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Arsenic and Arsenic Compounds

Arsenic and Arsenic Compounds

AND ARSENIC COMPOUNDS

Arsenic and arsenic compounds were considered by previous IARC Working Groups in 1979, 1987, and 2002 (IARC, 1980, 1987, 2004). Since that time, new data have become avail- able, these have been incorporated in the Monograph, and taken into consideration in the present evaluation.

1. Exposure Data From a biological and toxicological perspec- tive, there are three major groups of arsenic 1.1 Identification of the agents compounds: -inorganic arsenic compounds, Information on the physical and chemical -organic arsenic compounds, and properties of arsenic and arsenic compounds can - gas. be found in Table 1.1, for further details please Of the inorganic arsenic compounds, arsenic refer to IARC (1980). The list is not exhaus- trioxide, and tive, nor does it comprise necessarily the most are the most common trivalent compounds, commercially important arsenic-containing and , arsenic and arse- substances; rather, it indicates the range of nates (e.g. and arsenate) arsenic compounds available. are the most common pentavalent compounds. Common organic arsenic compounds include , methylarsonic acid, dimethyl- 1.2 Chemical and physical properties arsinic acid (), and of the agents (WHO, 2000). Arsenic (, 33; relative , 74.92) has chemical and physical proper- 1.3 Use of the agents ties intermediate between a and a non- metal, and is often referred to as a Arsenic and arsenic compounds have been or semi-metal. It belongs to VA of the produced and used commercially for centuries. , and can exist in four oxidation Current and historical uses of arsenic include states: –3, 0, +3, and +5. Arsenite, AsIII, and arse- pharmaceuticals, wood preservatives, agricul- nate, AsV, are the predominant oxidation states tural chemicals, and applications in the mining, under, respectively, reducing and oxygenated metallurgical, glass-making, and conditions (WHO, 2001; IARC, 2004). industries. Arsenic was used in some medicinal applica- tions until the 1970s. Inorganic arsenic was used

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

Chemical name CAS Reg. No. Synonyms Formula

Arsanilic acid 98-50-0 Arsonic acid, (4-aminophenyl)- C6H8AsNO3 Arsenica 7440-38-2 Metallic arsenic As b Arsenic(V) pentoxide 1303-28-2 Arsenic [As2O5] As2O5

Arsenic(III) 1303-33-9 Arsenic sulfide [As2S3] As2S3

Arsenic(III) trichloride 7784-34-1 Arsenic chloride [AsCl3] AsCl3 a,c Arsenic(III) trioxide 1327-53-3 Arsenic oxide [As2O3] As2O3

Arsenobetaine 64436-13-1 Arsonium, (carboxymethyl) trimethyl-, , C5H11AsO2 inner salt; 2-(trimethylarsonio)acetate

Arsine 7784-42-1 Arsenic AsH3

Calcium arsenate 7778-44-1 [H3AsO4] calcium salt (2:3) (AsO4)2.3Ca

Dimethylarsinic acid 75-60-5 Cacodylic acid C2H7AsO2

Lead arsenate 7784-40-9 Arsenic acid [H3AsO4], lead (2+) salt (1:1) HAsO4.Pb

Methanearsonic acid, 144-21-8 Arsonic acid, methyl-, disodium salt CH3AsO3.2Na disodium salt

Methanearsonic acid, 2163-80-6 Arsonic acid, methyl-, monosodium salt CH4AsO3.Na monosodium salt d arsenate 7784-41-0 Arsenic acid [H3AsO4], monopotassium salt H2AsO4.K

Potassium arsenite 13464-35-2 , potassium salt AsO2.K e 7631-89-2 Arsenic acid, [H3AsO4], monosodium salt H2AsO4.Na

Sodium arsenite 7784-46-5 Arsenous acid, sodium salt AsO2.Na

Sodium cacodylate 124-65-2 Arsinic acid, dimethyl-, sodium salt C2H6AsO2.Na a As2O3 is sometimes erroneously called ‘arsenic’. b The name ‘arsenic acid’ is commonly used for As2O5 as as for the various hydrated products (H3AsO4, H4As2O7). c As2O3 is sometimes called ‘arsenic oxide’, but this name is more properly used for As2O5. d The other salts, K3AsO4 and K2HAsO4, do not appear to be produced commercially. e The name ‘sodium arsenate’ is also applied to both the disodium [7778-43-0] and the trisodium [13464-38-5] salts; it is therefore not always possible to determine which substance is under discussion. in the treatment of leukaemia, , and Inorganic arsenic have not been used chronic bronchial asthma, and organic arsenic for agricultural purposes in the USA since 1993. was used in for the treatment of spiro- Organic forms of arsenic were constituents of some chetal and protozoal disease (ATSDR, 2007). agricultural pesticides in the USA. However, in Inorganic arsenic is an active component of 2009, the US Environmental Protection Agency chromated arsenate, an antifungal wood issued a cancellation order to eliminate and preservative used to make “pressure-treated” out the use of organic pesticides by wood for outdoor applications. Chromated 2013 (EPA, 2009). The one exception to the order copper arsenate is no longer used in residential is monosodium methanearsonate (MSMA), a applications, following a voluntary ban on its use broadleaf weed , which will continue to in Canada and the of America at be approved for use on cotton. Small amounts the end of 2003. of disodium methanearsonate (DSMA, or caco- In the agricultural industry, arsenic has dylic acid) were historically applied to cotton historically been used in a range of applications, fields as , but its use is now prohibited including pesticides, herbicides, , under the aforementioned US EPA 2009 organic cotton desiccants, defoliants, and sterilants. arsenical product cancellation. Other organic

42 Arsenic and arsenic compounds (e.g. , arsanilic acid and its 1.4 Environmental occurrence derivatives) are used as feed additives for poultry and swine to increase the rate of weight gain, Arsenic is the 20th most common element in to improve feed efficiencies, pigmentation, and the earth’s crust, and is emitted to the environ- disease treatment and prevention (EPA, 2000, ment as a result of volcanic activity and indus- 2006; FDA, 2008a, b). trial activities. Mining, of non-ferrous Arsenic and arsenic compounds are used for and burning of fossil fuels are the major a variety of other industrial purposes. Elemental anthropogenic sources of arsenic contamination arsenic is used in the manufacture of alloys, of air, water, and soil (primarily in the form of particularly with lead (e.g. in lead acid batteries) ). The historical use of arsenic- and copper. and arsine are containing pesticides has left large tracts of agri- widely used in the semiconductor and electronics cultural land contaminated. The use of arsenic industries. Because of its high mobility, in the preservation of timber has also led to as well as -emitting, electromagnetic and contamination of the environment (WHO, 2000, photovoltaic properties, is used 2001). in high-speed semiconductor devices, high- power microwave and millimetre-wave devices, 1.4.1 Natural occurrence and opto-electronic devices, including fibre- In nature, arsenic occurs primarily in its optic sources and detectors (IARC, 2006). Arsine sulfide form in complex containing is used as a agent to manufacture , lead, copper, , , , and for computer chips and fibre optics. . Arsenic is present in more than 200 Arsenic and arsenic compounds are used in species, the most common of which is arsenopy- the manufacture of , sheep-dips, leather rite. Terrestrial abundance of arsenic is approxi- preservatives, and poisonous baits. They are also mately 5 mg/kg, although higher concentrations used in catalysts, pyrotechnics, antifouling agents are associated with sulfide deposits. Sedimentary in paints, pharmaceutical substances, dyes and iron and ores as well as - soaps, ceramics, alloys (automotive and rock deposits occasionally contain levels of radiators), and electrophotography. arsenic up to 2900 mg/kg (WHO, 2001). Historically, the USA has been the world’s largest consumer of arsenic. Prior to 2004, about 1.4.2 Air 90% of the arsenic consumed, as arsenic trioxide, was in the manufacture of wood preservatives. Arsenic is emitted to the atmosphere from Since the voluntary ban on chromated copper both natural and anthropogenic sources. arsenate in residential applications came into Approximately one-third of the global atmos- effect at the end of 2003, the consumption of pheric flux of arsenic is estimated to be from arsenic for has declined, drop- natural sources (7900 tonnes per year). Volcanic ping to 50% in 2007 (USGS, 2008). During 1990– activity is the most important natural contrib- 2002, approximately 4% of arsenic produced was utor, followed by low-temperature volatilization, used in the manufacture of glass, and 1–4% was exudates from vegetation, and windblown dusts. used in the production of non-ferrous alloys Anthropogenic sources are estimated to account (NTP, 2005). for nearly 24000 tonnes of arsenic emitted to the global atmosphere per year. These emissions arise from the mining and smelting of base metals, fuel combustion (e.g. waste and low-grade brown

43 IARC MONOGRAPHS – 100C ), and the use of arsenic-based pesticides Republic of , Taiwan (China), and some (WHO, 2000, 2001). countries in Central and South America. More Arsenic is present in the air of suburban, recently, several other regions have reported urban, and industrial areas mainly as inorganic having drinking-water that is highly contami- particulate (a variable mixture of AsIII and AsV, nated with arsenic. In most of these regions, the with the pentavalent form predominating). drinking-water source is , natu- Methylated arsenic is assumed to be a minor rally contaminated from arsenic-rich geological component of atmospheric arsenic (WHO, 2000). formations. The primary regions where high Mean total arsenic concentrations in air range concentrations of arsenic have been measured in from 0.02–4 ng/m3 in remote and rural areas, drinking-water include large areas of Bangladesh, and from 3–200 ng/m3 in urban areas. Much China, (), and smaller areas higher concentrations (> 1000 ng/m3) have been of , , , , Taiwan measured in the vicinity of industrial sources, (China), the USA, and Viet Nam. In some areas such as non-ferrous metal smelters, and arsenic- of , Mexico, , Brazil, Australia, and rich coal-burning power plants (WHO, 2001). the USA, mining, smelting and other industrial activities have contributed to elevated concen- 1.4.3 Water trations of arsenic in local water sources (IARC, 2004). Arsenic, from both natural and anthropo- Levels of arsenic in affected areas may range genic sources, is mainly transported in the envi- from tens to hundreds or even thousands of ronment by water. The form and concentration micrograms per litre, whereas in unaffected of arsenic depends on several factors, including areas, levels are typically only a few micrograms whether the water is oxygenated (for example, per litre. Arsenic occurs in drinking-water predominate under reducing condi- primarily as AsV, although in reducing environ- tions such as those found in deep well-waters), ments significant concentrations of AsIII have the degree of biological activity (which is asso- also been reported. Trace amounts of methylated ciated with the conversion of inorganic arsenic arsenic species are typically found in drinking- to methylated arsenic ), the type of water water, and higher levels are found in biological source (for example, open ocean seawater versus systems. More complete data on arsenic in water surface freshwater versus groundwater), and the may be found in the previous IARC Monograph proximity of the water source to arsenic-rich (IARC, 2004). geological formations and other anthropogenic sources (WHO, 2000, 2001). 1.4.4 Soil and sediments The concentration of arsenic in surface fresh- water sources, like rivers and lakes, is typically less Natural and anthropogenic sources contribute than 10 µg/L, although it can be as high as 5 mg/L to the levels of arsenic found in soil and sedi- near anthropogenic sources. Concentrations of ments. Mean background concentrations in soil arsenic in open ocean seawater and groundwater are often around 5 mg/kg, but can range from as average 1–2 µg/L, although groundwater concen- low as 1 mg/kg to as high as 40 mg/kg. This vari- trations can be up to 3 mg/L in areas with volcanic ation in levels of naturally occurring arsenic in rock and sulfide mineral deposits WHO,( 2001). is associated with the presence of geological Exposure to high levels of arsenic in drinking- formations (e.g. sulfide ores, mineral sediments water has been recognized for many decades in beneath peat bogs). Soils contaminated with some regions of the world, notably in the People’s arsenic from anthropogenic sources (e.g. mine/

