arsenic compounds

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ARSENIC AND ARSENIC COMPOUNDSArsenic and arsenic compounds were considered by previous IARC Working Groups in1979, 1987, and 2002 ( IARC, 1980, 1987, 2004 ). Since that time, new data have become avail-able, these have been incorported in the Monograph , and taken into consideration in thepresent evaluation.

1. Exposure Data

1.1 Identi cation o the agents

In ormation on the physical and chemicalproperties o arsenic and arsenic compounds canbe ound in able 1.1, or urther details pleasere er to IARC (1980). Te list is not exhaus-tive, nor does it comprise necessarily the mostcommercially important arsenic-containing

substances; rather, it indicates the range o arsenic compounds available.

1.2 Chemical and physical propertieso the agents

Arsenic (atomic number, 33; relative atomicmass, 74.92) has chemical and physical proper-ties intermediate between a metal and a non-metal, and is o en re erred to as a metalloidor semi-metal. It belongs to Group VA o thePeriodic able, and can exist in our oxidationstates: 3, 0, +3, and +5. Arsenite, As III, and arse-nate, AsV, are the predominant oxidation statesunder, respectively, reducing and oxygenatedconditions ( WHO, 2001; IARC, 2004).

From a biological and toxicological perspec-tive, there are three major groups o arseniccompounds:

-inorganic arsenic compounds,-organic arsenic compounds, and-arsine gas.O the inorganic arsenic compounds, arsenic

trioxide, sodium arsenite and arsenic trichlorideare the most common trivalent compounds,and arsenic pentoxide, arsenic acid and arse-

nates (e.g. lead arsenate and calcium arsenate)are the most common pentavalent compounds.Common organic arsenic compounds includearsanilic acid, methylarsonic acid, dimethyl-arsinic acid (cacodylic acid), and arsenobetaine(WHO, 2000).

1.3 Use o the agents

Arsenic and arsenic compounds have beenproduced and used commercially or centuries.Current and historical uses o arsenic includepharmaceuticals, wood preservatives, agricul-tural chemicals, and applications in the mining,metallurgical, glass-making, and semiconductorindustries.

Arsenic was used in some medicinal applica-tions until the 1970s. Inorganic arsenic was used

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IARC MONOGRAPHS 100C

in the treatment o leukaemia, psoriasis, andchronic bronchial asthma, and organic arsenicwas used in antibiotics or the treatment o spiro-chetal and protozoal disease ( A SDR, 2007).

Inorganic arsenic is an active component o chromated copper arsenate, an anti ungal woodpreservative used to make pressure-treatedwood or outdoor applications. Chromatedcopper arsenate is no longer used in residentialapplications, ollowing a voluntary ban on its usein Canada and the United States o America atthe end o 2003.

In the agricultural industry, arsenic hashistorically been used in a range o applications,including pesticides, herbicides, insecticides,cotton desiccants, de oliants, and soil sterilants.

Inorganic arsenic pesticides have not been usedor agricultural purposes in the USA since 1993.

Organic orms o arsenic were constituents o someagricultural pesticides in the USA. However, in2009, the US Environmental Protection Agency issued a cancellation order to eliminate and phaseout the use o organic arsenical pesticides by 2013 (EPA, 2009). Te one exception to the orderis monosodium methanearsonate (MSMA), abroadlea weed herbicide, which will continue tobe approved or use on cotton. Small amountso disodium methanearsonate (DSMA, or caco-dylic acid) were historically applied to cotton

elds as herbicides, but its use is now prohibitedunder the a orementioned US EPA 2009 organicarsenical product cancellation. Other organic

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Table 1.1 Chemical names, CAS numbers, synonyms, and molecular formulae of arsenic andarsenic compounds

Chemical name CAS Reg. No. Synonyms Formula

Arsanilic acid 98-50-0 Arsonic acid, (4-aminophenyl)- C 6H8AsNO3Arsenica 7440-38-2 Metallic arsenic AsArsenic(V) pentoxide b 1303-28-2 Arsenic oxide [As2O5] As2O5Arsenic(III) sul de 1303-33-9 Arsenic sul de [As 2S3] As2S3Arsenic(III) trichloride 7784-34-1 Arsenic chloride [AsCl 3] AsCl3Arsenic(III) trioxide a,c 1327-53-3 Arsenic oxide [As2O3] As2O3Arsenobetaine 64436-13-1 Arsonium, (carboxymethyl) trimethyl-, hydroxide,

inner salt; 2-(trimethylarsonio)acetateC5H11AsO2

Arsine 7784-42-1 Arsenic hydride AsH 3Calcium arsenate 7778-44-1 Arsenic acid [H 3AsO4] calcium salt (2:3) (AsO 4)2.3CaDimethylarsinic acid 75-60-5 Cacodylic acid C 2H7AsO2Lead arsenate 7784-40-9 Arsenic acid [H 3AsO4], lead (2+) salt (1:1) HAsO 4.PbMethanearsonic acid,disodium salt

144-21-8 Arsonic acid, methyl-, disodium salt CH3AsO

3.2Na

Methanearsonic acid,monosodium salt

2163-80-6 Arsonic acid, methyl-, monosodium salt CH 4AsO3.Na

Potassium arsenate d 7784-41-0 Arsenic acid [H 3AsO4], monopotassium salt H 2AsO4.KPotassium arsenite 13464-35-2 Arsenous acid, potassium salt AsO 2.KSodium arsenate e 7631-89-2 Arsenic acid, [H 3AsO4], monosodium salt H 2AsO4.NaSodium arsenite 7784-46-5 Arsenous acid, sodium salt AsO 2.NaSodium cacodylate 124-65-2 Arsinic acid, dimethyl-, sodium salt C 2H6AsO2.Na

a As2O3 is sometimes erroneously called arsenic.b Te name arsenic acid is commonly used or As 2O5 as well as or the various hydrated products (H 3AsO4, H4As2O7).c As2O3 is sometimes called arsenic oxide, but this name is more properly used or As 2O5.d Te other salts, K 3AsO4 and K 2HAsO 4, do not appear to be produced commercially.e Te name sodium arsenate is also applied to both the disodium [7778-43-0] and the trisodium [13464-38-5] salts; it is there ore not alwayspossible to determine which substance is under discussion.


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arsenicals (e.g. roxarsone, arsanilic acid and itsderivatives) are used as eed additives or poultry and swine to increase the rate o weight gain,to improve eed e ciencies, pigmentation, anddisease treatment and prevention ( EPA, 2000,2006; FDA, 2008a, b).

Arsenic and arsenic compounds are used ora variety o other industrial purposes. Elementalarsenic is used in the manu acture o alloys,particularly with lead (e.g. in lead acid batteries)and copper. Gallium arsenide and arsine arewidely used in the semiconductor and electronicsindustries. Because o its high electron mobility,as well as light-emitting, electromagnetic andphotovoltaic properties, gallium arsenide is used

in high-speed semiconductor devices, high-power microwave and millimetre-wave devices,and opto-electronic devices, including bre-optic sources and detectors ( IARC, 2006). Arsineis used as a doping agent to manu acture crystals

or computer chips and bre optics.Arsenic and arsenic compounds are used in

the manu acture o pigments, sheep-dips, leatherpreservatives, and poisonous baits. Tey are alsoused in catalysts, pyrotechnics, anti ouling agentsin paints, pharmaceutical substances, dyes andsoaps, ceramics, alloys (automotive solder andradiators), and electrophotography.

Historically, the USA has been the worldslargest consumer o arsenic. Prior to 2004, about90% o the arsenic consumed, as arsenic trioxide,was in the manu acture o wood preservatives.Since the voluntary ban on chromated copperarsenate in residential applications came intoe ect at the end o 2003, the consumption o arsenic or wood preservation has declined, drop-

ping to 50% in 2007 (USGS, 2008). During 19902002, approximately 4% o arsenic produced wasused in the manu acture o glass, and 14% wasused in the production o non- errous alloys(N P, 2005).

1.4 Environmental occurrence

Arsenic is the 20 th most common element inthe earths crust, and is emitted to the environ-ment as a result o volcanic activity and indus-trial activities. Mining, smelting o non- errousmetals and burning o ossil uels are the majoanthropogenic sources o arsenic contaminationo air, water, and soil (primarily in the orm oarsenic trioxide). Te historical use o arsenic-containing pesticides has le large tracts o agri-cultural land contaminated. Te use o arsenicin the preservation o timber has also led tocontamination o the environment ( WHO, 2000,2001).

1.4.1 Natural occurrence

In nature, arsenic occurs primarily in itssul de orm in complex minerals containingsilver, lead, copper, nickel, antimony, cobalt, andiron. Arsenic is present in more than 200 mineralspecies, the most common o which is arsenopy-rite. errestrial abundance o arsenic is approxi-mately 5 mg/kg, although higher concentrationsare associated with sul de deposits. Sedimentary

iron and manganese ores as well as phosphate-rock deposits occasionally contain levels oarsenic up to 2900 mg/kg ( WHO, 2001).

