�1.1×106).

3.2.13. Genotoxic effectsThe repair inhibition may be a basic mechanism

for the comutagenecity and presumably the cocar-cinogenicity of arsenic [242]. Comparisons ofchromosome aberration frequencies induced bytri- and pentavalent arsenic indicate that the triva-lent forms are far more potent and genotoxic thanthe pentavalent forms [243], whereas DMA isgenotoxic in assays using mammalian and humancells [244–246] and MMA is less potent thanDMA, and TMAO is more potent in inducingboth mitotic arrest and tetraploids [245]. It issuggested that the higher mitotic toxicity reportedfor organoarsenicals in some studies is a functionof their greater disruptive effects on the micro-tubular organization of the cell [247].

3.2.14. Mutagenetic effectsMutagenesis includes the induction of DNA

damage and a wide variety of genetic alterations,which can range from simple gene mutations(DNA base-pair changed to grossly visiblechanges in chromosome structure or number clas-togenesis). Some of these changes may cause ge-netic damage transmissible to subsequentgenerations, and/or some may cause cancer ortheir problems in the exposed generation [248–250].

This apparent pardon, plus occasional poorcorrelation between arsenic exposures doses andresultant frequency of chromosomal aberrations,is explained by the concept that arsenic promotedgenetic damage in large part by inhibiting DNArepair [219,251,252]. Enzymes such as superoxidedismutase and catalase that scavenge for oxygen-free radicals seem to provide protection againstarsenic-induced DNA damage, indicating a possi-ble basis for the genotoxic effect of arsenic [253].

3.2.15. Carcinogenic effectsOver 100 years ago [254], it is observed that

patients who received chronic treatment with ar-senical medications have greatly increased inci-dence of both basal cell and squamous cellcarcinomas of the skin. These arsenical skin can-cers commonly occur in the presence of dermato-logic manifestations of arsenicism, and some hasinternal neoplasms that are regarded as arsenical


in origin and much of this type on the popula-tions in the BFD-endemic parts of Taiwan[118,255,256], but there are reports of elevatedcancer risks at multiple sites (notably lung, skin,bladder, kidney and liver) from other parts of theworld including Japan, Bangladesh, West Bengal-India, Chile and Argentina where subsets of thepopulation are exposed to arsenic-contaminateddrinking water [15,150,257,258]. A recent analysisby Lewis et al. [259] of cancer incidence amongMormons in Utah finds no evidence of excessdeaths for lung or bladder cancer among males orfemales. However, the study indicates a slightlyelevated, but not statistically significant mortalityfrom kidney cancer in both males and females(SMR=1.75 and 1.60, respectively). The mostimportant studies of exposure through inhalationare based on data obtained from three coppersmelters, in Tacoma (Washington, USA), Ana-conda (Montana, USA) and Ronnskar (Sweden).In all three cohorts, a statistically significant in-crease in lung cancer risk with increasing exposureis demonstrated.

Now it will seem to be a cancer promoter ratherthan a cancer initiator, the risk of cancer that itposed will indeed seem to be dose-dependent, andthat cancer risk will be expected to decline againwhen the arsenic exposure ceases and the sub-stance is cleared from the body. Lee-Feldstein[260], and Nordberg and Anderson [261] sug-gested an alternate mechanism, which was thatarsenate is incorporated in the DNA in place ofphosphate. This explanation of consistent withobservations that arsenate must be present duringDNA synthesis in order to be effective. This alsoexplains why arsenic is clastogenic, since the arse-nate�phosphate bond will be weaker than thenormal phosphodiester bond [262].

3.2.16. Diabetes mellitusDiabetes mellitus has been linked with drinking

water arsenic exposure. Lai et al. [263] assessedthe relationship between ingested inorganic ar-senic and prevalence of diabetes mellitus in 891adults residing in southern Taiwan. Their studyfinds that residents in the BFD–endemic areashas a twofold increase in the prevalence of dia-betes mellitus (after adjustment for age and sex)

when compared to residents in Taipei and theentire Taiwan population. Tsai et al. [264] re-ported an excess mortality from diabetes amongthe arsenic exposed population in four townships,relative to local and national rates. The incidenceof diabetes mellitus in a cohort of inhabitants ofthe Taiwan BFD area is related to the cumulativeexposure to arsenic in drinking water [265].

Rahman et al. [266,267] used the presence ofkeratosis as an indicator of arsenic exposure andshowed elevated risks for diabetes in those ex-posed to arsenic in their drinking water (preva-lence ratio=5.9) in Bangladesh, whereas in theUtah mortality study, Lewis et al. [268] failed tofind significant excess in the number of deathsfrom diabetes in males and females exposed toelevated levels of arsenic in drinking water. Twooccupational studies find an association betweenarsenic exposure and diabetes mellitus amongglass workers in Bangladesh [269] and a case-ref-erent study in the Ronnskar cohort [270].

3.2.17. Biochemical effectsArsenic compounds are known to inhibit more

than 200 enzymes in humans [271]. Kulanthaivelet al. [272] noted the catalytic action of vicinalthiol groups and that phenylarsine oxide (PAO)inhibited Na+ and H+ efflux of human placentalNa+–H exchanger [271]. Sheabar and Yanni[273] investigated the in vitro effects of arsenite onhuman blood enzymes. There is a 70–80% inhibi-tion of glutamylpyruvate transaminase, and glu-tathione peroxidase is also affected adversely by0.8 mg As l−1. Also, blood glucose-6-phosphataseand cholinesterase are completely inhibited. Otherstudies show that sodium arsenite causes amarked increase in the cellular heme oxygenaseactivity of human Hela cells [274]. Arsenite israpidly and extensively accumulates in the liver,where it inhibits NAD-linked oxidation of pyru-vate or alpha-ketoglutarate. This is occurred bycomplexation of trivalent arsenic with vicinal thi-ols necessary for the oxidation of these substrates[235].