44 Arsenic and arsenic compounds smelter wastes, agricultural land treated with arsenic and arsenic compounds have been devel- arsenical pesticides) can have concentrations of oped by the NIOSH in the USA and by CAREX arsenic up to several grams per kilogram. Mean in Europe. Based on the National Occupation sediment arsenic concentrations range from Exposure Survey (NOES), conducted during 5–3000 mg/kg, with the higher levels occurring 1981–83, NIOSH estimated that 70000 workers, in areas of anthropogenic contamination (WHO, including approximately 16000 female workers, 2001). were potentially exposed to arsenic and arsenic compounds in the workplace (NIOSH, 1990). 1.5 Human exposure Based on occupational exposure to known and suspected collected during 1990–93, 1.5.1 Exposure of the general population the CAREX ( EXposure) database estimated that 147569 workers were exposed to The primary route of arsenic exposure for arsenic and arsenic compounds in the European the general population is via the ingestion of Union, with over 50% of workers employed in the contaminated food or water. The daily intake of non-ferrous base metal industries (n = 40426), total arsenic from food and beverages is gener- manufacture of wood and wood and cork prod- ally in the range of 20–300 µg/day. ucts except furniture (n = 33959), and construc- Inhalation of arsenic from ambient air is tion (n = 14740). CAREX Canada estimates generally a minor exposure route for the general that 25000 Canadians are exposed to arsenic in 3 population. Assuming a breathing rate of 20 m / their workplaces (CAREX Canada, 2011). These day, the estimated daily intake may amount to industries include: sawmills and wood preser- about 20–200 ng in rural areas, 400–600 ng in vation, construction, farms, non-ferrous metal cities without substantial industrial emission (except ) production and processing, of arsenic, about 1 µg/day in a non-smoker and iron and steel mills and ferro-alloy manufac- more in polluted areas, and up to approximately turing, oil and gas extraction, metal ore mining, 10 µg/day in a smoker (WHO, 2000, 2001). glass and glass-product manufacturing, semi- conductor manufacturing, and basic chemical 1.5.2 Occupational exposure manufacturing. Inhalation of arsenic-containing particulates is the primary route of occupational exposure, 1.5.3 Dietary exposure but ingestion and dermal exposure may be Low levels of inorganic and organic arsenic significant in particular situations (e.g. during have been measured in most foodstuffs (typical preparation of timber treated with chromated concentrations are less than 0.25 mg/kg). Factors copper arsenate). Historically, the greatest occu- influencing the total concentration of arsenic in pational exposure to arsenic occurred in the food include: food type (e.g. seafood versus meat smelting of non-ferrous metal, in which arsenif- or dairy), growing conditions (e.g. soil type, erous ores are commonly used. Other industries water, use of arsenic-containing pesticides), and or industrial activities where workers are or were food-processing techniques. The highest concen- exposed to arsenic include: coal-fired power trations of arsenic have been found in seafood plants, battery assembly, preparation of or work (2.4–16.7 mg/kg in marine fish, 3.5 mg/kg in with pressure-treated wood, glass-manufac- mussels, and more than 100 mg/kg in certain turing, and the electronics industry. Estimates crustaceans), followed by meats, cereals, vegeta- of the number of workers potentially exposed to bles, fruit, and dairy products. Inorganic arsenic

45 IARC MONOGRAPHS – 100C is the predominant form found in meats, poultry, before the next shift. For example, at an airborne dairy products and cereal, and organic arsenic concentration of 50 µg/m3, the mean concentra- (e.g. arsenobetaine) predominates in seafood, tion of arsenic derived from the sum of the three fruit, and vegetables (WHO, 2000, 2001). inorganic arsenic metabolites in a post-shift Regional differences are seen in the daily urine sample was 55 µg/g of creatinine. In non- intake of total arsenic through food, and are occupationally exposed subjects, the sum of the mainly attributable to variations in the quan- concentration of the three metabolites in urine tity of seafood consumed. For example, the is usually less than 10 µg/g of creatinine (WHO, daily dietary intake of total arsenic in Japan is 2000). higher than that in Europe and the USA (WHO, 2000). Based on the limited data available, it is estimated that approximately 25% of daily 2. in Humans dietary arsenic intake is from inorganic sources. Arsenic intake is typically higher in men than it The epidemiological evidence on arsenic is in women and children, with estimated levels and cancer risk comes from two distinct lines ranging from 1.3 µg/day for infants under 1 year of population studies, characterized by the of age, 4.4 µg/day for 2-year olds, 9.9 µg/day for medium of exposure to arsenic. One set of 25–30-year-old men, 10 µg/day for 60–65-year- studies addresses the cancer risk associated with old women, and 13 µg/day for 60–65-year-old inhalation. These studies involve populations men (WHO, 2001). that are largely worker groups who inhaled air contaminated by arsenic and other agents, as a 1.5.4 Biomarkers of exposure consequence of various industrial processes. The Arsine generation atomic absorption spec- second set of studies was carried out in locations trometry (AAS) is the method of choice for biolog- where people ingested arsenic in drinking-water ical monitoring of exposure to inorganic arsenic at high concentrations over prolonged periods of (WHO, 2000). The absorbed dose of arsenic can time. be identified and quantified in hair, nail, blood or urine samples. Because arsenic accumulates 2.1 Types of human exposure in keratin-rich tissue, total arsenic levels in hair, circumstances studied fingernails or toenails are used as indicators of past exposures. In contrast, because of its rapid 2.1.1 Arsenic exposure by inhalation clearing and metabolism, blood arsenic, urine The cohort studies and nested case–control arsenic, and urine arsenic metabolites (inorganic studies considered in this Monograph that are arsenic, monomethylarsonic acid [MMAV] and relevant to airborne arsenic include workers dimethylarsinic acid [DMAV]) are typically used in metal smelters and refineries, and miners as indicators of recent exposure. of various ores. Case–control studies within The concentration of metabolites of inorganic the general population addressed occupational arsenic in urine generally ranges from 5–20 µg/L, exposures more generally. Consequently, the but may exceed 1000 µg/L (WHO, 2001). Time- exposure to inhaled arsenic was accompanied by weighted average (TWA) occupational exposure exposures to other potentially toxic and carci- to airborne arsenic trioxide is significantly corre- nogenic by-products of combustion, such as lated with the inorganic arsenic metabolites in with copper smelting, polycyclic urine collected immediately after a shift or just aromatic hydrocarbons, and particulate matter.

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Most studies did not attempt to estimate sepa- (a) Taiwan (China) rately exposures to the full set of agents in the Exposure to arsenic was endemic in two areas inhaled mixtures, leaving open the possibility of of Taiwan (China): The south-western coastal some confounding or modification of the effect area (Chen et al., 1985), and the north-eastern of arsenic by synergistic interactions. Lanyang Basin (Chiou et al., 2001). Residents in the south-western areas drank artesian 2.1.2 Arsenic exposure by ingestion well-water with high concentrations of arsenic For most human carcinogens, the major from the early 1910s to the late 1970s, with source of evidence contributing to causal infer- levels mostly above 100 μg/L (Kuo, 1968; Tseng ences arises from case–control and cohort et al., 1968). In the Lanyang Basin, residents used studies. In contrast, for arsenic in drinking- arsenic-contaminated water from household water, ecological studies provide important tube starting in the late 1940s. Arsenic in information on causal inference, because of the the water of 3901 wells, tested in 1991–94 ranged large exposure contrasts and the limited popula- from undetectable (< 0.15 μg/L) to 3.59 mg/L tion migration. For arsenic, ecological estimates (median = 27.3 μg/L) (Chiou et al., 2001). of relative risk are often so high that potential (b) Northern Chile confounding with known causal factors could not explain the results. Although food may also The population-weighted average concentra- be a source of some ingested arsenic, in several tion of arsenic in drinking-water in Region II, an regions of the world where the concentrations of arid region of northern Chile, was about 570 μg/L arsenic in drinking-water is very high, arsenic over 15 years (1955–69) (Smith et al., 1998). With intake through food consumption contributes a the introduction of a water-treatment plant in relatively small cancer risk to the local residents 1970, levels decreased. By the late 1980s, arsenic (Liu et al., 2006a). levels in drinking-water had decreased to less The strongest evidence for the association of than 100 μg/L in most places. With minor excep- human cancer with arsenic in drinking-water tions, water sources elsewhere in Chile have had comes from studies in five areas of the world with low concentrations of arsenic (less than 10 μg/L) especially elevated levels of naturally occurring (Marshall et al., 2007). arsenic: south-western and north-eastern Taiwan (c) Cordoba Province, Argentina (China), northern Chile, Cordoba Province in Argentina, Bengladesh, West Bengal (India), Of the 24 counties in Cordoba Province, two and other regions in the Ganga plain. Although have been characterized as having elevated expo- data contributing to our understanding also sure to arsenic in drinking-water (average level, come from many other places, the current 178 μg/L), six as having medium exposure, and review is largely restricted to the major studies the remaining 16 rural counties as having low from these regions. Some of the oral exposure exposure (Hopenhayn-Rich et al., 1996, 1998). may occur via seafood. However, no epidemio- (d) Bangladesh, West Bengal (India), and other logical studies were available with regard to the locations in the Ganga plain cancer risk associated with arsenic exposure via seafood, in which arsenic may occur as partic- Millions of tube wells were installed in West ular organic compounds such as arsenobetaine Bengal (India), Bangladesh, and other regions in and arsenocholine. the Ganga plain of India and Nepal starting in the late 1970s to prevent morbidity and mortality