1.4.2 Air

Arsenic is emitted to the atmosphere romboth natural and anthropogenic sources.Approximately one-third o the global atmos-pheric ux o arsenic is estimated to be romnatural sources (7900 tonnes per year). Volcanic

activity is the most important natural contrib-utor, ollowed by low-temperature volatilization,exudates rom vegetation, and windblown dusts.Anthropogenic sources are estimated to account

or nearly 24000 tonnes o arsenic emitted to theglobal atmosphere per year. Tese emissions arise

rom the mining and smelting o base metals,uel combustion (e.g. waste and low-grade brown

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coal), and the use o arsenic-based pesticides(WHO, 2000, 2001).

Arsenic is present in the air o suburban,urban, and industrial areas mainly as inorganicparticulate (a variable mixture o AsIII and AsV,with the pentavalent orm predominating).Methylated arsenic is assumed to be a minorcomponent o atmospheric arsenic ( WHO, 2000).Mean total arsenic concentrations in air range

rom 0.024 ng/m3 in remote and rural areas,and rom 3200 ng/m 3 in urban areas. Muchhigher concentrations (> 1000 ng/m 3) have beenmeasured in the vicinity o industrial sources,such as non- errous metal smelters, and arsenic-rich coal-burning power plants ( WHO, 2001).

1.4.3 Water

Arsenic, rom both natural and anthropo-genic sources, is mainly transported in the envi-ronment by water. Te orm and concentrationo arsenic depends on several actors, includingwhether the water is oxygenated ( or example,arsenites predominate under reducing condi-tions such as those ound in deep well-waters),the degree o biological activity (which is asso-

ciated with the conversion o inorganic arsenicto methylated arsenic acids), the type o watersource ( or example, open ocean seawater versussur ace reshwater versus groundwater), and theproximity o the water source to arsenic-richgeological ormations and other anthropogenicsources (WHO, 2000, 2001).

Te concentration o arsenic in sur ace resh-water sources, like rivers and lakes, is typically lessthan 10 g/L, although it can be as high as 5 mg/Lnear anthropogenic sources. Concentrations o arsenic in open ocean seawater and groundwateraverage 12 g/L, although groundwater concen-trations can be up to 3 mg/L in areas with volcanicrock and sul de mineral deposits ( WHO, 2001).

Exposure to high levels o arsenic in drinking-water has been recognized or many decades insome regions o the world, notably in the Peoples

Republic o China, aiwan (China), and somecountries in Central and South America. Morerecently, several other regions have reportedhaving drinking-water that is highly contami-nated with arsenic. In most o these regions, thedrinking-water source is groundwater, natu-rally contaminated rom arsenic-rich geological

ormations. Te primary regions where highconcentrations o arsenic have been measured indrinking-water include large areas o Bangladesh,China, West Bengal (India), and smaller areaso Argentina, Australia, Chile, Mexico, aiwan(China), the USA, and Viet Nam. In some areaso Japan, Mexico, Tailand, Brazil, Australia, andthe USA, mining, smelting and other industrial

activities have contributed to elevated concen-trations o arsenic in local water sources ( IARC, 2004).

Levels o arsenic in a ected areas may rangerom tens to hundreds or even thousands o

micrograms per litre, whereas in una ectedareas, levels are typically only a ew microgramsper litre. Arsenic occurs in drinking-waterprimarily as AsV, although in reducing environ-ments signi cant concentrations o As III havealso been reported. race amounts o methylatedarsenic species are typically ound in drinking-water, and higher levels are ound in biologicalsystems. More complete data on arsenic in watermay be ound in the previous IARC Monograph (IARC, 2004).

1.4.4 Soil and sediments

Natural and anthropogenic sources contributeto the levels o arsenic ound in soil and sedi-ments. Mean background concentrations in soilare o en around 5 mg/kg, but can range rom aslow as 1 mg/kg to as high as 40 mg/kg. Tis vari-ation in levels o naturally occurring arsenic insoils is associated with the presence o geological

ormations (e.g. sul de ores, mineral sedimentsbeneath peat bogs). Soils contaminated witharsenic rom anthropogenic sources (e.g. mine/

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smelter wastes, agricultural land treated witharsenical pesticides) can have concentrations o arsenic up to several grams per kilogram. Meansediment arsenic concentrations range rom53000 mg/kg, with the higher levels occurringin areas o anthropogenic contamination ( WHO, 2001).

1.5 Human exposure

1.5.1 Exposure of the general population

Te primary route o arsenic exposure orthe general population is via the ingestion o contaminated ood or water. Te daily intake o

total arsenic rom ood and beverages is gener-ally in the range o 20300 g/day.Inhalation o arsenic rom ambient air is

generally a minor exposure route or the generalpopulation. Assuming a breathing rate o 20 m 3/day, the estimated daily intake may amount toabout 20200 ng in rural areas, 400600 ng incities without substantial industrial emissiono arsenic, about 1 g/day in a non-smoker andmore in polluted areas, and up to approximately 10 g/day in a smoker ( WHO, 2000 , 2001).

1.5.2 Occupational exposure

Inhalation o arsenic-containing particulatesis the primary route o occupational exposure,but ingestion and dermal exposure may besigni cant in particular situations (e.g. duringpreparation o timber treated with chromatedcopper arsenate). Historically, the greatest occu-pational exposure to arsenic occurred in thesmelting o non- errous metal, in which arseni -erous ores are commonly used. Other industriesor industrial activities where workers are or wereexposed to arsenic include: coal- red powerplants, battery assembly, preparation o or work with pressure-treated wood, glass-manu ac-turing, and the electronics industry. Estimateso the number o workers potentially exposed to

arsenic and arsenic compounds have been devel-oped by the NIOSH in the USA and by CAREXin Europe. Based on the National OccupationExposure Survey (NOES), conducted during198183, NIOSH estimated that 70000 workers,including approximately 16000 emale workers,were potentially exposed to arsenic and arseniccompounds in the workplace ( NIOSH, 1990).Based on occupational exposure to known andsuspected carcinogens collected during 199093,the CAREX (CARcinogen EXposure) databaseestimated that 147569 workers were exposed toarsenic and arsenic compounds in the EuropeanUnion, with over 50% o workers employed in thenon- errous base metal industries ( n = 40426),

manu acture o wood and wood and cork prod-ucts except urniture (n = 33959), and construc-tion (n = 14740). CAREX Canada estimatesthat 25000 Canadians are exposed to arsenic intheir workplaces ( CAREX Canada, 2011). Teseindustries include: sawmills and wood preservation, construction, arms, non- errous metal(except aluminium) production and processing,iron and steel mills and erro-alloy manu ac-turing, oil and gas extraction, metal ore mining,glass and glass-product manu acturing, semi-conductor manu acturing, and basic chemicalmanu acturing.

1.5.3 Dietary exposure

Low levels o inorganic and organic arsenichave been measured in most oodstu s (typicalconcentrations are less than 0.25 mg/kg). Factorsin uencing the total concentration o arsenic in

ood include: ood type (e.g. sea ood versus meaor dairy), growing conditions (e.g. soil type,water, use o arsenic-containing pesticides), and

ood-processing techniques. Te highest concen-trations o arsenic have been ound in sea ood(2.416.7 mg/kg in marine sh, 3.5 mg/kg inmussels, and more than 100 mg/kg in certaincrustaceans), ollowed by meats, cereals, vegeta-bles, ruit, and dairy products. Inorganic arsenic

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is the predominant orm ound in meats, poultry,dairy products and cereal, and organic arsenic(e.g. arsenobetaine) predominates in sea ood,

ruit, and vegetables (WHO, 2000 , 2001).Regional di erences are seen in the daily

intake o total arsenic through ood, and aremainly attributable to variations in the quan-tity o sea ood consumed. For example, thedaily dietary intake o total arsenic in Japan ishigher than that in Europe and the USA ( WHO, 2000). Based on the limited data available, itis estimated that approximately 25% o daily dietary arsenic intake is rom inorganic sources.Arsenic intake is typically higher in men than itis in women and children, with estimated levels

ranging rom 1.3 g/day or in ants under 1 yearo age, 4.4 g/day or 2-year olds, 9.9 g/day or2530-year-old men, 10 g/day or 6065-year-old women, and 13 g/day or 6065-year-oldmen (WHO, 2001).

1.5.4 Biomarkers of exposure

Arsine generation atomic absorption spec-trometry (AAS) is the method o choice or biolog-ical monitoring o exposure to inorganic arsenic

(WHO, 2000). Te absorbed dose o arsenic canbe identi ed and quanti ed in hair, nail, bloodor urine samples. Because arsenic accumulatesin keratin-rich tissue, total arsenic levels in hair,

ngernails or toenails are used as indicators o past exposures. In contrast, because o its rapidclearing and metabolism, blood arsenic, urinearsenic, and urine arsenic metabolites (inorganicarsenic, monomethylarsonic acid [MMA V] anddimethylarsinic acid [DMA V]) are typically usedas indicators o recent exposure.