The theory that altered DNA repair is the causeof arsenic carcinogenesis, is particularly attractivebecause trivalent arsenic species, such as arsenite,can bind strongly to dithiols as well as free


sulfhydryl groups [275,276]. Such protein bindingcan induce inhibited DNA repair, mutation in keygenetic sites, or increased cell proliferation, whichcould then lead to subsequent mutation via inhib-ited DNA repair.

4. Arsenic episodes round the world

Arsenic poisoning episodes have been reportedall over the world. Exposure to arsenic may comefrom natural sources, from industrial sources, orfrom food and beverages. So, arsenic episodes allover the world are divided into three categories:1. Natural groundwater arsenic contamination.2. Arsenic contamination from industrial source.3. Arsenic contamination from food and

beverage.

4.1. Natural groundwater arsenic contamination

Background concentrations of arsenic ingroundwater are in most countries less than 10 �gl−1 [277] and sometimes substantially lower.However, values quoted in the literature shows avery large range from �0.5 to 5000 �g l−1 (i.e.four orders of magnitude). This range occurs un-der natural conditions. High concentrations ofarsenic are found in groundwater in a variety ofenvironments. This includes both oxidizing (underconditions of high pH) and reducing aquifers andin areas affected by geothermal, mining and in-dustrial activity. Most high-arsenic groundwaterprovinces are the result of natural occurrences ofarsenic.

4.1.1. Taiwan incidentThe arsenic contamination incident in well wa-

ter on the south-west coast of Taiwan (1961–1985) is well known [278–280]. The population ofendemic area is about 140,000. In the villagessurveyed, the arsenic content of the well waterexamined, ranges from 0.01 to 1.82 mg l−1. Mostof the well water in the endemic area has arseniccontent around 0.4–0.6 mg l−1. The predominantarsenic species in the well waters is iAsIII with anaverage iAsIII to iAsV ratio of 2.6. Chronic arseni-

cism is observed in a population of 40,421 in 37villages, and 7418 cases of hyperpigmentation,2868 of keratosis, 360 of BFD patients [281], andsome cases of cancer (liver, lung, skin, prostate,bladder, kidney) [281–285] are observed. Thesource material of the arsenic is likely to bepyretic material or black shale occurring in under-lying geological strata [278]. It is thought at be-ginning that arsenic alone is responsible for BFDof the area [286]. The discovery in 1975 of fluores-cent compounds in these well waters leads to theisolation of humic substances, which in combina-tion with arsenic is thought to be probable causefor the BFD [287]. To save the people of theTaiwan endemic areas, a water treatment plant isrun to remove arsenic from groundwater beforeuse.

4.1.2. Antofagasta, Chile incidentAbout 130,000 inhabitants of the city has been

drinking supplied water with high content of ar-senic (0.8 mg l−1) for 12 years from 1959 to 1970[288]. The source of the high arsenic content inwater is the Tocance River, of which water comesfrom the Andes Mountain at an altitude of 3000m and is brought 300 km to Antofagasta. At thebeginning of 1960s, the first dermatological mani-festation was noted, especially in children [288].Peripheral vascular manifestations in these chil-dren included Raynaud’s syndrome, ischemia ofthe tongue, hemiplegia with partial occlusion ofthe carotid artery, mesenteric arterial thrombosisand myocardial ischemia. One autopsy showedhyperplasia of the arterial media. In a survey of27,088 school children, 12% are found to have thecutaneous changes of arsenicism, one-fourth toone-third of these has suggestive systematic symp-toms. Eleven percent has acrocyanosis. Of theAntofagastan residents, 144 have abnormal skinpigmentation, compared with none in the 98 con-trol subjects. Recent studies [212,289] also docu-ment arsenic-induced skin lesions, and increasedbladder and lung cancer mortality in NorthernChile.

To save the people, a water treatment plant isrun to remove arsenic from drinking water beforeuse. The sources of arsenic have been reported asquaternary volcanogenic sediments, minerals and


soil [290]. Samples taken from 23 locations atAracamenan settlements near Calama range fromless than 100 to more than 800 �g As l−1. Mostof the arsenic is present as arsenate, but somearsenite is also determined. Five soils irrigatedwith high arsenic waters range from 86 to 446 mgAs kg−1 compared to 64 mg As kg−1 in onecontrol sample.

4.1.3. West Bengal-India incidentAround 1978 various aspects of arsenic ground-

water contamination and arsenicosis among peo-ple in some villages of West Bengal first came tothe notice of Government of West Bengal [291].Several recent studies [22,63,67,151,291–294] re-port that about 6 million people of 2600 villagesin 74 arsenic-affected blocks of West Bengal, In-dia are in risk and 8500 (9.8%) out of 86,000people examined are suffering from arsenicosis,while the source is oxidation of arsenic rich pyriteor anoxic reduction of ferric iron hydroxides inthe sediments to ferrous iron and thereby releas-ing the adsorbed arsenic to groundwater.