47 IARC MONOGRAPHS – 100C from gastrointestinal disease (Smith et al., Several analyses further explored the relation- 2000). Elevated arsenic in wells in Bangladesh ship between arsenic exposure and cancer was confirmed in 1993 Khan( et al., 1997). In risk using models based on either empirical, a Bangladesh survey by the British Geological i.e. descriptive, or biological data (see Table 2.4 Survey of 2022 water samples in 41 districts, 35% available at http://monographs.iarc.fr/ENG/ were found to have arsenic levels above 50 μg/L, Monographs/vol100C/100C-01-Table2.4.pdf). and 8.4% were above 300 μg/L, with an estimate Using data from the Tacoma, Washington of about 21 million persons exposed to arsenic smelter workers, Enterline et al. (1987) modelled concentrations above 50 μg/L (Smith et al., 2000). the relationship between risk and airborne arsenic exposure using power func- 2.2 Cancer of the lung tions, and found that the exposure–response relationship was steeper at lower concentrations 2.2.1 Exposure via inhalation than shown in conventional analyses, and was concave downwards at higher concentrations. Several ecological studies were conducted on By contrast, the relationship of risk with urine populations exposed to arsenic through industrial arsenic concentration was linear. Lubin et al. emissions. The worker studies primarily provide (2000, 2008) analysed the exposure–response information on lung cancer. The case–control relationship of lung cancer risk with arsenic expo- studies are also mostly directed at lung cancer, with sure in the cohort of Montana smelter workers, one on non-melanoma skin cancer (see Table 2.1 now followed for over 50 years. Overall, a linear available at http://monographs.iarc.fr/ENG/ relationship of risk with cumulative exposure Monographs/vol100C/100C-01-Table2.1.pdf). was found; however, the slope of the relation- The cohort studies reviewed previously and ship increased with the average concentration at here consistently show elevated lung cancer risk which exposure had taken place, that is, the effect in the various arsenic-exposed cohorts compared of a particular cumulative exposure was greater with the general population or other comparison if received at a faster rate. groups, with most values in the range of 2–3 For a comparison of the different (see Table 2.2 available at http://monographs. studies, see Table 2.5 available at http:// iarc.fr/ENG/Monographs/vol100C/100C-01- monographs.iarc.fr/ENG/Monographs/ Table2.2.pdf and Table 2.3 available at http:// vol100C/100C-01-Table2.5.pdf. monographs.iarc.fr/ENG/Monographs/ vol100C/100C-01-Table2.3.pdf). 2.2.2 Exposure via ingestion The studies incorporate diverse qualitative and quantitative indices of exposure that include A summary of the findings of epidemio- measures of average airborne concentration of logical studies on arsenic in drinking-water and exposure, cumulative exposure across the work risk for lung cancer are shown in Table 2.6 (water experience, and duration of exposure. There is exposures) available at http://monographs. consistent evidence for a positive exposure– iarc.fr/ENG/Monographs/vol100C/100C-01- response relationship between the indicators of Table2.6.pdf, and online Tables 2.1 to 2.4 (air exposure and lung cancer risk. Case–control exposures). studies nested within occupational cohorts provided similar evidence with regard to expo- sure–response relationships.

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(a) Ecological studies In a cohort from south-western Taiwan Ecological studies, based on mortality (China), Chen et al. (1986) observed a dose– records, were conducted in the arseniasis response relationship between the duration of endemic area of south-western Taiwan (China) consumption of artesian well-water containing (Chen et al., 1985, 1988a; Wu et al., 1989; Chen & high levels of arsenic and lung cancer mortality Wang, 1990; Tsai et al., 1999). All studies found risk, showing the highest age- and gender-adjusted elevated risks for lung cancer mortality associ- odds ratio among those who consumed artesian ated with levels of arsenic in drinking-water, or well-water for more than 40 years compared surrogate measurements. with those who never consumed artesian well- In Chile, Rivara et al. (1997) found an elevated water. Another cohort study from south-western relative risk (RR) for mortality from lung cancer Taiwan (China) endemic for arsenic found a in 1976–92 in Region II compared with Region smoking-adjusted increased risk for lung cancer VIII, a low-exposure area. Smith et al. (1998) in relation to increasing average concentrations found an elevated standardized mortality ratio of arsenic and increasing cumulative exposure to (SMR) of approximately 3 for lung cancer for arsenic (Chiou et al., 1995). both sexes in Region II, using the national rate A further study of combined cohorts in south- as standard. In Cordoba Province, Argentina, western (n = 2503) and north-eastern (n = 8088) significant increases in lung cancer mortality Taiwan (China) found a synergistic interaction were associated with increasing exposure to between arsenic in drinking-water and cigarette arsenic (Hopenhayn-Rich et al., 1998). Smith et smoking (Chen et al., 2004). al. (2006) found an elevated lung cancer mortality A case–control study from Bangladesh, (RR, 7.0; 95%CI: 5.4–8.9) among the 30–49-year- conducted in 2003–06, found an elevated risk old residents of Antofagasta and Mejillones born (odds ratio [OR], 1.65; 95%CI: 1.25–2.18) for in the 1950–57, just before the period of male smokers consuming tube well-water with exposure to high arsenic levels (1958–70). They arsenic levels of 101–400 μg/L (Mostafa et al., were exposed in early childhood to high levels 2008). In non-smokers, the study did not report of arsenic through the drinking-water. The an increased risk with increasing arsenic expo- temporal pattern of lung cancer mortality rate sure. [The Working Group noted the ecological ratios in Region II compared with that in Region nature of the exposure estimates, the possibility V (a low-exposure area) from 1950 to 2000, of greater sensitivity to arsenic exposure among showed an increase about 10 years after the onset smokers, and the relatively short latent period, of high arsenic exposure, and peaked in 1986–87, with almost two-thirds of the wells put in place with relative risks of 3.61 (95%CI: 3.13–4.16) and in 1990 or later.] 3.26 (95%CI: 2.50–4.23) for men and women, respectively (Marshall et al., 2007). 2.3 Cancer of the urinary bladder and (b) Case–control and cohort studies of the In northern Chile, a case–control study of The results of the epidemiological studies 151 cases and 419 controls reported significantly on arsenic in drinking-water and the risk increasing risks with increasing levels of arsenic for of the urinary bladder and of the during the 1958–70 high-exposure period, with kidney are summarized in Table 2.7 available an odds ratio increasing to 7.1 (95%CI: 3.4–14.8) at http://monographs.iarc.fr/ENG/Monographs/ (Ferreccio et al., 2000). vol100C/100C-01-Table2.7.pdf.

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2.3.1 Ecological studies kidney cancer may result in a dilution of the risk estimate for total kidney cancer.] In south-western and north-eastern Taiwan (China), the relation between cancer of the 2.3.2 Case–control and cohort studies urinary bladder and of the kidney and drinking- water containing arsenic was evaluated in many In a case–control study using death certifi- of the studies cited above (Chen et al., 1985, 1988a; cates (1980–82) from the area in Taiwan (China), Wu et al., 1989; Chen & Wang, 1990; Tsai et al., endemic for Blackfoot disease, Chen et al. (1986) 1999). Each reported an elevation in mortality reported increasing trends in odds ratios with from these cancers during various time periods increasing duration of consumption of artesian in 1971–94 associated with levels of arsenic in well-water containing arsenic. The highest risks well-water from rural artesian wells, with many were seen for over 40 years of exposure, with an reporting a dose–response relationship among odds ratio of 4.1 (P < 0.01) for bladder cancer in a both men and women. An additional study, multivariate analysis, after adjusting for smoking based on incidence records, found comparable and other factors from next-of-kin interviews. risks for (Chiang et al., 1993). In case–control studies of incident bladder In Region II of Chile, two studies found cancer that included analysis of arsenic species markedly high SMRs for cancer of the urinary in urine samples, a higher risk associated with bladder and of the kidney in 1950–92 (Rivara arsenic was found among persons with higher et al., 1997) and in 1989–93 (Smith et al., 1998). In MMAV:DMAV ratios or, alternatively, with a the latter study, mortality from chronic obstruc- higher percentage of MMAV (Chen et al., 2003, tive pulmonary disease was at the expected level, 2005a; Steinmaus et al., 2006; Pu et al., 2007a; suggesting that smoking was not involved. The Huang et al., 2008). temporal pattern of bladder cancer mortality Cohort studies from south-western and in Region II from 1950–2000 was compared north-eastern Taiwan (China) (Chen et al., with that in Region V (Marshall et al., 2007). 1988b; Chiou et al., 1995, 2001; Chen & Chiou, Increased relative risks were reported about 10 2001) Japan (Tsuda et al., 1995), and the United years after the start of exposure to high arsenic Kingdom (Cuzick et al., 1992) each observed levels, with peak relative risks of 6.10 (95%CI: elevated bladder cancer risk following long- 3.97–9.39) for men, and 13.8 (95%CI: 7.74–24.5) term exposure to ingested arsenic, with dose– for women in the period 1986–94. In Cordoba response relationships found where the numbers Province, Argentina, positive trends in SMRs of cases permitted such an analysis. The study were reported for bladder and kidney cancers from Taiwan (China), also found an elevated risk associated with estimates of exposure to arsenic of kidney cancer (OR, 2.8; 95%CI: 1.3–5.4, based in drinking-water (Hopenhayn-Rich et al., 1996, on nine cases) (Chiou et al., 2001). 1998), again with no findings for chronic obstruc- tive pulmonary disease. 2.4 Cancer of the skin [The Working Group noted that kidney cancers consist of both renal cell carcinoma and The recognition of arsenic as a carcinogen first transitional cell carcinoma of the renal pelvis, the came from case series describing skin cancers latter often being of the same etiology as bladder following the ingestion of medicines containing cancer. As arsenic causes transitional cell carci- arsenicals (Hutchinson, 1888; Neubauer, 1947), noma of the bladder, merging of the two types of and exposure to arsenical residues, and arsenic-contaminated wine (Roth, 1957; Grobe,