Te concentration o metabolites o inorganicarsenic in urine generally ranges rom 520 g/L,but may exceed 1000 g/L (WHO, 2001). ime-weighted average ( WA) occupational exposureto airborne arsenic trioxide is signi cantly corre-lated with the inorganic arsenic metabolites inurine collected immediately a er a shi or just

be ore the next shi . For example, at an airborneconcentration o 50 g/m3, the mean concentra-tion o arsenic derived rom the sum o the threeinorganic arsenic metabolites in a post-shiurine sample was 55 g/g o creatinine. In non-occupationally exposed subjects, the sum o theconcentration o the three metabolites in urineis usually less than 10 g/g o creatinine (WHO, 2000).

2. Cancer in Humans

Te epidemiological evidence on arsenicand cancer risk comes rom two distinct lineso population studies, characterized by themedium o exposure to arsenic. One set o studies addresses the cancer risk associated withinhalation. Tese studies involve populationsthat are largely worker groups who inhaled aircontaminated by arsenic and other agents, as aconsequence o various industrial processes. Tesecond set o studies was carried out in locationswhere people ingested arsenic in drinking-waterat high concentrations over prolonged periods o time.

2.1 Types o human exposurecircumstances studied

2.1.1 Arsenic exposure by inhalation

Te cohort studies and nested casecontrolstudies considered in this Monograph that arerelevant to airborne arsenic include workersin metal smelters and re neries, and miners

o various ores. Casecontrol studies withinthe general population addressed occupationalexposures more generally. Consequently, theexposure to inhaled arsenic was accompanied by exposures to other potentially toxic and carci-nogenic by-products o combustion, such assul ur oxides with copper smelting, polycyclicaromatic hydrocarbons, and particulate matter.

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Most studies did not attempt to estimate sepa-rately exposures to the ull set o agents in theinhaled mixtures, leaving open the possibility o some con ounding or modi cation o the e ecto arsenic by synergistic interactions.

2.1.2 Arsenic exposure by ingestion

For most human carcinogens, the majorsource o evidence contributing to causal in er-ences arises rom casecontrol and cohortstudies. In contrast, or arsenic in drinking-water, ecological studies provide importantin ormation on causal in erence, because o thelarge exposure contrasts and the limited popula-

tion migration. For arsenic, ecological estimateso relative risk are o en so high that potentialcon ounding with known causal actors couldnot explain the results. Although ood may alsobe a source o some ingested arsenic, in severalregions o the world where the concentrations o arsenic in drinking-water is very high, arsenicintake through ood consumption contributes arelatively small cancer risk to the local residents(Liu et al., 2006a).

Te strongest evidence or the association o

human cancer with arsenic in drinking-watercomes rom studies in ve areas o the world withespecially elevated levels o naturally occurringarsenic: south-western and north-eastern aiwan(China), northern Chile, Cordoba Province inArgentina, Bengladesh, West Bengal (India),and other regions in the Ganga plain. Althoughdata contributing to our understanding alsocome rom many other places, the currentreview is largely restricted to the major studies

rom these regions. Some o the oral exposuremay occur via sea ood. However, no epidemio-logical studies were available with regard to thecancer risk associated with arsenic exposure viasea ood, in which arsenic may occur as partic-ular organic compounds such as arsenobetaineand arsenocholine.

(a) Taiwan (China)

Exposure to arsenic was endemic in two areaso aiwan (China): Te south-western coastalarea (Chen et al., 1985), and the north-eastern

Lanyang Basin (Chiou et al., 2001). Residentsin the south-western areas drank artesianwell-water with high concentrations o arsenic

rom the early 1910s to the late 1970s, withlevels mostly above 100 g/L (Kuo, 1968; senget al., 1968). In the Lanyang Basin, residents usedarsenic-contaminated water rom householdtube wells starting in the late 1940s. Arsenic inthe water o 3901 wells, tested in 199194 ranged

rom undetectable (< 0.15 g/L) to 3.59 mg/L(median = 27.3 g/L) ( Chiou et al., 2001).

(b) Northern Chile

Te population-weighted average concentra-tion o arsenic in drinking-water in Region II, anarid region o northern Chile, was about 570 g/Lover 15 years (195569) (Smith et al., 1998). Withthe introduction o a water-treatment plant in1970, levels decreased. By the late 1980s, arseniclevels in drinking-water had decreased to lessthan 100 g/L in most places. With minor excep-

tions, water sources elsewhere in Chile have hadlow concentrations o arsenic (less than 10 g/L)(Marshall et al., 2007).

(c) Cordoba Province, Argentina

O the 24 counties in Cordoba Province, twohave been characterized as having elevated expo-sure to arsenic in drinking-water (average level,178 g/L), six as having medium exposure, andthe remaining 16 rural counties as having lowexposure (Hopenhayn-Rich et al., 1996, 1998).

(d) Bangladesh, West Bengal (India), and other locations in the Ganga plain

Millions o tube wells were installed in WestBengal (India), Bangladesh, and other regions inthe Ganga plain o India and Nepal starting inthe late 1970s to prevent morbidity and mortality

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rom gastrointestinal disease (Smith et al., 2000). Elevated arsenic in wells in Bangladeshwas con rmed in 1993 ( Khan et al., 1997). Ina Bangladesh survey by the British GeologicalSurvey o 2022 water samples in 41 districts, 35%were ound to have arsenic levels above 50 g/L,and 8.4% were above 300 g/L, with an estimateo about 21 million persons exposed to arsenicconcentrations above 50 g/L ( Smith et al., 2000).

2.2 Cancer o the lung

2.2.1 Exposure via inhalation

Several ecological studies were conducted on

populations exposed to arsenic through industrialemissions. Te worker studies primarily providein ormation on lung cancer. Te casecontrolstudies are also mostly directed at lung cancer, withone on non-melanoma skin cancer (see able 2.1available at http://monographs.iarc. r/ENG/Monographs/vol100C/100C-01- able2.1.pd ).

Te cohort studies reviewed previously andhere consistently show elevated lung cancer risk in the various arsenic-exposed cohorts comparedwith the general population or other comparison

groups, with most values in the range o 23(see able 2.2 available at http://monographs.iarc. r/ENG/Monographs/vol100C/100C-01-

able2.2.pd and able 2.3 available at http://monographs. iarc . r /ENG/Monographs/ vol100C/100C-01- able2.3.pd ).

Te studies incorporate diverse qualitativeand quantitative indices o exposure that includemeasures o average airborne concentration o exposure, cumulative exposure across the work experience, and duration o exposure. Tere isconsistent evidence or a positive exposureresponse relationship between the indicators o exposure and lung cancer risk. Casecontrolstudies nested within occupational cohortsprovided similar evidence with regard to expo-sureresponse relationships.

Several analyses urther explored the relation-ship between arsenic exposure and lung cancerrisk using models based on either empirical,i.e. descriptive, or biological data (see able 2.4available at http://monographs.iarc. r/ENG/Monographs/vol100C/100C-01- able2.4.pd ).

Using data rom the acoma, Washingtonsmelter workers, Enterline et al. (1987) modelledthe relationship between lung cancer risk andairborne arsenic exposure using power unc-tions, and ound that the exposureresponserelationship was steeper at lower concentrationsthan shown in conventional analyses, and wasconcave downwards at higher concentrations.By contrast, the relationship o risk with urine

arsenic concentration was linear. Lubin et al. (2000, 2008) analysed the exposureresponserelationship o lung cancer risk with arsenic expo-sure in the cohort o Montana smelter workers,now ollowed or over 50 years. Overall, a linearrelationship o risk with cumulative exposurewas ound; however, the slope o the relation-ship increased with the average concentration atwhich exposure had taken place, that is, the e ecto a particular cumulative exposure was greateri received at a aster rate.

For a comparison o the di erentstudies, see able 2.5 available at http://monographs. iarc . r /ENG/Monographs/ vol100C/100C-01- able2.5.pd .

2.2.2 Exposure via ingestion

A summary o the ndings o epidemio-logical studies on arsenic in drinking-water andrisk or lung cancer are shown in able 2.6 (waterexposures) available at http://monographs.iarc. r/ENG/Monographs/vol100C/100C-01-

able2.6.pd , and online ables 2.1 to 2.4 (airexposures).

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(a) Ecological studies

Ecological studies, based on mortality records, were conducted in the arseniasisendemic area o south-western aiwan (China)

(Chen et al., 1985, 1988a; Wu et al., 1989; Chen & Wang, 1990 ; sai et al., 1999). All studies oundelevated risks or lung cancer mortality associ-ated with levels o arsenic in drinking-water, orsurrogate measurements.