4.1.4. Mexico incidentChronic arsenic exposure via drinking water is

reported in six areas of Region Lagunera, situatedin the central part of North Mexico with a popu-lation of 200,000 during 1963–1983 [295]. Therange of total arsenic concentrations is 0.008–0.624 mg l−1, and concentrations greater than0.05 mg l−1 are found in 50% of them. Most ofthe arsenic is in inorganic form and pentavalentarsenic is the predominant species in 93% of thesamples [61]. In 36% of the rest samples, however,variable percentages (20–50%), of trivalent ar-senic are found. It is also observed that highconcentrations of fluoride in the range of 0.5–3.7mg l−1 and concentrations greater than 1.5 mgl−1 are found in 20% of the analysed samples[296].

The symptoms observed in this area are cuta-neous manifestations (skin pigmentation changes,keratosis and skin cancer), peripheral vasculardisease (BFD), gastrointestinal disturbances andalteration in the coporphyrin/uroporphyrin excre-tion ratio [297]. It is found that the proportion of

individuals (per age group) affected with cuta-neous lesion increase with age until the age of 50.The shortest is 8 years for hypopigmentation, 12years for hyperpigmentation and palmo-planterkeratosis, 25 years for papular keratosis and 38years for ulcerative lesions [298]. The source ofarsenic is assumed to be geological (volcanic sedi-ment) [61].

4.1.5. Argentina incidentSimilar incident of arsenic contamination in

groundwater is also reported in Monte Quemadoof Cordoba province, north of Argentina [62].The occurrence of endemic arsenical skin diseaseand cancer is first recognized in 1955. Total popu-lation of the endemic area is about 10,000. Fromthe observations in the Cordoba, it is concluded[62,209] that the regular intake of drinking watercontaining more than 0.1 mg l−1 of arsenic leadsto clearly recognizable signs of intoxication andultimately might develop into skin cancer. Biaginifollowed 116 patients with clear signs of chronicarsenic disease over a number of years [299]. After15 years of follow-up, 78 had died, 24 from cancer(i.e. 30.7% of total deaths). In Monte Quemado,the problem seems to be ultimately solved bybuilding a canal that supplies the town with ar-senic free water from Salta province.

Again, elevated concentrations of arsenic insurface waters, shallow wells and thermal springsare reported from the Salta and Jujay provinces innorthwestern Argentina [300]. This natural con-tamination is related to Tertiary-Quaternary vol-canic deposits, together with post-volcanic geysersand thermal springs. Waters abstracted for drink-ing supplies for the population of 5000 in thetown of San Antonio de los Cobres ranges from0.47 to 0.77 mg l−1. Thermal springs range from0.05 to 9.9 mg l−1 of arsenic.

A strong natural contamination of groundwaterwith arsenic and selenium is reported in thePampa Province of Cordoba, southeast Ar-gentina. The arsenic content of nearly 50% of thewater samples from this area ranges from 0.1 to0.316 mg l−1 with a maximum value of 3.81 mgl−1 [64,301]. Groundwater contamination iscaused from loess, which differed in composition


to loess from Europe, Asia and North America[64], with arsenic concentrations ranging from 5.5to 37.3 mg kg−1, and rhyolitic volcanic glassranging from 6.8 to 10.4 mg kg−1.

4.1.6. Millard County, Utah, USA incidentWest Millard County is a desert area with low

population density and around 250 people drink-ing well water of arsenic content between 0.18 and0.21 mg l−1 and the predominant arsenic speciesis arsenate (86% As5+) [302]. Participants areexamined for specific signs of arsenic toxicity in-cluding palmer and plantar (palms and soles)keratoses, diffuse palmer and plantar hyperker-atoses and skin suggestive of arsenic toxicity israre, with only 12 of 149 participants having anysigns associated with arsenic ingestion. Partici-pants from Deseret have the highest average ar-senic in urine concern of 0.211 mg l−1 (n=40)and that of Hinckley participants have 0.175 mgl−1 (n=95) compared to control from Delta of0.048 mg l−1 (n=99). The highest average arsenicconcentration in hair is 1.21 mg kg−1 (n=80)from Hinckley residents and that of Deseret resi-dents is 1.09 mg kg−1 (n=37) compared to con-trol from Delta of 0.32 mg kg−1 (n=68). Lewiset al. [303] recently reports hypertensive heartdisease, nephritis, nephrosis, and prostate canceramong the people of the arsenic-affected areas inUtah.

4.1.7. Lane County, Western Oregon, USAincident

Well water in Central Lane County [304], lo-cated in Western Oregon about midway betweenthe Colombia river and the northern boundary ofCalifornia gets contaminated with arsenic duringNovember 1962–March 1963. The concentrationrange of arsenic in wells is 0.05–1.7 mg l−1. Wellsin Eugene, Creswell, and Grove districts in Cen-tral Lane County which were known to yieldarsenic rich groundwater are in an area underlainby a particular group of sedimentary and volcanicrocks, which geologists have named the Fisherformation [305]. The largest concentrations ofarsenic are found in samples from the Creswelldistrict.

4.1.8. Lessen County, California, USA incidentIn the Lessen County, California, similar ar-

senic poisoning in well water is observed. Therange of arsenic in the well water is 0.05–1.4 mgl−1. It is found that arsenic is present in drinkingwater above 0.05 (�0.03) mg l−1 and an in-creased level of arsenic in their hairs reflects bodyburden due to arsenic exposure [306].