50 Arsenic and arsenic compounds

1977) or drinking-water, originating from many care, the SMRs reported here are so large as to countries. The characteristic arsenic-associated not be explained by any possible confounding.] skin tumours include squamous cell carcinomas arising in keratoses (including Bowen disease), 2.4.3 Cohort studies and multiple basal cell carcinomas. Findings of epidemiological studies on A retrospective cohort study of 789 (437 men, arsenic in drinking-water and risk for skin 352 women) of Blackfoot disease patients in cancer are summarized in Table 2.8 available at Taiwan (China) reported an SMR of 28 (95%CI: http://monographs.iarc.fr/ENG/Monographs/ 11–59) for skin cancer deaths (based on seven vol100C/100C-01-Table2.8.pdf. observed deaths), using Taiwan (China) regional rates as reference (Chen et al., 1988b). 2.4.1 Ecological studies of prevalence In a cohort of 654 persons in south-western Taiwan (China), an observed incidence rate of In south-western Taiwan (China), Tseng et al. 14.7 cases of skin cancer/1000 person–years was (1968) found an 8-fold difference in the preva- found (Hsueh et al., 1997), with risks significantly lence of skin cancer lesions from the highest related to duration of living in the area endemic (> 600 µg/L) to the lowest category (< 300 µg/L) for Blackfoot disease, duration of consumption of arsenic concentration in artesian wells, after of artesian well-water, average concentration an extensive examination survey of 40421 inhab- of arsenic, and index for cumulative exposure itants in 37 villages. to arsenic. Similar findings were observed in a nested case–control study conducted within this 2.4.2 Ecological studies based on mortality cohort (Hsueh et al., 1995). from cancer of the skin In Region II of Chile, a decrease in incidence rates of cutaneous lesions (leukoderma, melano- Studies in Taiwan (China) (Chen et al., 1985, derma, hyperkeratosis, and squamous cell carci- 1988a; Wu et al., 1989; Chen & Wang, 1990; Tsai noma) was observed during 1968–71 after a et al., 1999) analysed skin cancer mortality in lowering of waterborne arsenic levels from a filter relation to levels of arsenic in well-water. These plant, which started operation in 1970 (Zaldívar, investigations found consistent gradients of 1974). increasing risk with average level of arsenic in drinking-water, as measured on the township or precinct level. 2.5 Cancer of the Rivara et al. (1997) observed an SMR for 2.5.1 Ecological studies skin cancer of 3.2 (95%CI: 2.1–4.8), comparing mortality from skin cancer in 1976–92 between The relation between liver cancer risk and Region II and the unexposed control Region VIII drinking-water contaminated with arsenic was of Chile. Later, Smith et al. (1998) found SMRs of evaluated in many of the studies from south- 7.7 (95%CI: 4.7–11.9) among men and 3.2 (95%CI: western Taiwan (China), cited above (Chen et al., 1.3–6.6) among women for the years 1989–93 in 1985, 1988a; Wu et al., 1989; Chen & Wang, 1990; Region II of Chile, using national mortality rates Chiang et al., 1993; Tsai et al., 1999; see Table 2.9 as reference. [The Working Group noted that the available at http://monographs.iarc.fr/ENG/ histological type of skin cancer was reported Monographs/vol100C/100C-01-Table2.9.pdf), in only a few instances. Although skin cancer with positive associations found in all studies. mortality can be influenced by access to health

51 IARC MONOGRAPHS – 100C

In northern Chile, Rivara et al. (1997) 2.6 Cancer of the prostate observed a relative risk for liver cancer mortality of 1.2 (95%CI: 0.99–1.6) in arsenic-exposed Studies conducted in Taiwan (China) (Chen Region II compared with Region VIII. Liver et al., 1985, 1988a; Wu et al., 1989; Chen & Wang, cancer mortality in Region II of northern Chile 1990; Tsai et al., 1999) analysed prostate cancer during the period 1989–93 among persons ≥ 30 mortality in relation to levels of arsenic in well- years of age was not significantly elevated, using water, with some overlap among the respective national rates as reference (Smith et al., 1998). study populations. Using several methodolog- SMRs were 1.1 (95%CI: 0.8–1.5) both for men and ical approaches and comparison populations for women. Liaw et al. (2008) found an elevated including direct and indirect standardization relative risk (10.6; 95%CI: 2.9–39.3, P < 0.001) of rates, all studies reported significant dose– for liver cancer among children in Region II of response relationships between the level of Chile born in 1950–57 and exposed in utero or arsenic in drinking-water and the risk for pros- shortly thereafter, compared to rates in Region tate cancer mortality (see Table 2.10 available at V of Chile. http://monographs.iarc.fr/ENG/Monographs/ In Cordoba Province, Argentina, SMRs were vol100C/100C-01-Table2.10.pdf). not related to arsenic exposure (Hopenhayn- In Chile, Rivara et al. (1997) found a relative Rich et al., 1998). risk of 0.9 (95%CI: 0.54–1.53) for prostate cancer, [The Working Group noted that the finding comparing the 1990 mortality rate for prostate of an association with liver cancer in Taiwan cancer of Region II with that of Region VIII. (China), but not in South America may reflect a more sensitive population in the former region, 2.7 Synthesis due to endemic hepatitis B. The elevated risk of those exposed in utero and as young children The Working Group reviewed a large body may reflect a combination of greater biological of evidence that covers ecological studies, case– vulnerability in early life (Waalkes et al., 2007) control studies and cohort studies in a variety plus the fact that young children consume 5–7 of settings and populations exposed either by times more water per kilogram body weight per ingestion (primarily to AsIII and AsV in drinking- day than adults (NRC, 1993).] water) or inhalation (with exposure to a mixture of inorganic arsenic compounds). The evidence 2.5.2 Case–control studies also relates to historical exposure from pesticidal and pharmaceutical uses. The epidemiological In a case–control study investigating the evidence from drinking-water exposure permits consumption artesian well-water containing the evaluation of the carcinogenicity that is high concentrations of arsenic and mortality related to exposure to AsIII and AsV. The epidemi- from liver cancer in four townships of south- ological evidence from inhaled arsenic mixtures westernern Taiwan (China), Chen et al. (1986) permits the evaluation of the carcinogenicity observed an exposure–response relationship that is related to inorganic arsenic compounds. between the duration of consumption of the However, it does not allow a separation of the contaminated well-water and risk for liver cancer, carcinogenic risk associated with particular adjusted for cigarette smoking, habitual alcohol arsenic species that occur in these mixtures. and tea drinking, and consumption of vegetables The observed associations between exposure and fermented beans. to arsenic in drinking-water and lung cancer, and between exposure to arsenic in air and lung

52 Arsenic and arsenic compounds cancer, cannot be attributed to chance or bias. 3. Cancer in Experimental Animals The evidence is compelling for both the inhala- tion and ingestion routes of exposure. There is Over the years, it has proved difficult to evidence of dose–response relationships within provide evidence for the of inor- exposed populations with both types of exposure. ganic arsenic compounds. More recent work The observed association between exposure has focused on methylated arsenic metabolites to arsenic in drinking-water and bladder cancer in humans or exposure to inorganic arsenic cannot be attributed to chance or bias. There is during early life, and has provided the informa- evidence of dose–response relationships within tion to show potential links between arsenic and exposed populations. carcinogenesis. The observed association between exposure Studies published since the previous IARC to arsenic in drinking-water and skin cancer Monograph (IARC, 2004) are summarized below. cannot be attributed to chance or bias. There is evidence of dose–response relationships within exposed populations. The evidence is primarily 3.1 Oral administration for squamous cell carcinoma of the skin. 3.1.1 Mouse Although the data for kidney cancer are suggestive of a relationship with exposure to The oral administration of sodium arsenate arsenic in drinking-water, overall, the small in drinking-water for 18 months increased lung possibility of chance or bias cannot be completely tumour multiplicity and lung tumour size in ruled out. male A/J mice (Cui et al., 2006; see Table The evidence for an association between 3.1). liver cancer and long-term exposure to arsenic Similarly, drinking-water exposure to in drinking-water relies on mortality data. the organo-arsenical DMAV for 50 weeks or Although the data strongly suggest a causal asso- more increased the incidence and multiplicity ciation with some evidence of a dose–response of lung adenoma or carcinoma in strain A/J relationship, the Working Group could not rule mice (Hayashi et al., 1998), and increased lung out possible chance or bias. The evidence comes tumours in mutant Ogg−/− mice (which cannot mainly from Taiwan (China) where hepatitis B is repair certain types of oxidative DNA damage) highly prevalent. but not in Ogg+/+ mice (Kinoshita et al., 2007; The evidence for an association for pros- see Table 3.2). tate cancer and long-term exposure to arsenic in drinking-water relies on mortality data. 3.1.2 Rat In the studies from Taiwan (China), there is some evidence of a dose–response relationship. In male F344 rats, the oral administration V However, the data from South America are not of DMA in drinking-water for up to 2 years consistent with this observation. Although the produced clear dose–response relationships for evidence on prostate cancer suggests the possi- the induction of urinary bladder transitional cell bility of a causal association, the Working Group carcinoma and combined papilloma or carci- could not rule out the possibility of chance or noma (Wei et al., 1999, 2002). V bias. When DMA was added to the feed of male and female F344 rats for 2 years, a clear dose– response relationship for urinary bladder benign and/or malignant transitional cell tumours

53 IARC MONOGRAPHS – 100C

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

Species, strain (sex) Dosing regimen, Incidence of tumours Significance Comments Duration Animals/group at start Reference Mouse, A/J (M) 0, 1, 10, 100 ppm Lung (adenomas): [NS, (any dose)]a Age at start, 5 wk 18 mo arsenate in 0/19, 0/13, 0/15, 4/30 Purity, NR Cui et al. (2006) drinking-water, ad (13%) Redundant Student libitum Lung (adenocarcinomas): [NS, (any dose)]a t-test used for multiple 30/group 9/19 (47%), 10/13 (77%), comparisons of lung 11/15 (73%), 19/30 (63%) tumour multiplicity and size Average tumours/mouse P < 0.01 (all Survival significantly lung: doses) increased at high dose b 0.59, 1.1, 1.3, 1.4 Non-dose-related, Average number P < 0.01 (all modest changes in bw, tumours > 4 mm/mouse doses) lung weight, and lung bw lung: ratio 17, 32, 44, 60b a Performed during review. One-sided Fisher Exact test–control 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 significant; wk, week or weeks occurred in female but not male rats (Arnold et al., 3.2 Intratracheal administration 2006). Preneoplasia (urothelial cell hyperplasia) was clearly increased in female rats (Arnold et al., 3.2.1 Hamster 2006; see Table 3.2). Repeated weekly intratracheal instilla- In male F344 rats, the oral administration tions of , at levels sufficient of oxide in drinking-water for to caused moderate early mortality, increased 2 years caused a significant increase of benign lung adenoma formation in male Syrian golden liver tumours (adenoma) (Shen et al., 2007; see hamsters when observed over their lifespan Table 3.3). V (Pershagen & Björklund, 1985). Oral exposure to MMA for 2 years was In a similarly designed study, male hamsters negative in a comprehensive dose–response received multiple weekly intratracheal instil- study including male and female rats and mice, lations of calcium arsenate at the start of the although body weight suppression and reduced experiment, and developed an increased inci- survival with the higher doses confounded the dence of lung adenoma formation, and combined rat segment of the study (Arnold et al., 2003; see lung adenoma or carcinoma formation over their Table 3.4). lifespan (Yamamoto et al., 1987; see Table 3.6). A 2-year dose–response study with sodium Intratracheal instillations of calcium arsenite arsenite showed some evidence of renal tumour increased the incidence of respiratory tract carci- formation in female Sprague-Dawley rats but not noma and combined adenoma, papilloma and in males (Soffrittiet al., 2006). Tumour incidence adenomatoid lesion formation in male Syrian did not reach significance (see Table 3.5). Hamsters (Pershagen et al., 1984; see Table 3.7).