In Chile, Rivara et al. (1997) ound an elevatedrelative risk (RR) or mortality rom lung cancerin 197692 in Region II compared with RegionVIII, a low-exposure area. Smith et al. (1998)

ound an elevated standardized mortality ratio(SMR) o approximately 3 or lung cancer orboth sexes in Region II, using the national rateas standard. In Cordoba Province, Argentina,signi cant increases in lung cancer mortality were associated with increasing exposure toarsenic (Hopenhayn-Rich et al., 1998). Smith et al. (2006) ound an elevated lung cancer mortality (RR, 7.0; 95%CI: 5.48.9) among the 3049-year-old residents o Anto agasta and Mejillones bornin the period 195057, just be ore the period o exposure to high arsenic levels (195870). Tey

were exposed in early childhood to high levelso arsenic through the drinking-water. Tetemporal pattern o lung cancer mortality rateratios in Region II compared with that in RegionV (a low-exposure area) rom 1950 to 2000,showed an increase about 10 years a er the onseto high arsenic exposure, and peaked in 198687,with relative risks o 3.61 (95%CI: 3.134.16) and3.26 (95%CI: 2.504.23) or men and women,respectively (Marshall et al., 2007).

(b) Casecontrol and cohort studiesIn northern Chile, a casecontrol study o

151 cases and 419 controls reported signi cantly increasing risks with increasing levels o arsenicduring the 195870 high-exposure period, withan odds ratio increasing to 7.1 (95%CI: 3.414.8)(Ferreccio et al., 2000).

In a cohort rom south-western aiwan(China), Chen et al. (1986) observed a doseresponse relationship between the duration o consumption o artesian well-water containinghigh levels o arsenic and lung cancer mortality risk, showing the highest age- and gender-adjustedodds ratio among those who consumed artesianwell-water or more than 40 years comparedwith those who never consumed artesian well-water. Another cohort study rom south-western

aiwan (China) endemic or arsenic ound asmoking-adjusted increased risk or lung cancerin relation to increasing average concentrationso arsenic and increasing cumulative exposure toarsenic (Chiou et al., 1995).

A urther study o combined cohorts in south-western (n = 2503) and north-eastern ( n = 8088)

aiwan (China) ound a synergistic interactionbetween arsenic in drinking-water and cigarettesmoking (Chen et al., 2004).

A casecontrol study rom Bangladesh,conducted in 200306, ound an elevated risk (odds ratio [OR], 1.65; 95%CI: 1.252.18) ormale smokers consuming tube well-water witharsenic levels o 101400 g/L (Mosta a et al.,2008). In non-smokers, the study did not reportan increased risk with increasing arsenic expo-sure. [Te Working Group noted the ecologicalnature o the exposure estimates, the possibility o greater sensitivity to arsenic exposure amongsmokers, and the relatively short latent period,with almost two-thirds o the wells put in placein 1990 or later.]

2.3 Cancer o the urinary bladder ando the kidney

Te results o the epidemiological studieson arsenic in drinking-water and the risk

or cancers o the urinary bladder and o thekidney are summarized in able 2.7 availableat http://monographs.iarc. r/ENG/Monographs/ vol100C/100C-01- able2.7.pd .

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2.3.1 Ecological studies

In south-western and north-eastern aiwan(China), the relation between cancer o theurinary bladder and o the kidney and drinking-water containing arsenic was evaluated in many o the studies cited above (Chen et al., 1985, 1988a;Wu et al., 1989; Chen & Wang, 1990 ; sai et al., 1999). Each reported an elevation in mortality

rom these cancers during various time periodsin 197194 associated with levels o arsenic inwell-water rom rural artesian wells, with many reporting a doseresponse relationship amongboth men and women. An additional study,based on incidence records, ound comparablerisks or bladder cancer (Chiang et al., 1993).

In Region II o Chile, two studies oundmarkedly high SMRs or cancer o the urinary bladder and o the kidney in 195092 (Rivara et al., 1997) and in 198993 (Smith et al., 1998). Inthe latter study, mortality rom chronic obstruc-tive pulmonary disease was at the expected level,suggesting that smoking was not involved. Tetemporal pattern o bladder cancer mortality in Region II rom 19502000 was comparedwith that in Region V ( Marshall et al., 2007).

Increased relative risks were reported about 10years a er the start o exposure to high arseniclevels, with peak relative risks o 6.10 (95%CI:3.979.39) or men, and 13.8 (95%CI: 7.7424.5)

or women in the period 198694. In CordobaProvince, Argentina, positive trends in SMRswere reported or bladder and kidney cancersassociated with estimates o exposure to arsenicin drinking-water ( Hopenhayn-Rich et al., 1996,1998), again with no ndings or chronic obstruc-tive pulmonary disease.

[Te Working Group noted that kidney cancers consist o both renal cell carcinoma andtransitional cell carcinoma o the renal pelvis, thelatter o en being o the same etiology as bladdercancer. As arsenic causes transitional cell carci-noma o the bladder, merging o the two types o

kidney cancer may result in a dilution o the risk estimate or total kidney cancer.]

2.3.2 Casecontrol and cohort studies

In a casecontrol study using death certi -cates (198082) rom the area in aiwan (China),endemic or Black oot disease,Chen et al. (1986) reported increasing trends in odds ratios withincreasing duration o consumption o artesianwell-water containing arsenic. Te highest riskswere seen or over 40 years o exposure, with anodds ratio o 4.1 (P < 0.01) or bladder cancer in amultivariate analysis, a er adjusting or smokingand other actors rom next-o -kin interviews.

In casecontrol studies o incident bladdercancer that included analysis o arsenic speciesin urine samples, a higher risk associated witharsenic was ound among persons with higherMMAV:DMAV ratios or, alternatively, with ahigher percentage o MMAV (Chen et al., 2003,2005a; Steinmaus et al., 2006; Pu et al., 2007a;Huang et al., 2008).

Cohort studies rom south-western andnorth-eastern aiwan (China) ( Chen et al., 1988b; Chiou et al., 1995, 2001; Chen & Chiou,

2001) Japan ( suda et al., 1995), and the UnitedKingdom (Cuzick et al., 1992) each observedelevated bladder cancer risk ollowing long-term exposure to ingested arsenic, with doseresponse relationships ound where the numberso cases permitted such an analysis. Te study

rom aiwan (China), also ound an elevated risk o kidney cancer (OR, 2.8; 95%CI: 1.35.4, basedon nine cases) ( Chiou et al., 2001).

2.4 Cancer o the skinTe recognition o arsenic as a carcinogen rst

came rom case series describing skin cancersollowing the ingestion o medicines containing

arsenicals (Hutchinson, 1888 ; Neubauer, 1947 ),and exposure to arsenical pesticide residues, andarsenic-contaminated wine ( Roth, 1957; Grobe,

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1977) or drinking-water, originating rom many countries. Te characteristic arsenic-associatedskin tumours include squamous cell carcinomasarising in keratoses (including Bowen disease),and multiple basal cell carcinomas.

Findings o epidemiological studies onarsenic in drinking-water and risk or skincancer are summarized in able 2.8 available athttp://monographs.iarc. r/ENG/Monographs/ vol100C/100C-01- able2.8.pd .

2.4.1 Ecological studies of prevalence

In south-western aiwan (China), seng et al. (1968) ound an 8- old di erence in the preva-

lence o skin cancer lesions rom the highest(> 600 g/L) to the lowest category (< 300 g/L)o arsenic concentration in artesian wells, a eran extensive examination survey o 40421 inhab-itants in 37 villages.

2.4.2 Ecological studies based on mortality from cancer of the skin

Studies in aiwan (China) ( Chen et al., 1985,1988a; Wu et al., 1989; Chen & Wang, 1990 ; sai

et al., 1999) analysed skin cancer mortality inrelation to levels o arsenic in well-water. Teseinvestigations ound consistent gradients o increasing risk with average level o arsenic indrinking-water, as measured on the township orprecinct level.

Rivara et al. (1997) observed an SMR orskin cancer o 3.2 (95%CI: 2.14.8), comparingmortality rom skin cancer in 197692 betweenRegion II and the unexposed control Region VIIIo Chile. Later,Smith et al. (1998) ound SMRs o 7.7 (95%CI: 4.711.9) among men and 3.2 (95%CI:1.36.6) among women or the years 198993 inRegion II o Chile, using national mortality ratesas re erence. [Te Working Group noted that thehistological type o skin cancer was reportedin only a ew instances. Although skin cancermortality can be in uenced by access to health

care, the SMRs reported here are so large as tonot be explained by any possible con ounding.]

2.4.3 Cohort studies

A retrospective cohort study o 789 (437 men,352 women) o Black oot disease patients in

aiwan (China) reported an SMR o 28 (95%CI:1159) or skin cancer deaths (based on sevenobserved deaths), using aiwan (China) regionalrates as re erence (Chen et al., 1988b).

In a cohort o 654 persons in south-westernaiwan (China), an observed incidence rate o

14.7 cases o skin cancer/1000 personyears wasound (Hsueh et al., 1997), with risks signi cantly

related to duration o living in the area endemicor Black oot disease, duration o consumptiono artesian well-water, average concentrationo arsenic, and index or cumulative exposureto arsenic. Similar ndings were observed in anested casecontrol study conducted within thiscohort ( Hsueh et al., 1995).