4.1.9. Ontario, Canada incidentIn 1937, Wyllie [307] reported that water from

some deep wells in Rocky Mountain areas ofOntario, Canada were known to contain largeamounts of arsenic. The source of arsenic in wellwater is ferrous arsenate where arsenic in watervaries from 0.10 to 0.41 mg l−1 as As2O3. Prelim-inary experiments show that arsenic as arsenate isthe primary source of arsenic, which contami-nated the well water. One person died of arsenicdermatosis. The whole family members of thevictim died are also afflicted due to this arsenicpoisoning.

4.1.10. No�a Scotia, Canada incidentIn 1976, several wells in Halifax County, Nova

Scotia are contaminated with arsenic [308] withconcentration greater than 3 mg l−1. More than50 families have been affected due to arsenicpoisoning [309]. Recently, Boyle et al. [310] re-ports also occurrences of elevated arsenic concen-trations in bedrock groundwaters used forindividual and municipal water supplies in themainland coast of southern British Columbia,Canada.

4.1.11. Hungary incidentIn Hungary also similar arsenic contamination

in the well water is observed [311,312] in the years1941–1983. The amount of arsenic present in thewell water is in the range of 0.06–4.00 mg l−1.Recently, concentrations of arsenic above 50 �gl−1 are identified in groundwaters from alluvialsediments associated with the River Danube inthe southern part of the Great Hungarian Plain.Concentrations up to 150 �g l−1 (average 32 �gl−1, 85 samples) are found by Varsanyi et al. [54].The Plain, some 110,000 km2 in area, consists of athick sequence of subsiding Quaternary sedi-


ments. The groundwaters have highest arsenicconcentrations in the lowest parts of the basin,where the sediment is fine-grained [54]. A fewthousand people are affected and several symp-toms of arsenic poisoning viz, melanosis, hyperk-eratosis, skin cancer, internal cancer, bronchitis,gastroenteritis, haematologic abnormalities arefound among them [313].

4.1.12. New Zealand incidentIn 1939, Grimmet and McIntosh described ar-

senic contamination of groundwater and the re-sulting effects on the health of livestock [314].Later on in 1961, high levels of arsenic werefound in water from areas of thermal activity.Thermal waters in New Zealand contain up to 8.5mg As l−1 [315]. Aggett and Aspell [316] studiedthe chemical forms of arsenic in water samples. Inthe geothermal bores, more than 90% of the ar-senic is present in the trivalent form.

4.1.13. Poland incidentA small case is observed in Poland in 1898 [317]

with some skin cancer among the arsenic affectedpersons. It is interesting to note that there is nopublished data on this incident.

4.1.14. Fairbanks, Alaska incidentIn the well water, spring of Fairbanks, Alaska,

arsenic is found above 0.05 mg l−1. The study isinitiated to evaluate the arsenic content of streamsand groundwaters of the Pedro-Dome ClearySummit area approximately 30 km north of Fair-banks, Alaska in the heart of the historic Fair-banks Mining District. Arsenic is associated withgold mineralization here and is believed to reachthe water of the area through weathering of ar-senic containing rocks.

The arsenic concentrations in 53 water samplesfrom wells and springs range from less than 0.005to 0.07 mg l−1. Eighty percent of the samplescontain less than 0.01 mg l−1 and 95% of thesamples contained less than 0.05 mg l−1 [318].The arsenic levels in 243 well water range fromless than 0.05 to greater than 0.10 mg l−1. About28% of the samples contain arsenic less than 0.05mg l−1, 40% of the samples contained less than0.10 mg l−1 and about 20% of the samples con-

tain greater than 0.10 mg l−1. Well water arsenicconcentrations in the Ester Dome study arearange from less than 1.0 to 14 mg l−1 and for thestudy population range from less than 1.0 to 2.45mg l−1 with a mean of 0.224 mg l−1. An epidemi-ological study was made in 1976 [319], whichsuggested no clinical or haematological abnormal-ities among these people. Urine arsenic levelsabove 0.02 mg l−1 are found in 130/198 (66%),hair arsenic levels above 1 mg kg−1 occur in74/181 (41%) and nail arsenic levels above 4 mgkg−1 in 49/132 (37%) of the study population.

4.1.15. Srilanka incidentIn a clinical study of 13 cases of polyneuropa-

thy connected with arsenic poisoning, in Srilanka,Senanayake et al. [320] found Mee’s line, i.e.transverse white bands across finger nails, to bethe constant feature at least 6 weeks after theonset of initial symptoms. In seven of these cases,the source of arsenic was contaminated well wa-ter, four others had a long history of consumingillicit liquor.

4.1.16. Spain incidentManzano and Tellow summarized their experi-

ences in treating arsenic poisoning caused by wellwater in certain areas of Spain [321].

4.1.17. China incidentDuring the 1980s, the endemic arsenicosis was

found successively in many areas on mainlandChina such as Xinjiang Uygur A. R., Inner Mon-golia, Shanxi, Liaoning, Jilin, Ningxia, Qinghai,and Henan provinces [322–328]. The arsenic con-centration in the groundwater in these affectedareas is in the range of 220–2000 �g l−1 with thehighest level at 4440 �g l−1. Consequently, a largesector of the rural population has been exposed tochronic arsenic poisoning (CAP) resulting fromconsuming well water with naturally occurringhigh levels of arsenic during the past decades. Atpresent, the population exposed to high amountsof arsenic is estimated to be over 2 million andmore than 20,000 arsenicosis patients are confi-rmed [328]. The water of the deep-wells, howevercontains fluoride and arsenic [323]. Fluorosis wasfirst found in the 1970s and arsenicism in 1980.