54 Arsenic and arsenic compounds

showed modest showed decreased

Ogg1−/− survival late compared to (~20%) phenotypic control Small groups Age start, at wk 14 Purity, 99% Bw and food and water consumption unremarkable Leftlobe and visiblelung nodules used for histopathological tumour analysis Treated Comments Age start, at 5 wk Purity, NR [Only histologically confirmed tumours consideredwere the by Working Group] Survival unremarkable (oral exposure) (oral V ] b < 0.01 < 0.05 < 0.05 < 0.01 < 0.01 (high < 0.01 dose) P NS P P [ P NS NS NS NS NS Significance P

– –

0/10, 5/10 (50%) Adenocarcinomas: 0/10, 3/10 (30%) lung tumours:Total Lung lesionsLung 0/10, 2/10 (20%) Tumours/mouse: 0, 0.5 Ogg1+/+: Tumour-bearing mice site): (any (60%) 6/10 (50%), 5/10 lesionsLung Hyperplasias: 10/10 (100%), 10/10 (100%) Adenomas: Hyperplasias: 2/10 (20%), 10/10 (100%) Tumour-bearing mice site): (any 0/10, 10/10 (100%) Ogg1-/-: Adenocarcinomas: 0/10, 0/10 tumours:Total 1/10 (10%), 0/10 Tumours/mouse: Tumours/mouse: Adenomas: 1/10 (10%), 0/10 0.1, 0 0.1, 0 Incidence tumours of Number mice of with lung papillary adenocarcinomas: or adenomas 2/14 (14%), 5/14 (36%), 7/14 (50%), (50%), 7/14 (36%), 5/14 (14%), 2/14 10/13 (77%)

V

; controls Ogg1-/-) (Ogg1+/+) ad libitum in drinking- in V 12/group 0, 50, 200, 400 ppm DMA Dosing regimen Animals/group at start water, 24/group in drinking-water, drinking-water, in ad libitum received 10/group ( 0, 200 DMA ppm

and . . (1998) et al

et al (M, F) Ogg1-/-

72 wk Kinoshita Hayashi Ogg1+/+ Table 3.2 of Studies experimental cancer in exposed animals acid, dimethylarsinic to DMA Table Species, strain (sex) Mouse, A/J (M) 50 wk Mouse, Duration Reference (2007)

55 IARC MONOGRAPHS – 100C

Purity > 99%; age, 5 wk treatment-relatedNo differences in mortality or bw Sporadic changes in food consumption not treatment-related consumptionWater increased with treatment consumptionWater increased with treatment Complete necropsies performed Comments Survival and food intake unaltered Incidence rates based rats on risk at (surviving to time the of firstbladder tumour 97 at wk) Age start, at wk 10 Purity, 99% Transient suppression bw early with high and middle dose then but similar to control intakeWater increased highest at two doses Extensive necropsy

b b b

b b b b

c c c c

b < 0.05 (high dose)] < 0.01 (high < 0.01 dose)] < 0.05 (high dose)] < 0.01 (highest, < 0.01 and second < 0.01 (trend) < 0.01 < 0.01 (trend) < 0.01 < 0.01 (trend) < 0.01 < 0.01 (trend) < 0.01 (trend) < 0.01 < 0.01 (middle < 0.01 and high dose) < 0.05 (middle dose) (high < 0.01 dose) (middle < 0.01 and high dose) (trend) < 0.01 P P P P [ [NS (high[NS dose)] [NS (high[NS dose)] P [ (high[NS dose)] [ (high[NS dose)] P Significance P P P P NS P P P P [ highest dose)]

0/60, 0/59, 0/60, 0/59, 6/60 (10%) 6/60 0/60, 0/59, 0/60, 0/59, Urinary (papillomas): bladder 4/60 (7%) 0/60, 0/59, 0/60, 0/59, Urinary bladder (carcinomas): Urinary (papillomas): bladder 0/59 (2%), 1/58 (2%), 1/60 0/60, 0/59, 0/60, 0/59, 0/60, 6/58 (10%), 40/59 40/59 0/60, (10%), 6/58 0/60, 0/59, (68%) Urinary bladder (papillomas and carcinomas combined): Males Urothelial cell (hyperplasias, simple, nodular and papillary): Urinary bladder (carcinomas): (3%) 2/59 0/60, 0/58, (2%), 0/60, 1/59 Urinary bladder (papillomas and carcinomas combined): 0/60, 0/59, 0/60, 0/59, 10/60 (3%) 10/60 0/60, 0/59, 0/60, 0/59, 1/580/60, (2%), 1/60 (2%), (2%), 1/59 2/59 (3%) Incidence tumours of Urinary bladder (carcinomas): (39%) 12/31 (19%), 6/31 0/28, 0/33, Urinary bladder (hyperplasias): (45%) 14/31 (39%), 12/31 0/28, 0/33, Urinary (papillomas): bladder (2%) 2/31 (2%), 2/31 0/28, 0/33, Urinary bladder (papillomas or carcinomas): (39%) 12/31 (26%), 8/31 0/28, 0/33, Females Urothelial cell (hyperplasias, simple, nodular and papillary): (49%), 0/60, 29/59 (2%), 0/60, 1/59 (80%) 48/60

ad libitum in drinking- in in feed, ad V V Dosing regimen Animals/group at start water, 36/group libitum 60/group 0, 2, 40, 10, 100 ppm DMA 0, 12.5, 50, 200 ppm DMA

,

d

. (2006)

. (1999) . et al

) et al 104 wk Arnold Table 3.2 (continued) Table Species, strain (sex) Rat, F344 (M) Rat, F344 (M, F) Duration Reference 104 wk Wei 2002

56 Arsenic and arsenic compounds

). Comments Fibrosarcomas not considered related to treatment by authors Bw reduced 500 at throughout ppm study Survival, and bw water consumption unchanged Sporadic, small changes in food early consumption Age start, at 5 wk Purity 99% Complete necropsies performed ., 2006 et al Arnold < 0.01 (high < 0.01 dose) Significance P

Incidence tumours of Any organ (fibrosarcomas): (2%), 1/56 (2%), 1/56 0/55, (5%), 3/56 6/56 (11%) Males treatment-relatedNo changes in urinary bladder preneoplasia or tumour incidence noted Females treatment-relatedNo changes in urinary bladder preneoplasia or tumour incidence noted

in feed, V

Dosing regimen Animals/group at start 56/group ad libitum 0, 8, 40, 200, 500 ppm DMA

. (2006)

et al

Performed during review. One-sided Fisher exact test control versus treated. Data also included descriptive statistics (i.e. SD). The lack of information on group size and the lack of descriptive statistics makes these data impossible to independently re-evaluate for statistical significance. Short communication of tumour data only. On a C57BL/6 background. Trend analysisTrend performed after combination femaleof and male data for urinary bladder lesions from this same study ( As stated by the authors.

Table 3.2 (continued) Table Species, strain (sex) Mouse, B6C3F1 (F) Duration Reference 104 wk Arnold

a b c d e f g bw, bodybw, weight; female; F, M, male; NR, not reported; NS, not significant; wk,week weeksor

57 IARC MONOGRAPHS – 100C

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

Species, strain (sex) Dosing regimen Incidence of tumours Significance Comments Duration Animals/group at start Reference Rat, F344 (M) 0, 50, 200 ppm Liver (adenomas): P < 0.05 (high Age at start, 10 wk 2 yr trimethylarsine oxide 6/42 (9%), 10/42 (14%), dose) Purity, 99% Shen et al. (2003) in drinking-water, ad 16/45 (24%) Body weights, food intake, libitum water intake, survival 42–45; 42 controls rate, and average survival unaltered with treatment Extensive necropsy performed Various other sites negative bw, body weight; M, male; yr, year or years

3.3 Intravenous administration developed dose-related benign and/or malig- nant ovarian tumours, and lung adenocarci- 3.3.1 Mouse noma. During the next 74 weeks, a dose-related Multiple intravenous injections of sodium increase in the incidences of liver adenoma and/ arsenate in male and female Swiss mice provided or carcinoma, and adrenal cortical adenoma was no evidence of elevated tumour formation observed in the male offspring Waalkes( et al., (Waalkes et al., 2000; see Table 3.8). 2003). A second study looked at the carcino- genic effects in C3H mice of various doses of 3.4 Transplacental and perinatal sodium arsenite (two levels) in the maternal exposures drinking-water from Days 8 to 18 of gestation, with or without subsequent 12-O-tetradecanoyl 3.4.1 Mouse phorbol-13-acetate (TPA) applied to the skin of Pregnant mice were treated subcutaneously the offspring after weaning from 4–25 weeks of with arsenic trioxide on a single specific day age. Over the next 2 years, with arsenic alone, during gestation (Days 14, 15, 16 or 17), and the the female offspring developed an increased inci- offspring were then treated subcutaneously on dence of ovarian tumours. The male offspring postpartum Days 1, 2 and 3 with arsenic trioxide. developed arsenic dose-related increases in the The offspring initially treated on Day 15 of incidences of liver adenoma and/or carcinoma gestation developed an excess of lung adenoma and adrenal cortical adenoma (Waalkes et al., compared to controls, and the other groups did 2004). not (Rudnai & Borzsanyi, 1980, 1981; see Table Pregnant CD1 mice received sodium arsenite 3.9). (one level) in the drinking-water from gestation Pregnant C3H mice were exposed to various Days 8 to 18, were allowed to give birth, and the doses of sodium arsenite in the drinking-water female (Waalkes et al., 2006a) or male (Waalkes from Days 8–18 of gestation. They were allowed et al., 2006b) offspring were treated with diethyl- to give birth and their offspring were put into stilbestrol or tamoxifen subcutaneously on post- gender-based groups at weaning. Over the partum Days 1, 2, 3, 4 and 5. In female offspring next 90 weeks, arsenic-treated female offspring over the next 90 weeks, arsenic exposure alone