In Region II o Chile, a decrease in incidencerates o cutaneous lesions (leukoderma, melano-derma, hyperkeratosis, and squamous cell carci-noma) was observed during 196871 a er a

lowering o waterborne arsenic levels rom a lterplant, which started operation in 1970 ( Zaldvar,1974).

2.5 Cancer o the liver

2.5.1 Ecological studies

Te relation between liver cancer risk anddrinking-water contaminated with arsenic wasevaluated in many o the studies rom south-western aiwan (China), cited above ( Chen et al.,1985, 1988a; Wu et al., 1989; Chen & Wang, 1990 ;Chiang et al., 1993; sai et al., 1999; see able 2.9available at http://monographs.iarc. r/ENG/Monographs/vol100C/100C-01- able2.9.pd ),with positive associations ound in all studies.

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In northern Chile, Rivara et al. (1997) observed a relative risk or liver cancer mortality o 1.2 (95%CI: 0.991.6) in arsenic-exposedRegion II compared with Region VIII. Livercancer mortality in Region II o northern Chileduring the period 198993 among persons 30years o age was not signi cantly elevated, usingnational rates as re erence (Smith et al., 1998).SMRs were 1.1 (95%CI: 0.81.5) both or men and

or women. Liaw et al. (2008) ound an elevatedrelative risk (10.6; 95%CI: 2.939.3, P < 0.001)

or liver cancer among children in Region II o Chile born in 195057 and exposed in utero orshortly therea er, compared to rates in RegionV o Chile.

In Cordoba Province, Argentina, SMRs werenot related to arsenic exposure ( Hopenhayn-Rich et al., 1998).

[Te Working Group noted that the ndingo an association with liver cancer in aiwan(China), but not in South America may re ect amore sensitive population in the ormer region,due to endemic hepatitis B. Te elevated risk o those exposed in utero and as young childrenmay re ect a combination o greater biological vulnerability in early li e (Waalkes et al., 2007)plus the act that young children consume 57times more water per kilogram body weight perday than adults ( NRC, 1993).]

2.5.2 Casecontrol studies

In a casecontrol study investigating theconsumption artesian well-water containinghigh concentrations o arsenic and mortality

rom liver cancer in our townships o south-westernern aiwan (China), Chen et al. (1986) observed an exposureresponse relationshipbetween the duration o consumption o thecontaminated well-water and risk or liver cancer,adjusted or cigarette smoking, habitual alcoholand tea drinking, and consumption o vegetablesand ermented beans.

2.6 Cancer o the prostate

Studies conducted in aiwan (China) ( Chen et al., 1985, 1988a; Wu et al., 1989; Chen & Wang, 1990; sai et al., 1999) analysed prostate cancermortality in relation to levels o arsenic in well-water, with some overlap among the respectivestudy populations. Using several methodolog-ical approaches and comparison populationsincluding direct and indirect standardizationo rates, all studies reported signi cant doseresponse relationships between the level o arsenic in drinking-water and the risk or pros-tate cancer mortality (see able 2.10 available athttp://monographs.iarc. r/ENG/Monographs/

vol100C/100C-01- able2.10.pd ).In Chile, Rivara et al. (1997) ound a relativerisk o 0.9 (95%CI: 0.541.53) or prostate cancer,comparing the 1990 mortality rate or prostatecancer o Region II with that o Region VIII.

2.7 Synthesis

Te Working Group reviewed a large body o evidence that covers ecological studies, casecontrol studies and cohort studies in a variety o settings and populations exposed either by ingestion (primarily to As III and AsV in drinking-water) or inhalation (with exposure to a mixtureo inorganic arsenic compounds). Te evidencealso relates to historical exposure rom pesticidaland pharmaceutical uses. Te epidemiologicalevidence rom drinking-water exposure permitsthe evaluation o the carcinogenicity that isrelated to exposure to As III and AsV. Te epidemi-ological evidence rom inhaled arsenic mixtures

permits the evaluation o the carcinogenicity that is related to inorganic arsenic compounds.However, it does not allow a separation o thecarcinogenic risk associated with particulararsenic species that occur in these mixtures.

Te observed associations between exposureto arsenic in drinking-water and lung cancer,and between exposure to arsenic in air and lung

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cancer, cannot be attributed to chance or bias.Te evidence is compelling or both the inhala-tion and ingestion routes o exposure. Tere isevidence o doseresponse relationships withinexposed populations with both types o exposure.

Te observed association between exposureto arsenic in drinking-water and bladder cancercannot be attributed to chance or bias. Tere isevidence o doseresponse relationships withinexposed populations.

Te observed association between exposureto arsenic in drinking-water and skin cancercannot be attributed to chance or bias. Tere isevidence o doseresponse relationships withinexposed populations. Te evidence is primarily

or squamous cell carcinoma o the skin.Although the data or kidney cancer are

suggestive o a relationship with exposure toarsenic in drinking-water, overall, the smallpossibility o chance or bias cannot be completely ruled out.

Te evidence or an association betweenliver cancer and long-term exposure to arsenicin drinking-water relies on mortality data.Although the data strongly suggest a causal asso-ciation with some evidence o a doseresponserelationship, the Working Group could not ruleout possible chance or bias. Te evidence comesmainly rom aiwan (China) where hepatitis B ishighly prevalent.

Te evidence or an association or pros-tate cancer and long-term exposure to arsenicin drinking-water relies on mortality data.In the studies rom aiwan (China), there issome evidence o a doseresponse relationship.However, the data rom South America are not

consistent with this observation. Although theevidence on prostate cancer suggests the possi-bility o a causal association, the Working Groupcould not rule out the possibility o chance orbias.

3. Cancer in Experimental Animals

Over the years, it has proved di cult toprovide evidence or the carcinogenesis o inor-

ganic arsenic compounds. More recent work has ocused on methylated arsenic metabolitesin humans or exposure to inorganic arsenicduring early li e, and has provided the in orma-tion to show potential links between arsenic andcarcinogenesis.

Studies published since the previous IARC Monograph (IARC, 2004) are summarized below.

3.1 Oral administration

3.1.1 Mouse

Te oral administration o sodium arsenatein drinking-water or 18 months increased lungtumour multiplicity and lung tumour size inmale strain A/J mice ( Cui et al., 2006; see able3.1).

Similarly, drinking-water exposure tothe organo-arsenical DMA V or 50 weeks ormore increased the incidence and multiplicity o lung adenoma or carcinoma in strain A/Jmice (Hayashi et al., 1998), and increased lungtumours in mutant Ogg/ mice (which cannotrepair certain types o oxidative DNA damage)but not in Ogg+/+ mice (Kinoshita et al., 2007;see able 3.2).

3.1.2 Rat

In male F344 rats, the oral administrationo DMAV in drinking-water or up to 2 yearsproduced clear doseresponse relationships orthe induction o urinary bladder transitional cellcarcinoma and combined papilloma or carci-noma ( Wei et al., 1999, 2002).

When DMAV was added to the eed o maleand emale F344 rats or 2 years, a clear doseresponse relationship or urinary bladder benignand/or malignant transitional cell tumours

53


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occurred in emale but not male rats ( Arnold et al., 2006). Preneoplasia (urothelial cell hyperplasia)was clearly increased in emale rats (Arnold et al., 2006; see able 3.2).

In male F344 rats, the oral administrationo trimethylarsine oxide in drinking-water or

2 years caused a signi cant increase o benignliver tumours (adenoma) ( Shen et al., 2007; seeable 3.3).

Oral exposure to MMA V or 2 years wasnegative in a comprehensive doseresponsestudy including male and emale rats and mice,although body weight suppression and reducedsurvival with the higher doses con ounded therat segment o the study (Arnold et al., 2003; see

able 3.4).A 2-year doseresponse study with sodium

arsenite showed some evidence o renal tumourormation in emale Sprague-Dawley rats but not

in males (So ritti et al., 2006). umour incidencedid not reach signi cance (see able 3.5).

3.2 Intratracheal administration

3.2.1 Hamster

Repeated weekly intratracheal instilla-tions o calcium arsenate, at levels su cientto caused moderate early mortality, increased

lung adenoma ormation in male Syrian goldenhamsters when observed over their li espan(Pershagen & Bjrklund, 1985 ).

In a similarly designed study, male hamstersreceived multiple weekly intratracheal instil-lations o calcium arsenate at the start o theexperiment, and developed an increased inci-dence o lung adenoma ormation, and combinedlung adenoma or carcinoma ormation over theirli espan (Yamamoto et al., 1987; see able 3.6).

Intratracheal instillations o calcium arseniteincreased the incidence o respiratory tract carci-noma and combined adenoma, papilloma andadenomatoid lesion ormation in male SyrianHamsters ( Pershagen et al., 1984; see able 3.7).