One of the characteristics of the Kuitun case is thefact that there are three groups of patients amongthe residents who drank the same well water for along time. Namely, one group suffers from fluoro-sis, the second group from arsenicism and thethird group from both fluorosis and arsenicismcombined.

The cause of contamination is considered to begeological. Major clinical symptoms observed arekeratosis, pigmentation, melanosis or leucodermaon the skin, often accompanied with peripheralneuritis, gastroenteritis, and hypertrophy of theliver, bronchitis or cardiac infarction. At laterstages skin cancer and gangrene are also found.Feng et al. [329] recently reports DNA damage inbuccal epithelial cells from individuals from thisarsenic-affected area. Various measures are takento supply clean water.

4.1.18. Northern India incidentIn Ropar, Manimajra, Chandigarh, N. Garh,

Patiala and Ambala around Chandigarh of Pun-jab and Haryana of India, the arsenic concentra-tion in water from wells and springs were higherthan the WHO limit of safety for human con-sumption [330] with 0.05–0.545 mg l−1 of arsenic.Cirrhosis (adult and childhood), non-cirrhoticportal fibrosis and extra hepatic portal vein ob-struction in adults are very common in India andsuggests that consumption of arsenic-contami-nated water may have some role in the pathogen-esis of these clinical states [331]. The patients whoconsumed the water containing arsenic 0.545 mgl−1 throughout life are suffering from non-cir-rhotic portal fibrosis (N.C.P.F.), whereas theirtwo relatives consuming same water reveal grosssplenomegaly, but with normal liver function tests[332]. The source of arsenic is still unknown.

4.1.19. Bangladesh incidentSeveral recent studies [23,216,292,333] report

that about 25 million people of 2000 villages in178 arsenic-affected blocks of Bangladesh are inrisk and 3695 (20.6%) out of 17,896 people exam-ined are suffering from arsenicosis, while thesource is oxidation of arsenic rich pyrite or anoxicreduction of ferric iron hydroxides in the sedi-ments to ferrous iron and thereby releasing the

adsorbed arsenic to groundwater. To combat thesituation, Bangladesh need a proper utilization ofits vast surface and rainwater resources andproper watershed management.

4.1.20. Fallon, Ne�ada IncidentIn 1984, Viz et al. [334] were unable to detect

any increase in chromosomal aberrations or sisterchromatid exchange in residents of Fallon, Ne-vada, where drinking water contained about 0.10mg As l−1. From literature it is found that thehealth status of these arsenic exposed populationsis not adversely affected [335].

4.1.21. Fukuoka Prefecture, Japan incidentIn March 1994, arsenic over the permissible

level for drinking use (0.01 mg l−1) is detected inwell waters in the southern region of FukuokaPrefecture, Japan [71]. The highest concentrationfound is 0.293 mg l−1, being quite high comparedto other arsenic-containing well waters reported inJapan as a geological process. The mechanisms ofarsenite/arsenate elution from the soil proposedare which involved: (i) anion exchange with OH−;and (ii) reductive labialization of arsenic throughconversion of arsenate to arsenite.

4.1.22. New Hampshire, USA incidentArsenic concentrations are measured in 992

drinking water samples collected from NewHampshire households and in randomly selectedhouseholds, concentrations ranged from �0.0003to 180 �g l−1, with water from domestic wellscontaining significantly more arsenic than waterfrom municipal sources. Water samples fromdrilled bedrock wells have the highest arsenicconcentrations, while samples from surficial wellshas the lowest arsenic concentrations. The authors[336] suggested that much of the groundwaterarsenic in New Hampshire was derived fromweathering of bedrock materials and not fromanthropogenic contamination. The spatial distri-bution of elevated arsenic concentrations (�50�g l−1) correlates with Late-Devonian Concord-type granite bedrock. Analysis of rock digestsindicates arsenic concentrations up to 60 mg kg−1

in pegmatites, with much lower values in sur-rounding schists and granites.


4.1.23. Vietnam incidentThis is the first publication on arsenic contami-

nation of the Red alluvial tract (Mekong deltaregion) in the city of Hanoi and in the surround-ing rural districts [72]. The contamination levelsvary from 1 to 3050 �g l−1 in rural groundwatersamples from private small-scale tube-wells withan average arsenic concentration of 159 �g l−1. Ina highly affected rural area, the groundwater useddirectly as drinking water has an average concen-tration of 430 �g l−1. Analysis of raw groundwa-ter pumped from the lower aquifer for the Hanoiwater supply show arsenic levels of 240–320 �gl−1 in three of eight treatment plants and 37–82�g l−1 in another five plants. Aeration and sandfiltration that are applied in the treatment plantsfor iron removal lowers the arsenic concentrationsto levels of 25–91 �g l−1, but 50% remains abovethe Vietnamese Standard of 50 �g l−1. The ar-senic in the sediments may be associated with ironoxyhydroxides and releases to the groundwater byreductive dissolution of iron. The high arsenicconcentrations found in the tube-wells (48%above 50 �g l−1 and 20% above 150 �g l−1)indicate that several million people consuminguntreated groundwater may be at a considerablerisk of CAP. No people were found in theseaffected regions with symptoms of chronic arsenictoxicity.