58 Arsenic and arsenic compounds

(oral exposure) (oral V Survival unremarkable Complete necropsy performed Bw reduced 400 at throughout ppm study Food and water consumption similar or increased the at two higher doses Age start, at 6 wk Purity, 99% Food consumption generally similar consumptionWater similar increased or theat two higher doses Survival reduced high at dose Bw reduced two at highest doses in second half study of Complete necropsy performed Purity, 99% Age start, at 6 wk Comments Significance No treatment-relatedNo changes No treatment-relatedNo changes Incidence tumours of

V

V

ppm MMA a in feed, ad libitum 52/group/sex in feed, ad libitum 60/group/sex Dosing regimen Animals/group at start 50,0, 200, 10, 400 MMA ppm 0, 50, 400, 1 300

. (2003) . (2003)

et al et al

Due to a high mortality in male and female rats fed this level, it was reduced to 1000 ppm during and 53, Week further reduced to 800 ppm during 60. Week

104 wk Arnold Table 3.4 of Studies experimental cancer in exposed animals monomethylarsonic to acid, MMA Table Species, strain (sex) Mouse, B6C3F1 (M, F) Rat, F344 (M, F) Duration Reference 104 wk Arnold a bw, bodybw, weight; female; F, M, male; wk, week or weeks

59 IARC MONOGRAPHS – 100C

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

Species, strain (sex) Dosing regimen Incidence of tumours Significance Comments Duration Animals/group at Reference start Rat, Sprague-Dawley 0, 50, 100, 200 mg/L Kidney (tumours): NS for both sexes Age at start, 8 wk

(M, F) NaAsO2 in drinking- F– Purity 98% 167 wk (lifespan) water, ad libitum from 1/50 (2%), 1/50 (2%), Complete necropsy Soffritti et al. (2006) onset to 104 wk 5/50 (10%), 5/50 (10%)c performed 50/group M– Reduced water and food 0/50, 2/50 (4%), 2/50 intake especially at two (4%), 0/50 highest doses Dose-related reduced bw a As stated by the authors. b The lack of information on group size and lack of descriptive statistics makes the data from this work impossible to re-evaluate for statistical significance. c Includes three carcinomas at the high dose and one at the second highest dose in females and a carcinoma in females at the second highest dose. Bw, body weight; F, female; M, male; NS, not significant; wk, week or weeks increased the incidence of tumours of the ovary, In the studies of Germolec et al. (1997, 1998), uterus, and adrenal cortex. In the male offspring, oral sodium arsenite was given to Tg.AC mice prenatal arsenic exposure alone increased liver with TPA by skin painting, and an approxi- adenoma and/or carcinoma, lung adenocarci- mately 4-fold increase in skin tumour response noma, and adrenal cortical adenoma (see Table was reported. 3.10). Combined treatment with oral sodium arsenite in drinking-water and multiple expo- 3.5 Studies in which arsenic modifies sures to excess topical UV irradiation in Crl:SKl- hrBR hairless mice showed that arsenic treatment the effects of other agents alone was consistently without carcinogenic 3.5.1 Mouse effect, but markedly enhanced UV-induced skin tumours including squamous cell carcinoma Mice exposed to DMAV in drinking-water (Rossman et al., 2001; Burns et al., 2004; Uddin after subcutaneous injection of 4-nitroquino- et al., 2005). In another skin study, mice exposed line 1-oxide showed an increase in lung tumour to topical 9,10-dimethyl-1,2-benzanthracene for multiplicity compared to mice exposed to the 2 weeks concurrently with oral sodium arsenate organic carcinogen alone (Yamanaka et al., in drinking-water for 25 weeks showed that 1996). In K6/ODC mice first treated topically arsenic treatment alone was without carcino- with 7,12-dimethylbenz[α]anthracene (DMBA) genic effect, but enhanced skin tumour multi- then with DMAV in a cream applied to the same plicity and tumour size when combined with skin area for 18 weeks, the organo-arsenical the organic carcinogen compared to the organic doubled the skin tumour multiplicity compared carcinogen alone (Motiwale et al., 2005; see Table to treatment with DMBA alone (Morikawa et al., 3.12). 2000; see Table 3.11). [The Working Group noted When pregnant Tg.AC mice were treated that this study had too few DMAV controls for an with oral sodium arsenite in drinking-water appropriate interpretation.] from Days 8–18 of gestation, and their offspring were topically exposed to TPA from 4–40 weeks

60 Arsenic and arsenic compounds

Age start, at 8 wk Purity, ultrapure Mortality during dosing ~15%; mortality increased in arsenate group during second yr Dose approximate Comments Age start, at 8 wk Purity, chemical grade Instillations caused mortality 10% and reduced survival post- ~10% instillation recordedBw not during experiment

] ] a a < 0.01 < 0.01 < 0.05 -value not reported reported not -value P P P Significance [ NS P but stated as significant [

Lung (adenomas): 0/26, 4/35 (11%) Incidence tumours of Lung (adenomas): 0/22, 6/25 (24%) Lung (carcinomas): Lung 1/25 (4%) 1/22 (4%), Lung (adenomas and carcinomas combined): 1/22 (4%), 7/25 (3%)

once/wk wk for 15 controls 29 41; 0, ~3 mg As/kg0, ~3 mL in bw 0.15 saline Dosing regimen Animals/group at start 0, 0.25 mg As in mL 0.1 saline once/wk wk for 15 30; 22 controls

. (1987)

et al

Calculated by the Working Group. One-sided Fisher exact test control versus treated.

Pershagen & Björklund (1985) Table 3.6 Studies of cancer in experimental animals exposed to calcium arsenate (intratracheal instillation) 3.6 of Studies experimental cancer in exposedinstillation) animals calcium to arsenate (intratracheal Table Species, strain (sex) Hamster, Syrian golden (M) Hamster, Syrian golden (M) Duration Reference wk (lifespan)~145 wk in treated to 115 Up and animals, 121 wk in controls121 (lifespan) Yamamoto a bw, bodybw, weight; M, male; NS, not significant; wk,week weeksor

61 IARC MONOGRAPHS – 100C

Age start, at wk 7–9 Purity, 99.5% Doses approximate Instillation mixture arsenic for contained dust and 2 mM sulfuric in acid controls) (not Significant mortalityduring dosing (29%) lesion” not defined,“Adenomatoid presumably focal hyperplasia Comments < 0.01] P NS Significance [

Larynx, trachea, bronchus, or (carcinomas): lung (6%) 3/47 0/53, Incidence tumours of Larynx, trachea, bronchus, or lung (adenomas, adenomatoid lesions, and papillomas combined): 7/53 (13%), 24/47 (51%)

]pyrene and the combination appeared to increase combined adenoma, adenocarcinoma and adenosquamous carcinoma in the bronchi a 0 or ~3 mg As/kg ~3 0 or in bw 0.15 saline mL once/wk wk for 15 68 controls67; Dosing regimen Animals/group at start

]pyrene alone but the data are listed (total tumours/group and not incidence) such that this cannot be independently confirmed. a

a

. (1984) et al

Arsenic trioxide was also given with benzo[

Table 3.7 Studies of cancer in experimental animals exposed to arsenic trioxide (intratracheal instillation) of Studies experimental cancer in instillation) 3.7 exposed animals (intratracheal arsenic to trioxide Table Species, strain (sex) Hamster, Syrian golden (M) Duration Reference wk (lifespan) to ~140 Up Pershagen and compared to benzo[ bw, bodybw, weight; M, male; NS, not significant; wk,week weeksor a

62 Arsenic and arsenic compounds

Comments Survival and not remarkable bw leukaemiasNo observed were Age start, at 8 wk Purity, NR < 0.05 < 0.05 P Significance NS P NS NS

b

Incidence tumours of M Lymphomas: 1/25 1/25 (4%), (4%) Testicular interstitial cell cell interstitial Testicular hyperplasias: (64%) 16/25 (32%), 8/25 Skin hyperkeratosis: 5/25 (20%) 1/25 (4%), F Lymphomas: (12%) 3/25 (20%), 5/25 Uterine cystic hyperplasias: (56%) 14/25 (20%), 5/25

a .

Dosing regimen Animals/group at start 0, 0.5 mg As/kg in bw 10 mL/ kg in saline once/wk 20 for wk staring at onset; controls received saline 25/group/sex

. (2000) .

et al

A uterine adenocarcinoma was also observed with arsenate treatment that is noteworthy because of its spontaneous rarity in historical controls of this strain. Based on the treatment regimen of Osswald & Goerttler (1971)

Table 3.8 Studies of cancer in experimental animals exposed to sodium arsenate (intravenous exposure) 3.8 exposure) of Studies experimental cancer in exposed animals sodium to arsenate (intravenous Table Duration Reference Species, strain (sex) Mouse, Swiss CR:NIH(S) (M, F) 96 wk Waalkes a b bw, bodybw, weight; female; F, M, male; NR, not reported; NS, not significant; wk,week weeksor

63 IARC MONOGRAPHS – 100C

Purity stated as “purum” Pregnancy verifiedby smear and when positive designated Day 0 Dam number used to derive offspring groups NR Lung and gross lesions histologically examined Survival and NR bw Gender NR and probably mixed Numbers specific of lung tumours NR Comments b < 0.01 (Day 15) (Day < 0.01 P Significance

b

Lung (adenomas and adenocarcinomas): Control–3/17 (17%) Day 14–14/36 (39%) Day 15–12/19 (63%) Day 15–12/19 Day 16–3/20 (15%) Day 17–6/20 (30%) Incidence tumours of

) is due to a difference in calling the firstday on which pregnancy was indicatedDay 1 of gestation rather thanDay 0 as in the

). Thus,). the treatment regimen and data from theprimary paper are herein reported. Single dose mg/kg 1.2 of arsenic trioxide s.c. bw gestation at Day 17 or 16, 15, 14, offspring: Test 5 µg arsenic trioxide/mouse s.c. postpartum 2 and Day 1, 3 untreated Controls Offspring sizesgroup at start (NR) Dosing regimen Animals/group at start Rudnai & Borzsanyi, 1981 , a

Rudnai & Borzsanyi, 1980

The gestational treatment day is given in parentheses before incidence or after indication of significance. In Hungarian. incidence Tumour data are numerically the same for this and the Rudnai & Borzsanyi manuscript, (1980) but vary in that the treatment day of pregnancy which lead