54

Table 3.1 Studies of cancer in experimental animals exposed to sodium arsenate (oral exposure)

Species, strain (sex)DurationRe erence

Dosing regimen,Animals/group at start

Incidence o tumours Signifcance Comments

Mouse, A/J (M)18 moCui et al . (2006)

0, 1, 10, 100 ppmarsenate indrinking-water, ad libitum 30/group

Lung (adenomas):0/19, 0/13, 0/15, 4/30(13%)

[NS, (any dose)] a Age at start, 5 wk Purity, NRRedundant Studentt -test used or multiplecomparisons o lungtumour multiplicity andsizeSurvival signi cantly increased at high doseNon-dose-related,modest changes in bw,lung weight, and lung bwratio

Lung (adenocarcinomas):9/19 (47%), 10/13 (77%),11/15 (73%), 19/30 (63%)

[NS, (any dose)] a

Average tumours/mouselung:0.59, 1.1, 1.3, 1.4b

P < 0.01 (alldoses)

Average numbertumours > 4 mm/mouselung:

17, 32, 44, 60b

P < 0.01 (alldoses)

a Per ormed during review. One-sided Fisher Exact testcontrol versus all treated.b Numbers are estimates at review because data are presented graphically in original work.bw, body weight; M, male; mo, month or months; NR, not reported; NS, not signi cant; wk, week or weeks


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55

T a b l e 3

. 2 S t u d i e s o c a n c e r

i n e x p e r i m e n

t a l a n

i m a l s e x p o s e

d t o d i m e

t h y

l a r s

i n i c a c i

d , D

M A V

( o r a

l e x p o s u r e

)

S p e c

i e s , s t r a

i n ( s e x

)

D u r a t i o n

R e e r e n c e

D o s i n g r e g i m e n

A n i m a l s / g r o u p a t

s t a r t

I n c i

d e n c e o t u m o u r s

S i g n

i f c a n c e

C o m m e n t s

M o u s e , A

/ J ( M )

5 0 w

k

H a y a s

h i e t a l . (

1 9 9 8 )

0 , 5 0 , 2 0 0 , 4 0 0 p p m

D M A V

i n d r i n k i n g -

w a t e r , a

d l i b i t u m

2 4 / g r o u p

N u m

b e r o

m i c e w i t h

l u n g p a p i l l a r y

a d e n o m a s o r a d e n o c a r c i n o m a s :

2 / 1 4 ( 1 4 % ) , 5 / 1 4 ( 3 6 % ) , 7 / 1 4 ( 5 0 % ) ,

1 0 / 1 3 ( 7 7 % )

P < 0 . 0 1 ( h i g h d o s e )

A g e a t s t a r t , 5 w

k

P u r i t y , N R

S u r v i v a l u n r e m a r

k a b l e

[ O n l y

h i s t o l o g i c a l

l y c o n r m e d t u m o u r s

w e r e c o n s i d e r e d

b y t h e W o r k i n g G r o u p

]

M o u s e , O

g g 1 - / - a n

d

O g g

1 + / + ( M

, F )

7 2 w

k

K i n o s

h i t a e t a l .

( 2 0 0 7 )

0 , 2 0 0 p p m D M A V

i n d r i n k i n g - w a t e r ,

a d l i b i t u m ; c o n t r o l s

r e c e i v e

d t a p w a t e r

1 0 / g r o u p ( O

g g 1 - / -

)

1 2 / g r o u p ( O g g

1 + / +

)

O g g 1 - / - :

u m o u r -

b e a r i n g m i c e ( a n y s i t e ) :

0 / 1 0 , 1

0 / 1 0 ( 1 0 0 % )

P < 0 . 0 1

A g e a t s t a r t , 1 4 w

k

P u r i t y , 9 9 %

B w a n

d o o d a n

d w a t e r c o n s u m p t i o n

u n r e m a r

k a b l e

L e l o b e a n

d v i s i b

l e l u n g n o d u l e s u s e d

o r

h i s t o p a t

h o l o g i c a

l t u m o u r a n a l y s i s

r e a t e d O

g g 1 / s h o w e d m o d e s t d e c r e a s e d

s u r v i v a l

( ~ 2 0 % ) l a t e c o m p a r e

d t o

p h e n o t y p i c c o n t r o

l

S m a l

l g r o u p s

L u n g

l e s i o n s

H y p e r p l a s i a s :

1 0 / 1 0 ( 1 0 0 % ) , 1 0 / 1 0 ( 1 0 0 % )

A d e n o m a s :

0 / 1 0 , 2

/ 1 0 ( 2 0 % )

N S

A d e n o c a r c i n o m a s :

0 / 1 0 , 3

/ 1 0 ( 3 0 % )

o t a l l u n g t u m o u r s :

0 / 1 0 , 5

/ 1 0 ( 5 0 % )

P < 0 . 0 5

u m o u r s / m o u s e :

0 , 0 . 5

P < 0 . 0 5

O g g 1 + / + :

u m o u r -

b e a r i n g m i c e ( a n y s i t e ) :

5 / 1 0 ( 5 0 % ) , 6 / 1 0 ( 6 0 % )

L u n g

l e s i o n s

H y p e r p l a s i a s :

2 / 1 0 ( 2 0 % ) , 1 0 / 1 0 ( 1 0 0 % )

[ P < 0 . 0 1

b ]

A d e n o m a s :

1 / 1 0 ( 1 0 % ) , 0 / 1 0

N S

A d e n o c a r c i n o m a s :

0 / 1 0 , 0

/ 1 0

N S

o t a l t u m o u r s :

1 / 1 0 ( 1 0 % ) , 0 / 1 0

N S


0 . 1 , 0

N S


0 . 1 , 0

N S


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56

S p e c

i e s , s t r a

i n ( s e x

)

D u r a t i o n

R e e r e n c e



s t a r t

I n c i


S i g n

i f c a n c e

C o m m e n t s

R a t , F 3 4 4 ( M )

1 0 4 w

k

W e i e t a l . (

1 9 9 9 ) d

,

2 0 0 2 )

0 , 1 2 . 5 , 5 0 , 2

0 0 p p m

D M A V

i n d r i n k i n g -

w a t e r , a

d l i b i t u m

3 6 / g r o u p

U r i n a r y

b l a d

d e r (

h y p e r p l a s i a s ) :

0 / 2 8 , 0

/ 3 3 , 1 2 / 3 1 ( 3 9 % ) , 1 4 / 3 1 ( 4 5 % )

P < 0 . 0 1 ( m i d d l e a n d

h i g h

d o s e

) A g e a t s t a r t , 1 0 w

k

P u r i t y , 9 9 %

S u r v i v a l a n

d o o d i n t a k e u n a

l t e r e

d

r a n s i e n t

b w s u p p r e s s i o n e a r

l y w i t h

h i g h a n

d m i d d l e d o s e b u t t

h e n s i m i l a r t o

c o n t r o

l

W a t e r i n t a k e i n c r e a s e

d a t h i g h e s t t w o

d o s e s

I n c i

d e n c e r a t e s

b a s e

d o n r a t s a t r i s

k

( s u r v i v i n g t o t i m e o

t h e r s t b l a d d e r

t u m o u r a t 9 7 w

k )

E x t e n s i v e n e c r o p s y

U r i n a r y

b l a d

d e r ( p a p i l l o m a s

) :

0 / 2 8 , 0

/ 3 3 , 2 / 3 1 ( 2 % ) , 2 / 3 1 ( 2 % )

N S

U r i n a r y

b l a d

d e r ( c a r c i n o m a s

) :

0 / 2 8 , 0

/ 3 3 , 6 / 3 1 ( 1 9 % ) , 1 2 / 3 1 ( 3 9 % )

P < 0 . 0 5 ( m i d d l e d o s e )

P < 0 . 0 1 ( h i g h d o s e )

U r i n a r y

b l a d

d e r ( p a p i l l o m a s o r

c a r c i n o m a s

) :

0 / 2 8 , 0

/ 3 3 , 8 / 3 1 ( 2 6 % ) , 1 2 / 3 1 ( 3 9 % )

P < 0 . 0 1 ( m i d d l e a n d

h i g h

d o s e

)

R a t , F 3 4 4 ( M

, F )

1 0 4 w

k

A r n o l

d e t a l . (

2 0 0 6 )

0 , 2 , 1

0 , 4 0 , 1

0 0 p p m

D M A V

i n e e d , a

d

l i b i t u m

6 0 / g r o u p

F e m a l e s

U r o t h e l i a l c e l

l ( h y p e r p

l a s i a s , s i m p l e ,

n o d u l a r a n d p a p i l l a r y ) :

0 / 6 0 , 1

/ 5 9 ( 2 % ) , 0 / 6 0 , 2 9 / 5 9 ( 4 9 % ) ,

4 8 / 6 0 ( 8 0 % )

P < 0 . 0 1 ( t r e n

d )

[ P < 0 . 0 1 ( h i g h e s t , a n

d s e c o n d

h i g h e s t d o s e ) ]

b

P u r i t y > 9 9 % ; a g e , 5 w

k

C o m p l e t e n e c r o p s i e s p e r o r m e d

N o t r e a t m e n t - r e l a t e d

d i f e r e n c e s i n

m o r t a l i t y o r

b w

U r i n a r y

b l a d


) :