4.2. Arsenic contamination from industrial sources

4.2.1. Ronphibun, Thailand incidentIn 1987, the skin manifestation of CAP was

first diagnosed among the residents of Ronphibundistrict, Nakorn Srithammarat Province [337]. Itis seen that 85% of all reported of CAP are fromRonphibun sub-district of Ronphibun district.Most cases are of relatively mild disease, with21.6%, however having very significant lesions[338]. Rophibun district has eight sub-districtsand 65 villages with a population of 14,085. Threeout of 14 villages of Ronphibun sub-district with19.9% of the population of the sub-district ac-count for 60.9% of the cases. These villages usewater with drains from the high-contaminatedarea of Suan Jun and Ronna Mountains. Theirattack rate is 8.8 times, the rate in the remainder

of the sub-district. This area has 0.1% arsenopy-rite. Recently, Oshikawa et al. [339] reports thelong-term changes in arsenical skin lesions amongthis population. At many sites, the arsenic contentof water exceeds by 8–100 times the 0.05 mg l−1

concentration, which is the accepted safety levelset down by WHO for occasional exposure [15].

4.2.2. Mindanao Island, Philippines incidentSoon after the construction of a geothermal

power plant on Mt. Apo started in January 1992,people living downstream along the Matingao andMarbol rivers which run through the constructionsite, complained of symptoms such as eruption,headache or stomach-ache. An environmental in-vestigation carried out in August 1993, whichrevealed that river water downstream of the con-struction site contained 0.1 mg l−1 of arsenic andhair samples of some residents showed high con-centrations of mercury and manganese as well asarsenic [340]. As a result, the construction of thegeothermal power plant is suspected as the causeof arsenic contamination. In 1995, a medical sur-vey of 39 residents who had rashes on their skinreveals that a few of them are suspected to bepatients suffering from CAP [341].

4.2.3. Nakajo, Japan incidentWaste water from a factory producing arsenic

sulfide contaminated nearby well water in Nakajo,Japan in 1960 [342,343]. In this place a very smallnumber of people drank the well water, which wascontaminated with arsenic (0.025–4.00 mg l−1).Melanosis, hyperkeratosis, cardiovascular disease,hepatopathy, haematologic abnormalities wereobserved among the residents of Nakajo.

4.2.4. Toroku and Matsuo, Japan incidentToroku is a small mountain village to the north

of Miyazaki prefecture with a population ofabout 300 where arsenious acid was produced byroasting arsenopyrite ore from 1920 to 1962 [344].Similarly, Matsuo is a small mountain village inthe north of Miyazaki prefecture. Here, whitearsenic was produced by calcinating arsenopyriteat very primitive stone-made furnaces for nearlyhalf a century since about 1920. In this systemabout 10% or more of As2O3 was lost as fumes


through the refining process. The arsenic-rich re-mains of calcinated ore were dumped into theriver. Many mine workers and nearby residentsdied from acute and sub-acute arsenic poisoning.A 6-year follow-up study reveals a high preva-lence of malignant neoplasms especially in res-piratory tract, which was the main cause of deathin the patient [345]. A total of 147 persons areexamined in the study. Out of them, 125 arediagnosed as CAP. A total of 58 malignant skintumors are noted out of 125 patients with skinlesions of CAP and out of these 58 malignant skintumors, 51 occur on trunk and times. The appear-ance of multiple malignant tumors was noted in24 cases (58.5%), including 15 cases of doublecancers. The phenomenon is noted in 14 cases(42.4%) among cases of malignant skin tumor.Multiple Bowen’s disease is found in 12 cases(37.5%). As of 1995, there were 153 patients inToroku and 64 in Matsuo who are recognized bythe government as suffering from CAP [346].

4.2.5. Other incidents in JapanA severe cutaneous manifestations of CAP are

detected in seven out of 28 male Japanese work-ers, who are exposed to arsenic in the form of leadarsenate and Ca3AsO4 in the manufacture of in-secticides [347]. The lesions are symmetric punctu-ated palmo-planter hyperkeratosis and bronzehyper-pigmentation.

A retrospecific cohort study of a Japanese pop-ulation in between 1954 and 1959 used well watercontaminated with arsenic from a dye factory.During the follow-up period until 1987, therewere 18 deaths from cancer, of which seven fromlung cancer and six in the high exposure group[348].

4.2.6. P.N. Mitra Lane, Behala, Calcutta, Indiaincident

Arsenic contamination episode in residentialarea of Behala, Calcutta during 1969–1989 is wellknown [68,92,349]. The concentration of arsenicin the tube-well water varies from 0.05 to 58 mgl−1. Chronic arsenic toxicity, resulting fromhousehold use of arsenic contaminated water oc-curs in 53 out of 79 members (67% of 17 families)residing near this factory area within age range

1–69 years. Typical skin manifestations are foundin all of them but pulmonary symptoms arepresent in 40% and neurological symptoms in 65%of cases. Hematomegaly (2–6 cm) is found in 80%of cases and splenomegaly (1.5–2.6 cm) in 35% ofcases. A few died due to arsenicosis.

4.2.7. Rajnandgaon district, Madhya Pradesh,India incident

Arsenic contamination of groundwater inKoudikasa village of Rajnandgaon district, Mad-hya Pradesh-India with a population of 1.5 mil-lion was reported first on 1999 [350]. Most of thevillagers of Koudikasa used water from a forestdug-well (0.52 mg As l−1) along with a PHEDtube-well (0.88 mg As l−1). Out of the totalnumber of adults (150 nos.) and children (58 nos.)examined at random, 42 and 9%, respectively,have arsenical skin lesions. The source of arseniccontamination is speculated to be due to percola-tion of gold and uranium mine’s tailings.