Rudnai & Borzsanyi (1981) Table 3.9 Studies of cancer in experimental animals exposed to arsenic trioxide (perinatal exposure) of Studies experimental cancer in 3.9 exposed exposure) animals (perinatal arsenic to trioxide Table Species, strain (sex) Mouse, CFLP (NR) Duration Reference 1 yr Rudnai & Borzsanyi (1980) a b bw, bodybw, weight; NR, not reported; s.c., subcutaneously; yr, year or years original report ( to a significant increase lungin adenoma in the first 15)paper shifted(Day to one day later in the 16).second paperCommunication(Day with the primary authordiscrepancy revealed that in the this re-reporting (

64 Arsenic and arsenic compounds

NR a 10 Pregnant10 mice used to derive each group offspring of Offspringweaned at 4 wk Maternal water consumption and bw unaltered Offspringbw unaltered Survival in offspring unaltered in females Survival reduced high at dose in due to liver carcinoma in males Comments Purity,

< 0.05 < 0.05 (high dose) < 0.05 (trend) < 0.05 (high dose) < 0.05 (trend) (high < 0.01 dose) < 0.05 (high dose) < 0.01 (trend) < 0.01 < 0.05 (high dose) (trend) < 0.01 < 0.05 (high dose) (trend) < 0.01 < 0.05 (high dose) (trend) < 0.01 < 0.05 (high dose) < 0.05 (trend) Significance P (high dose plus trend) NS P P P P P P P P P P P P P P P

Incidence tumours of Females Ovary (tumours): 8/24 4/23 (17%), Benign–2/25 (8%), (33%) Malignant–0/25, 2/23 1/24 (9%), (4%) Benign malignant or combined– (37%) 9/24 (26%), 6/23 2/25 (8%), (carcinomas): Lung (20%) 5/24 (4%), 1/23 0/25, Males (adenomas): Liver 20/23 (87%) (43%), 9/21 (37%), 9/24 (hepatocellularLiver carcinomas): (61%) 14/23 (38%), 8/21 2/24 (8%), Liver (adenomas or hepatocellular or (adenomas Liver carcinomas): 20/23 (87%) (52%), 11/21 (42%), 10/24 Liver tumours/mouse: 0.87, 1.81, 4.91 Adrenal cortex (adenomas): (91%) 21/23 (67%), 14/21 (37%), 9/24 Adrenal adenomas/mouse: 0.71, 1.10, 1.57

ad

from gestation Dosing regimen Animals/group at start Offspring; 25/group/sex Maternal exposure: 0, 42.5, As ppm 85 in drinking-water, libitum Day 8–18

) for F ) for ) for M ) for . (2003)

et al postpartum postpartum Table 3.10 Studies of cancer in experimental animals exposed to sodium arsenite (transplacental exposure) of Studies experimental cancer in exposure) exposed animals sodium to arsenite (transplacental 3.10 Table Species, strain (sex) Mouse, C3H/HeNCr (M, F) Duration Reference 90 wk ( wk ( 74 Waalkes

65 IARC MONOGRAPHS – 100C to no

NR a Purity, Arsenic to due group given not TPA liver carcinoma (males) 10 Pregnant10 mice used to derive each group offspring of Litters culled 4 d postpartum at thanmore 8 pups Maternal water consumption and bw unaltered Small reductions bw (~10%) occurred in the late (> 95 wk) high- female offspringdose (85 ppm) did alter not TPA bw Survival unaltered did an have not Inclusion TPA of impact skin on cancers Comments

< 0.05 (high dose) (trend) < 0.01 < 0.05 (high dose) (trend) < 0.01 < 0.05 (high dose) (trend) < 0.01 < 0.05 (high dose < 0.05 (high dose) (trend) < 0.01 < 0.05 (both doses) < 0.05 (both doses) < 0.05 (high dose < 0.05 (high dose < 0.05 (high dose P P P P P P P and trend) P P Significance P P NS P and trend) NS P and trend) NS P and trend) c

Adenomas with TPA–8/23 (35%), 12/23 12/23 Adenomas with (35%), TPA–8/23 (52%), 16/21 (76%) Hepatocellular carcinomas without 10/21 (35%), 8/23 (12%), TPA–3/24 (48%) Hepatocellular carcinomas with (33%) 7/21 (26%), 6/23 (9%), TPA–2/23 Adenomas or hepatocellular carcinomas (50%), without TPA–12/24 (90%) 19/21 (52%), 14/23 Incidence tumours of Females hepatocellular or (adenomas Liver carcinomas): Without TPA–0/24, 5/23 (22%), 4/21 4/21 Without TPA–0/24, (22%), 5/23 (19%) (19%) 4/21 With (23%), 5/22 TPA–0/24, Lung (adenomas): 2/21 2/23 (9%), (4%), Without TPA–1/24 (9%) 6/21 2/22 (9%), (4%), With TPA–1/24 (29%) Males Liver (tumours): Adenomas (42%), without TPA–10/24 (90%) 19/21 (52%), 12/23 Without TPA–3/24 (12%), 6/23 (26%), 6/23 (26%), (12%), Without TPA–3/24 4/21 (19%) 8/21 (27%), 6/22 (12%), With TPA–3/24 (38%) Liver tumour multiplicity (tumours/ mouse): 0.29 0.41, Without TPA–0.13, 0.32,With 0.71 TPA–0.13, Ovary (tumours):

ad TPA/0.1 b

from gestation Offspring exposure: topical 2 µg 0, 42.5, As ppm 85 in drinking-water, libitum Day 8–18 Dosing regimen Animals/group at start Maternal exposure: mL acetone, twice/ acetone, mL wk from 4–25 wk of age applied to shaved received controls back, acetone Offspring groups: 25/group/sex

) . (2004)

et al postpartum Table 3.10 (continued) 3.10 Table Species, strain (sex) Mouse, C3H/HeNCr (M, F) Duration Reference wk104 ( Waalkes

66 Arsenic and arsenic compounds

2

Litters culled afterbirth no more to than 8 pups Maternal water consumption unaltered Maternal and offspringbw unaltered 12 Pregnant12 mice used to derive each group offspring of Comments Purity 97.0% NaAsO Purity 97.0%

< 0.05 + DES) (As < 0.05 (As, As + < 0.05 + DES) (As < 0.05 (As, As + < 0.05 (high dose) (trend) < 0.01 < 0.05 (both doses) (trend) < 0.01 < 0.05 (both doses) (trend) < 0.01 < 0.05 (high dose < 0.05 (low dose) < 0.05 (low dose) < 0.05 (As, As + P P DES, As + TAM) Significance NS P P DES) P P P P P P P and trend) P NS P P DES, As + TAM)

(15%), 0/35 g

h

Adrenal cortex (adenomas): 2/35 (9%), 3/33 (26%), 9/34 (3%), 1/33 (6%), 8/33 (24%), 7/35 (20%) Urinary bladder lesions: Females Ovary (tumours): Incidence tumours of Uterus (adenomas): 0/33, 3/34 0/33, 0/35, (9%), 0/33, 0/35 (carcinomas): Uterus 7/33 (6%), 2/35 0/33, 2/34 (6%), 0/33, (21%), 2/35 (6%) Uterus (adenomas or carcinomas): 7/33 (6%), 2/35 0/33, (15%), 5/34 0/33, (21%), 2/35 (6%) (carcinomas): Vagina 0/33, 0/34, 1/33, 0/35, 5/33 Adenomas or hepatocellular carcinomas 15/23 with (39%), TPA–9/23 (65%), 18/21 (90%) Multiplicity without 0.75, 1.87, TPA: 2.14 Multiplicity 1.44, with 2.14 0.61, TPA: Adrenal cortex Without (adenomas): 15/21 (65%), 15/23 (37%), TPA–9/24 (71%) (65%), 15/23 (30%), With TPA–7/23 12/21 (57%) Lung (adenomas): 6/23 (26%), Without TPA–4/24 (17%), 5/21 (24%) 5/21 (43%), 10/23 (9%), With TPA–2/23 (24%) 0/33, 7/34 (21%), 2/33 (6%), 1/35 (3%), (3%), 1/35 (6%), 2/33 (21%), 7/34 0/33, (14%) 5/35 (26%), 9/33

ad /pup/d e Day 1, 2, Day3, 1, /pup/d s.c., /pup/d

d

from gestation or 10 µg TAM 10 or s.c., vehicle or oil; (corn control) As,(control, DES, TAM, As + DES, As + TAM) 35/group/sex Dosing regimen Animals/group at start Offspring exposure: Postpartum 4, and 5 2 µg DES 0, As ppm 85 in drinking-water, libitum Day 8–18 Maternal exposure: k ) b ,

) . (2004) . (2006a

et al et al postpartum Table 3.10 (continued) 3.10 Table Species, strain (sex) Waalkes (M, F) Mouse, CD1 Duration Reference (contd.) 90 wk ( Waalkes

67 IARC MONOGRAPHS – 100C

(males) l

Purity sodium arsenite DES 97.0%; 99%, TAM 99% by Bw transiently reduced (~15%) DES TAM early or recovery but to control levels 5–20 by wk postpartum Survival unaltered by prenatal arsenic alone. Survival reduced in all other treatment groups (DES, TAM, As + DES, As wk from + TAM) ~20 comparedon to control Comments < 0.05 + DES, (As < 0.05 + DES, (As < 0.05 + DES) (As < 0.05 (As, As + < 0.05 (As, As + < 0.05 (As, As + < 0.05 (As) < 0.05 (As, As + < 0.05 + DES, (As Significance P As + TAM) NS P As + TAM) P NS P DES, As + TAM) P DES, As + TAM) P DES,) P P DES, As + TAM) P As + TAM) NS

–

j

(29%) g (30%) g

–

i

(45%), 9/30 (38%), 10/35 (38%), g g Incidence tumours of 1/33 (3%), 5/34 (15%), 1/33 (3%), 0/35, 0/35, (3%), 1/33 (15%), 5/34 (3%), 1/33 13/33 Papillomas– (10%) 3/30 0/30, 0/29, 0/33, 0/35, 0/35, Liver (tumours any type): 5/33 0/35, (3%), 1/33 4/34 (12%), 0/33, (15%), 4/35 (11%) Males Liver (tumours): 0/33, 0/34, 0/33, 0/35 0/35, (9%), 3/33 proliferativeTotal lesions Adenomas– 0/30, (3%), 1/33 (23%), 8/35 (6%), 2/35 (30%) 9/30 (41%), 12/29 Hepatocellular carcinomas– 0/30, 4/29 (14%), 0/33, (14%), 5/35 0/35, 5/30 (17%) Adenomas or carcinomas– 0/30, (3%), 1/33 (31%), 11/35 (6%), 2/35 (47%) 14/30 (48%), 14/29 Lung (adenocarcinomas): 0/30, (6%), 2/33 (26%), 9/35 (6%), 2/35 (20%) 6/30 4/29 (14%), Adrenal cortex (adenomas): (31%), 0/30, 9/29 0/33, (37%), 13/35 0/35, 11/30 (37%) Urinary bladder lesions: Hyperplasias– (10%), 3/30 (12%), 4/33 (9%), 3/35 0/35, 13/29 Hyperplasias– 0/35, (3%), 1/33 (15%), 5/34 (3%), 1/33 (26%) 9/35 (30%), 10/33 Papillomas– 0/33, 0/34, 0/33, 0/35, 0/33, 1/35 (3%) Carcinomas

Dosing regimen Animals/group at start ) b ,

. (2006a

et al Table 3.10 (continued) 3.10 Table Species, strain (sex) Waalkes Duration Reference (contd.)