0 / 6 0 , 0

/ 5 9 , 0 / 6 0 , 0

/ 5 9 , 4

/ 6 0 ( 7 % )

S p o r a d i c c h a n g e s i n

o o d c o n s u m p t i o n n o t

t r e a t m e n t - r e l a t e d

W a t e r c o n s u m p t i o n i n c r e a s e

d w i t h

t r e a t m e n t

U r i n a r y

b l a d


) :

0 / 6 0 , 0

/ 5 9 , 0 / 6 0 , 0

/ 5 9 , 6

/ 6 0 ( 1 0 % )

[ N S ( h i g h d o s e

) ] b

P < 0 . 0 1 ( t r e n

d ) c

U r i n a r y

b l a d

d e r ( p a p i l l o m a s a n

d

c a r c i n o m a s c o m

b i n e d ) :

0 / 6 0 , 0

/ 5 9 , 0 / 6 0 , 0

/ 5 9 , 1

0 / 6 0 ( 3 % )

[ P < 0 . 0 5 ( h i g h d o s e )

] b

P < 0 . 0 1 ( t r e n

d ) c

[ P < 0 . 0 5 ( h i g h d o s e )

] b

M a l e s

U r o t h e l i a l c e l

l ( h y p e r p

l a s i a s , s i m p l e ,

n o d u l a r a n d p a p i l l a r y ) :

0 / 6 0 , 0

/ 5 9 , 0 / 6 0 , 6

/ 5 8 ( 1 0 % ) , 4 0 / 5 9

( 6 8 % )

P < 0 . 0 1 ( t r e n

d )

[ P < 0 . 0 1 ( h i g h d o s e )

] b

W a t e r c o n s u m p t i o n i n c r e a s e

d w i t h

t r e a t m e n t

U r i n a r y

b l a d


) :

0 / 6 0 , 0

/ 5 9 , 1 / 6 0 ( 2 % ) , 1 / 5 8 ( 2 % ) , 0 / 5 9


) ] b

P < 0 . 0 1 ( t r e n

d ) c

U r i n a r y

b l a d


) :

0 / 6 0 , 1

/ 5 9 ( 2 % ) , 0 / 6 0 , 0 / 5 8 , 2

/ 5 9 ( 3 % )


) ] b

P < 0 . 0 1 ( t r e n

d ) c

U r i n a r y

b l a d

d e r ( p a p i l l o m a s a n

d


b i n e d ) :

0 / 6 0 , 1

/ 5 9 ( 2 % ) , 1 / 6 0 ( 2 % ) , 1 / 5 8 ( 2 % ) ,

2 / 5 9 ( 3 % )


) ] b

T a b l e 3

. 2 ( c o n

t i n u e d

)


17/54


57

S p e c

i e s , s t r a

i n ( s e x

)

D u r a t i o n

R e e r e n c e



s t a r t

I n c i


S i g n

i f c a n c e

C o m m e n t s

M o u s e , B

6 C 3 F 1 ( F )

1 0 4 w

k

A r n o l

d e t a l . (

2 0 0 6 )

0 , 8 , 4

0 , 2 0 0 , 5 0 0

p p m

D M A V

i n e e d ,

a d l i b i t u m

5 6 / g r o u p

F e m a l e s

N o t r e a t m e n t - r e l a t e d c h a n g e s i n

u r i n a r y

b l a d

d e r p r e n e o p l a s i a o r

t u m o u r i n c i d e n c e n o t e d


k

P u r i t y 9 9 %

C o m p l e t e n e c r o p s i e s p e r o r m e d

S u r v i v a l , b w a n

d w a t e r c o n s u m p t i o n

u n c h a n g e

d

S p o r a d i c , s m a l

l c h a n g e s i n

o o d

c o n s u m p t i o n e a r l y

F i b r o s a r c o m a s n o t c o n s i d e r e

d r e

l a t e d t o

t r e a t m e n t b y a u t h o r s

B w r e

d u c e

d a t 5 0 0 p p m t h r o u g

h o u t s t u d y

A n y o r g a n

( b r o s a r c o m a s

) :

3 / 5 6 ( 5 % ) , 0 / 5 5 , 1

/ 5 6 ( 2 % ) , 1 / 5 6 ( 2 % ) ,

6 / 5 6 ( 1 1 % )

P < 0 . 0 1 ( h i g h d o s e )

M a l e s

N o t r e a t m e n t - r e l a t e d c h a n g e s i n

u r i n a r y

b l a d

d e r p r e n e o p l a s i a o r

t u m o u r i n c i d e n c e n o t e d

a D a t a a

l s o i n c l u d e d

d e s c r i p t i v e s t a t i s t i c s ( i . e . S

D ) .

b P e r o r m e d

d u r i n g r e v i e w . O n e - s i d e d F i s h e r e x a c t t e s t c o n t r o l v e r s u s t r e a t e d .

c r e n

d a n a l y s i s p e r o r m e d a e r c o m

b i n a t i o n o

e m a l e a n d m a l e d a t a o r u r i n a r y

b l a d

d e r l e s i o n s

r o m t h i s s a m e s t u d y ( A r n o l

d e t a l . ,

2 0 0 6 ) .

d S h o r t c o m m u n i c a t i o n o t u m

o u r d a t a o n l y .

e O n a C 5 7 B L / 6 b a c k g r o u n d .

A s s t a t e d b y t h e a u t

h o r s .

g T e l a c

k o i n o r m a t i o n o n g r o u p s i z e a n d t h e l a c

k o

d e s c r i p t i v e s t a t i s t i c s m a k e s t h e s e d a t a i m p o s s i b l e t o i n d e p e n d e n t

l y r e - e v a

l u a t e o r s t a t i s t i c a l s i g n i

c a n c e .

b w , b o d y w e i g h t ; F , e m a l e ; M , m a l e ; N R , n o t r e p o r t e d ; N S , n o t s i g n i

c a n t ; w

k , w e e k o r w e e k s

T a b l e 3

. 2 ( c o n

t i n u e d

)


18/54


3.3 Intravenous administration3.3.1 Mouse

Multiple intravenous injections o sodiumarsenate in male and emale Swiss mice providedno evidence o elevated tumour ormation(Waalkes et al., 2000; see able 3.8).

3.4 Transplacental and perinatalexposures

3.4.1 Mouse

Pregnant mice were treated subcutaneously with arsenic trioxide on a single speci c day during gestation (Days 14, 15, 16 or 17), and theo spring were then treated subcutaneously on postpartum Days 1, 2 and 3 with arsenic trioxide.Te o spring initially treated on Day 15 o gestation developed an excess o lung adenomacompared to controls, and the other groups did

not (Rudnai & Borzsanyi, 1980, 1981; see able 3.9).Pregnant C3H mice were exposed to various

doses o sodium arsenite in the drinking-waterrom Days 818 o gestation. Tey were allowed

to give birth and their o spring were put intogender-based groups at weaning. Over thenext 90 weeks, arsenic-treated emale o spring

developed dose-related benign and/or malig-nant ovarian tumours, and lung adenocarci-noma. During the next 74 weeks, a dose-relatedincrease in the incidences o liver adenoma and/or carcinoma, and adrenal cortical adenoma wasobserved in the male o spring ( Waalkes et al., 2003).

A second study looked at the carcino-genic e ects in C3H mice o various doses o sodium arsenite (two levels) in the maternaldrinking-water rom Days 8 to 18 o gestation,

with or without subsequent 12- O-tetradecanoylphorbol-13-acetate ( PA) applied to the skin o the o spring a er weaning rom 425 weeks o age. Over the next 2 years, with arsenic alone,the emale o spring developed an increased inci-dence o ovarian tumours. Te male o springdeveloped arsenic dose-related increases in theincidences o liver adenoma and/or carcinomaand adrenal cortical adenoma ( Waalkes et al., 2004).