4.2.8. Australia incidentIn Australia, old stocks of lead arsenate, that

was used as pesticides prior to 1970 remained insheds and caused chronic poisoning among theworkers [351].

4.2.9. Czechoslo�akia incidentPeople living near a plant burning arsenic con-

taminated coal containing 900–1500 mg As kg−1

was responsible for the episode [352].

4.2.10. Toronto, Ontario, Canada incidentVegetation and soil samples collected in 1974 in

the vicinities of two secondary lead smelters lo-cated in a large urban area near Toronto, On-tario, Canada showed arsenic concentrations over30 times higher than normal urban backgroundlevels of arsenic in unwashed plant foliage and200 times higher than normal soil which werefound about 200 m away from the smelters. Alarge number of people were found suffering fromarsenic toxicity in this region [353].

4.2.11. Greece incidentSystematic sampling of soils and dusts in and

around the ancient lead mining and smelting site


at Lavrion, Greece, indicated extensive contami-nation with arsenic as well as lead and had insti-gated studies into possible health implications tothe local community [354]. Concentrations of ar-senic in garden soils and house dusts were rangedup to 14,800 and 3800 mg kg−1, respectively.

4.2.12. Ghana incidentArsenic in drinking water from streams, shal-

low wells and boreholes in the Obuasi gold-min-ing area of Ghana ranges from �0.002 to 0.175mg l−1. The main source of pollution is due tomining activities and oxidation of naturally occur-ring sulfide minerals, predominantly arsenopyrite(FeAsS). Some of the water samples have higharsenite content. Soils are leached kaolinite–mus-covite laterites overlying saprolite [355]. It is re-ported that in the saprolite, arsenopyrite appearsto have been replaced by secondary As- and Fe-bearing minerals, including scorodite(FeAsO4·2H2O), arsenolite and arsenates [356].

4.2.13. USA incidentThe serious incident of air pollution by arsenic

from copper smelters in the U.S. is recorded inAnaconda, Montana [357,358] with the rate ofemissions of arsenic trioxide of 16,884 kg per day.Although no atmospheric concentrations are inrecord, edible plants contain arsenic trioxide up to482 �g g−1, causing serious health hazard sur-rounding the area. Mortality from ischemic heartdisease is significantly increased among arsenicexposed workers of this smelter [359]. The initial1938–1963 mortality analysis of workers at thecopper smelter at Anaconda, Montana, demon-strated a more than threefold excess respiratorycancer ratio, with an excess risk as high as high aseightfold among heavily exposed men who hadworked there 8 years or more [360]. A seriousincident of air pollution by arsenic also occurs ina small Western town near a gold-smelter, USAmanufacturing 36 tons of arsenic trioxide per day[361].

Some studies [362,363] involved a copper smelt-ing plant at Tacoma in the state of Washingtonthat produced As2O3 as a by-product. The planthad an average employment of 904 during theyears 1944–1960 when a total of 229 deaths were

reported among active plant employees, 38 of thedeath were classified as exposed to arsenic. Out ofthese six died of cancer, including three cases ofcancer of the respiratory tract.

In literature [364], Perham was a town of 1900situated on the agricultural area of western Min-nesota, USA and a core sample to a depth of 20cm revealed 3000 parts per million (mg l−1) ofarsenic. The symptoms of sub-acute or chronicarsenic intoxication were confirmed to the threepersons out of 13 with the highest intake.

4.2.14. British incidentIn 1910 and 1943, a British plant manufactured

a sodium arsenite sheep dip [365,366]. The factorywas in a small county town within a specific birthand death registration sub-district. Here 75 deathsare reported among factory workers 22 (29%) dueto cancer.

4.2.15. Southern Rhodesia incidentThere was excess lung cancer mortality among

southern Rhodesia miners of gold bearing orescontaining large amounts of arsenic [367].

4.2.16. Torreon, Mexico incidentIn the city of Torreon, Mexico, Espinosa Gon-

zalez [368] reported the presence of arsenic indrinking water from a deep well range from 4 to6 mg l−1. In Silesia, Mexico the concentration ofarsenic in spring water arose through leaching ofarsenic wastes from mining operations (coalpreparations wastes and fly ash from coal-firedpower plants) into spring water leading to con-tamination [369].

4.2.17. Northern Sweden incidentAt the Ronnskar smelter in northern Sweden,

ores with a high arsenic content were handled.Women employed in the plant as well as thosewho lived nearby deliver babies having signifi-cantly lower weight than those delivered bywomen who are not so exposed [231]. Amongthose same women, the frequency of spontaneousabortion is generally higher with closer proximityof residence to the smelter [232]. Although resi-dential proximity to the Ronnskar smelter has noeffect on the incidence of congenital malforma-


tions, pregnancies during which the mother hadworked at the smelter are significantly more apt tobabies with single or multiple malformations, par-ticularly urogenital malformations or hip-jointdislocation [231].

4.2.18. Armadale, central Scotland incidentIn Armadale, a town in central Scotland

[370,371] having population 7000, the standard-ized mortality ratio (SMR) for respiratory cancerare high and high sex-ratios of births were ob-served during 1969–1973 which was due to ar-senic contamination from a steel foundry locatedin that area. The arsenic concentrations in soilsamples in Armadale were higher (52–64 �g g−1)than those in the white burn soils.

4.2.19. Srednogorie, Bulgaria incidentHeavy air pollution as well as high arsenic

contamination of soil occur due to copper smelterlocated in close vicinity to the Srednogorie [372]with a population of 32,000 inhabitants and con-stituted the largest metallurgical center in Bul-garia. The smelter started operation in 1959 andhad been processing high arsenic containingsulfide ores, mainly from Tjelopet ch causing con-tamination of Topolnitza river water having ar-senic concentration of 0.75–1.5 mg l−1 during thetime period of 1987–1990. The aerial emission isestimated at 50–100 tons per year. Exposure tothe general population is mostly by inhalation andpartly by ingestion of locally produced food prod-ucts, like vegetables. Several health hazards areobserved around the area of the exposed popula-tion with high arsenic content in hair, nails andurine.

4.3. Arsenic contamination from food andbe�erage

4.3.1. Soyasauce incident in JapanSeveral instances of accidental arsenic poison-

ing through contaminated food-stuffs are re-ported in Japan. Soyasauce, which containedarsenic at 5.6–71.6 mg l−1, is implicated in atoxicity outbreak. The arsenic is in the aminoacids (260–275 mg l−1) used in making the sauce;hydrochloric acid may have been the source of

arsenic in the preparation of amino acid [373].Mizuta et al. [374] examined 220 out of 417patients, who had been poisoned by Soyasaucecontaminated with inorganic arsenic at a concen-tration of 0.1 mg l−1. The average estimatedinjection of arsenic per person was 3 mg, daily for2–3 weeks. The main findings are facial oedema,anorexia, and upper respiratory symptoms fol-lowed by skin and neuritic signs at a later stage,i.e. after 10–20 days. Though the livers of mostpatients were enlarged, relatively few abnormali-ties were found in the liver function tests and liversize gradually decreased after cessation of expo-sure. Abnormal electrocardiograms are found in16 out of 20 cases tested [375].

4.3.2. Powdered milk incident in JapanContaminated powdered milk was implicated in

a similar outbreak in Japan. It contains arsenic at13.5–21 mg kg−1 [376]. Contamination of themilk is from sodium phosphate (7.11% arsenic)used in its manufacture [377].

4.3.3. Wine incident in Manchester, EnglandAbout 500 patients of North England drinking

arsenic contaminated beer of 2–16 pints a day(1.14–9.12 l per day) for many months developedcardiac, skin, neurological symptoms, either pre-dominated or were equally mixed [378]. Repeatedtestimony before the Royal commission by vari-ous chemists demonstrated repeatedly the pres-ence of toxic amount of arsenic in beer fromseveral parts of the country [379,380].

4.3.4. Wine Incident in GermanyExposure to arsenic-containing pesticides and

contaminated wine is claimed to be the causativefactor in the large number of cases of liver cirrho-sis among German vintners in the 40s and 50s[381]. It is found that out of 180 vinedressers andsellarman with symptoms of CAP about 23% hasevidence of vascular disorders of the extremities[382]. Of 27 moselle vintners autopsied between1950 and 1956, 11 had lung cancers and three hadhepatic angiosarcomas [383]. The number of casesdiminished in the late 50s; however, less severeliver changes continued to be found regularlyamong the vintners [384,385]. In a 1960–1977


series of 163 postmortem examinations of Ger-man wine growers diagnosed on the basis ofcutaneous signs as having had CAP. Luchtrath[386] found five cases with liver tumors, none wereangiosarcomas.

4.3.5. Guizhou Pro�ince, China IncidentIn the Guizhou province, some coals contain

high arsenic (100–9600 mg kg−1) and fluorineand caused arsenic poisoning among residents inone city and four prefectures. Approximately,3000 patients were found by 1992. According tothe research carried out by the Institute of Geo-chemistry of the Academia sinica during 1991 and1994 in Xingren County, among 9202 people in-vestigated, 1546 people were affected by arseni-cism. The average daily intake of arsenic perperson in the affected area was estimated to be 2.4mg of which 87.92% came from food, 5.53% fromair and 6.55% from drinking water. In additionsto skin lesions characteristic of arsenic poisoning,many cases of them are cirrhosis, ascites, polyneu-titus and skin cancer. Drastic measures are badlyneeded to identify alternatives to coal [387].Zheng and Long [388] and Sun et al. [328] re-cently report about this incidence.

4.3.6. Yunan Incident, ChinaThe typical type of arsenic poisoning was found

in 1993 in a non-ferrous smelter township with apopulation over 100,000 in the southern Yunanprovince, Dali. The air-arsenic concentrationcaused by smelter contaminants always exceededthe National maximum allowable (0.003 mg m−3)by several-fold contaminating the food (rice, corn)grown in the area [328]. It (food) is responsiblefor more than 90% of total arsenic intake, only10% or less is directly from inhalation. By inter-polation, the daily arsenic intake is in the range of0.3–1.1 mg. In 1992 WHO suggested ‘a dailyintake of 2 �g of inorganic arsenic per kg bodyweight, that should not be exceeded’ [389].

Acknowledgements

The authors acknowledge the help of JapanSociety for the Promotion of Science, JSPS Fel-

lows Plaza, Japan for the financial support to DrBadal Kumar Mandal who is working in thisUniversity. This study was supported by Grants-in-Aid of Ministry of Education, Science, Sportsand Culture (Nos. 12000236 and 12470509). Also,the authors thank Dr T. Roy Chowdhury, NIHS,Tokyo, Japan for his cordial help for the prepara-tion of this manuscript.

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arsenic round the world

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