Pregnant CD1 mice received sodium arsenite(one level) in the drinking-water rom gestationDays 8 to 18, were allowed to give birth, and the

emale (Waalkes et al., 2006a) or male ( Waalkes et al., 2006b) o spring were treated with diethyl-stilbestrol or tamoxi en subcutaneously on postpartum Days 1, 2, 3, 4 and 5. In emale o springover the next 90 weeks, arsenic exposure alone

58

Table 3.3 Studies of cancer in experimental animals exposed to trimethylarsine oxide (oralexposure)


Dosing regimenAnimals/group at star t


Rat, F344 (M)2 yrShen et al . (2003)

0, 50, 200 ppmtrimethylarsine oxidein drinking-water, ad libitum 4245; 42 controls

Liver (adenomas):6/42 (9%), 10/42 (14%),16/45 (24%)

P < 0.05 (highdose)

Age at start, 10 wk Purity, 99%Body weights, ood intake,water intake, survivalrate, and average survivalunaltered with treatmentExtensive necropsy per ormedVarious other sites negative

bw, body weight; M, male; yr, year or years


19/54


59

T a b l e 3



t a l a n


d t o m o n o m e

t h y

l a r s o n

i c a c i

d , M

M A V

( o r a

l e x p o s u r e )

S p e c

i e s , s t r a

i n ( s e x

)

D u r a t i o n

R e e r e n c e

D o s

i n g r e g i m e n

A n

i m a l s / g r o u p a t s t a r t

I n c i


S i g n

i f c a n c e

C o m m e n t s

M o u s e , B

6 C 3 F 1 ( M

, F )

1 0 4 w

k

A r n o l

d e t a l . (

2 0 0 3 )

0 , 1 0 , 5

0 , 2 0 0 , 4 0 0 p p m M M A V

i n e e d , a

d l i b i t u m

5 2 / g r o u p / s e x


c h a n g e s


k

P u r i t y , 9 9 %

B w r e

d u c e

d a t 4 0 0 p p m t h r o u g

h o u t s t u d y

F o o d a n

d w a t e r c o n s u m p t i o n s i m i l a r o r

i n c r e a s e

d a t t h e t w o

h i g h e r d o s e s

S u r v i v a l u n r e m a r

k a b l e

C o m p l e t e n e c r o p s y p e r o r m e d

R a t , F 3 4 4 ( M

, F )

1 0 4 w

k

A r n o l

d e t a l . (

2 0 0 3 )

0 , 5 0 , 4

0 0 , 1

3 0 0 a

p p m M M A V

i n e e d , a

d l i b i t u m

6 0 / g r o u p / s e x


c h a n g e s


k

P u r i t y , 9 9 %

B w r e

d u c e

d a t t w o

h i g h e s t d o s e s i n

s e c o n d

h a l o s t u d y

F o o d c o n s u m p t i o n g e n e r a

l l y s i m i l a r

W a t e r c o n s u m p t i o n s i m i l a r o r i n c r e a s e

d

a t t h e t w o

h i g h e r

d o s e s

S u r v i v a l r e

d u c e

d a t

h i g h d o s e

C o m p l e t e n e c r o p s y p e r o r m e d

a D u e t o a h i g h m o r t a l i t y i n m a l e a n d

e m a l e r a t s e d t h i s l e v e

l , i t w a s r e

d u c e d t o 1 0 0 0 p p m

d u r i n g W e e

k 5 3 , a n d

u r t

h e r r e

d u c e

d t o 8 0 0 p p m

d u r i n g W e e

k 6 0 .

b w , b o d y w e i g h t ; F , e m a l e ; M , m a l e ; w

k , w e e k o r w e e k s


20/54


increased the incidence o tumours o the ovary,uterus, and adrenal cortex. In the male o spring,prenatal arsenic exposure alone increased liveradenoma and/or carcinoma, lung adenocarci-noma, and adrenal cortical adenoma (see able 3.10).

3.5 Studies in which arsenic modi es

the efects o other agents3.5.1 Mouse

Mice exposed to DMAV in drinking-watera er subcutaneous injection o 4-nitroquino-line 1-oxide showed an increase in lung tumourmultiplicity compared to mice exposed to theorganic carcinogen alone ( Yamanaka et al., 1996). In K6/ODC mice rst treated topically with 7,12-dimethylbenz[]anthracene (DMBA)then with DMA V in a cream applied to the sameskin area or 18 weeks, the organo-arsenicaldoubled the skin tumour multiplicity comparedto treatment with DMBA alone ( Morikawa et al., 2000; see able 3.11). [Te Working Group notedthat this study had too ew DMAV controls or anappropriate interpretation.]

In the studies o Germolec et al. (1997, 1998),oral sodium arsenite was given to g.AC micewith PA by skin painting, and an approxi-mately 4- old increase in skin tumour responsewas reported.

Combined treatment with oral sodiumarsenite in drinking-water and multiple expo-sures to excess topical UV irradiation in Crl:SKl-hr BR hairless mice showed that arsenic treatment

alone was consistently without carcinogenice ect, but markedly enhanced UV-induced skintumours including squamous cell carcinoma(Rossman et al., 2001; Burns et al., 2004; Uddin et al., 2005). In another skin study, mice exposedto topical 9,10-dimethyl-1,2-benzanthracene or2 weeks concurrently with oral sodium arsenatein drinking-water or 25 weeks showed thatarsenic treatment alone was without carcino-genic e ect, but enhanced skin tumour multi-plicity and tumour size when combined withthe organic carcinogen compared to the organiccarcinogen alone ( Motiwale et al., 2005; see able 3.12).

When pregnant g.AC mice were treatedwith oral sodium arsenite in drinking-water

rom Days 818 o gestation, and their o springwere topically exposed to PA rom 440 weeks

60

Table 3.5 Studies of cancer in experimental animals exposed to sodium arsenite (oral exposure)


Dosing regimenAnimals/group atstart


Rat, Sprague-Dawley (M, F)167 wk (li espan)So ritti et al . (2006)

0, 50, 100, 200 mg/LNaAsO2 in drinking-water, ad libitum romonset to 104 wk 50/group

Kidney (tumours):F1/50 (2%), 1/50 (2%),5/50 (10%), 5/50 (10%)c M0/50, 2/50 (4%), 2/50(4%), 0/50

NS or both sexes Age at start, 8 wk Purity 98%Complete necropsy per ormedReduced water and oodintake especially at twohighest dosesDose-related reduced bw

a As stated by the authors.b Te lack o in ormation on group size and lack o descriptive statistics makes the data rom this work impossible to re-evaluate or statisticalsigni cance.c Includes three carcinomas at the high dose and one at the second highest dose in emales and a carcinoma in emales at the second highestdose.

Bw, body weight; F, emale; M, male; NS, not signi cant; wk, week or weeks


21/54


61

T a b l e 3



t a l a n


d t o c a

l c i u m

a r s e n a t e

( i n

t r a

t r a c h e a

l i n s t

i l l a t i o n

)

S p e c

i e s , s t r a

i n ( s e x

)

D u r a t i o n

R e e r e n c e

D o s

i n g r e g i m e n

A n


I n c i


S i g n

i f c a n c e

C o m m e n t s

H a m s t e r , S y r i a n g o

l d e n

( M )

~ 1 4 5 w

k ( l i e s p a n

)

P e r s

h a g e n & B j r k l u n

d ( 1 9 8 5 )

0 , ~ 3 m g A s /

k g b w i n 0 . 1 5 m L

s a l i n e

o n c e / w k o r 1 5 w

k

4 1 ; 2 9 c o n t r o

l s

L u n g

( a d e n o m a s

) :

0 / 2 6 , 4

/ 3 5 ( 1 1 % )

P < 0 . 0 5


k

P u r i t y , u l t r a p u r e

M o r t a l i t y

d u r i n g

d o s i n g ~ 1 5 % ;

m o r t a l i t y i n c r e a s e

d i n

a r s e n a t e g r o u p

d u r i n g s e c o n d y r

D o s e a p p r o x i m a t e


l d e n

( M )

U p t o 1 1 5 w

k i n t r e a t e d

a n i m a l s , a n

d

1 2 1 w

k i n c o n t r o

l s ( l i e s p a n )

Y a m a m o t o e

t a l . (

1 9 8 7 )

0 , 0 . 2 5 m g A s i n 0 . 1 m L s a

l i n e

o n c e / w k o r 1 5 w

k

3 0 ; 2 2 c o n t r o

l s

L u n g

( a d e n o m a s

) :

0 / 2 2 , 6

/ 2 5 ( 2 4 % )

[ P < 0 . 0 1 a ]


k

P u r i t y , c h e m i c a l g r a d e

I n s t i l l a t i o n s c a u s e d 1 0 % m o r t a l i t y

a n d r e

d u c e

d s u r v i v a l ~ 1 0 % p o s t -

i n s t i l l a t i o n

B w n o t r e c o r

d e d d u r i n g e x p e r i m e n t

L u n g

( c a r c i n o m a s

) :

1 / 2 2 ( 4 % ) , 1 / 2 5 ( 4 % )

N S

L u n g

( a d e n o m a s a n

d


b i n e

d ) :

1 / 2 2 ( 4 % ) , 7 / 2 5 ( 3 % )

P - v a l u e n o t r e p o r t e d

b u t s t a t e d a s

s i g n i c a n t

[ P < 0 . 0 1 a ]

a C a l c u l a t e d

b y t h e W o r

k i n g G

r o u p . O n e - s i d e d F i s h e r e x a c t t e s t c o n t r o l v e r s u s t r e a t e d .

b w , b o d y w e i g h t ; M , m a l e ; N S , n o t s i g n i

c a n t ; w

k , w e e

k o r w e e k s


22/54


62

T a b l e 3



t a l a n


d t o a r s e n

i c t r i o x

i d e ( i n

t r a t r a c h e a

l i n s t

i l l a t i o n

)

S p e c

i e s , s t r a

i n ( s e x

)

D u r a t i o n

R e e r e n c e

D o s

i n g r e g i m e n

A n


I n c i


S i g n

i f c a n c e

C o m m e n t s


l d e n

arsenic compounds

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