68 Arsenic and arsenic compounds Comments < 0.05 + DES, (As < 0.05 + TAM) (As P As + TAM) Significance P NS

g

g study but reported separately. – 0/35, 3/35 j . (2006a) et al (40%) – g i < 0.05) higher than arsenic alone. P Incidence tumours of (13%) proliferativeTotal lesions (9%), 4/33 (12%), 3/30 (10%), 13/29 (10%), 3/30 (12%), 4/33 (9%), (45%), 14/30 0/35, 0/35, 0/33, 0/30, 1/29 (3%), 1/30 1/30 (3%), 0/30, 1/29 0/33, 0/35, 0/35, (3%) Papillomas or carcinomas– 4/30 (3%), 0/30, 1/29 0/33, 0/35, 0/35, Carcinomas

using same chemical source is 97.0%. Dosing regimen Animals/group at start . (2006a) ) et al b ,

. (2006a

et al -tetradecanoyl phorbol-13-acetate. O Primarily adenoma. Defined by theauthors as the incidence of mice bearing at least one uroepithelialpreneoplasia (hyperplasia), papilloma, or carcinoma. Exclusively transitional cell carcinoma. Run concurrently with and derived from the same mothers as the females in Waalkes Purity given in Waalkes Incidence for arsenic plus DES or arsenic plus TAM was significantly ( Exclusively epithelial and primarily adenoma. Included benign and malignant epithelial and mesenchymal tumours within components of the urogenital system (ovary, oviduct, uterus, cervix, vagina, kidney, and urinary bladder). Reduced survival in these groups appeared dependent on moderate to extensive kidney damage due to DES and TAM in male mice and appeared unrelated to arsenic exposure. Two renal tumoursTwo also occurred in this group including, an adenoma and a renal cell carcinoma, against none in control, which are noteworthy because of their rare spontaneous

Diethylstilbestrol 12-

Tamoxifen

Table 3.10 (continued) 3.10 Table Species, strain (sex) Waalkes Duration Reference (contd.)

a b c d e f g h i j k l m occurrence in mice. d, day or days; DES, diethylstilbestrol; female; F, M, male; NR, not reported; NS, not significant, s.c., subcutaneously;TAM, tamoxifen; wk,week weeksor

69 IARC MONOGRAPHS – 100C

purity, NR alone group not included purity, NR -alone group had only 2 mice; V V V V skin tumours reported not Small group sizes Skin only quantitativeNo microscopic analysis of skin tumours Bw and survival unremarkable DMA Bw and survival unremarkable DMA Lung only Microscopic analysis lung of tumours reportednot (largely confirmed as tumours) Small group sizes Comments Age start, at wk 10–14 DMA Age start, at 6 wk DMA Age start, at NR Purity, NR Arsenic lowered and bw water intake reported never reporting and Limited full in < 0.05 < 0.05 (high dose) < 0.05 Significance P P P

Incidence tumours of Macroscopic skin tumours/ mouse: 9.7, 19.4 Macroscopic lung tumours/ mouse: 0.22, 3.92, 4.38 Renal tumours: 7/10 0/9, (14%), 1/7 0/10, (70%)

V in V

/mouse f

/kg bw bw /kg e

/mouse in “neutral V /kg 7 d later i.p.; a

topical dorsal skin then 1; Week at 3.6 mg DMA Dosing regimen Animals/group at start 7; 8 controls 7; (DMBA) drinking-water 25 wk for Groups: 4NQO alone, 4NQO + 200 ppm DMA, 4NQO + 400 ppm DMA 9–13/group s.c. then 200 400 or DMA ppm cream” to dorsal skin twice/wk, Week 2–19 Groups: DMBA, + DMA DMBA 160 ppm As in160 ppm drinking-water Number start, at NR Initiation mg 4NQO 10 Single 50 µg dose DMBA of arsenite Sodium Partial later 18–24 h heptectomy, 30 mg DEN

. (1996) . (2000) . . (1983) et al et al

et al K6/ODC

(C57BL/6J background) (C57BL/6J 20 wk Morikawa 175 d Shirachi Table 3.11 Studies where Studies after arsenicals given other no effect carcinogenesis agents enhance while having in alone 3.11 Table animals experimental Species, strain (sex) Mouse, ddy (M) 25 wk Yamanaka Mouse, Rat, Wistar (M) Duration Reference

70 Arsenic and arsenic compounds

initially V

purity, 99%; DMA increased water intake high at alone groups were included but V V V

lowered but then but lowered increased bw; changes moderate and high at dose DMA Age start, at 7 wk DMA dose Survival unremarkable Separate 100 and 400 (12 each) ppm DMA had tumours no preneoplastic or lesions Comments

treatment treatment V V

< 0.01 (second < 0.01 (high < 0.01 dose < 0.05 (trend) < 0.05 (highest two < 0.05 (highest two) (trend) < 0.01 < 0.05 (highest) (trend) < 0.01 < 0.01 (three lowest) < 0.01 < 0.05 (highest) < 0.01 Significance P (all DMA P highest) P and trend) P P and trend) P P P P groups) groups) P P P (all DMA

c

Incidence tumours of Urinary bladder: Papillomas or carcinomas– 16/19 (85%), 17/20 2/20 (10%), (84%), 17/20 (85%), 16/20 (80%) Kidney: Adenomas– 1/19 3/201/20 (15%), (5%), (5%), 7/20 (35%), 3/20 (15%) Adenocarcinomas– 1/20 (10%), 0/20, 0/20, 2/19 (5%), 7/20 (35%) Total– 6/19 (15%), 3/20 (25%), 5/20 13/20 (65%), 13/20 (30%), (65%) Liver: Hepatocellular carcinomas– 8/20 0/19, 0/20, 2/20 (10%), (40%), 8/20 (40%) Total– (10%), 2/19 0/20, 2/20 (10%), 17/20 (85%), 13/20 (65%) thyroidTotal gland tumours: 8/19 2/20 (10%), (15%), 3/20 (45%) 9/20 6/20 (30%), (40%), Papillomas– 12/19 12/20 (60%), (5%), 1/20 (63%), 11/20 (55%), 7/20 (35%) Transitional cell carcinomas– 10/20 11/19 1/20 (50%), (5%), 13/20 12/20 (60%), (60%), (65%) , V in ) then V b

V

, DMBDD + 100 ppm + 100 ppm , DMBDD V , DMBDD + 200, DMBDD DMA ppm V

the drinking-water during Week Week during drinking-water the 6–30 Groups: alone, DMBDD + DMBDD 50 DMA ppm 0, 50, 100, 200, 400 DMA ppm DMA Dosing regimen Animals/group at start Initial pretreatment with 5 known carcinogens DMBDD (termed DMBDD + 400DMBDD DMA ppm 20/group

. (1995) et al

Table 3.11 (continued) 3.11 Table Species, strain (sex) Rat, F344/DuCrj (M) Duration Reference 30 wk Yamamoto

71 IARC MONOGRAPHS – 100C

-nitrosourea mg/kg, (20 s.c.) on N purity, 99% alone groups included were (12 V V Separate 0 and control 100 ppm and DMA urinary no showed but each) bladder tumours or preneoplastic lesions water intakeBw, and survival unremarkable Urinary bladder only Comments Age start, at ~6 wk DMA -methyl- N

< 0.05 (highest two < 0.01 (highest < 0.01 three < 0.05 (third highest (highest < 0.01 two Significance P doses) P doses) P dose) P doses) -bis(2-hydroxypropyl)nitrosamine in the drinking-water, (0.1% Weeks 3 and 4).

Incidence tumours of Urinary bladder: Papillary/nodular hyperplasias– (65%), 13/20 (70%), 14/20 (95%), 18/19 (70%), 14/20 (100%) 20/20 (100%), 20/20 Papillomas– 7/20 2/20 (10%), (15%), 3/20 13/20 (58%), 11/19 (35%), (65%), 17/20 (85%) Carcinomas– 3/20 2/20 (10%), (5%), 1/20 (15%), 7/19 (37%), 10/20 (50%), 12/20 (60%) , BBN in V V

0.05% in d

, BBN + 100 ppm + 100 ppm , BBN V

, BBN + 10 ppm DMA ppm + 10 , BBN V V DMA Dosing regimen Animals/group at start Pretreatment with BBN drinking-water wk 32 for alone,Groups: BBN + 2 ppm BBN DMA drinking-water 4 wk for then 0, 2, 25, 50, DMA 100 ppm or 10, 20/group + 50 DMA ppm

-(4-hydroxybutyl)nitrosamine in (0.05% the drinking-water Weeks 1 and and 2) N . (1996) N

et al -(4-hydroxybutyl)nitrosamine

-butyl- N N

-butyl- The organic carcinogen treatment consisted of a single dose of diethylnitrosamine(100 mg/kg, at the i.p.) start of the experiment) and Estimated from graphical presentation. N For brevity, only significantproliferative lesions are noted for each tissue

Diethylnitrosamine 4-Nitroquinoline

Table 3.11 (continued) 3.11 Table Species, strain (sex) Rat, F344 (M) Duration Reference 36 wk Wanibuchi 7,12-dimethylbenz[α]anthracene Altogether this was defined DMBDDas treatment. Rats received no treatment for 2 wk after DMBDD exposure and before DMA exposure. experimental Days and 5, Thereafter, 8, 14. 11 rats received 1,2-dimethylhydrazine (40 mg/kg, onDays s.c.) 18, 22, 26,30). and During the same period (experimentalreceived Days 0–30) the rats a b c d e f g d, day or days; DMA, dimethylarsinic acid; female; F, i.p., intraperitoneal; M, male; NR, not reported; s.c., subcutaneously; wk, week or weeks

72 Arsenic and arsenic compounds

Age start, at NR Purity, NR Survival unremarkable Specific quantitative microscopic analysis skin of tumours not included confirmed but as papillomas at termination Skin lesions only Incomplete reporting makes independent statistical analysis impossible Age start, at 8 wk Purity, NR Survival impacted high-dose by co-treatmentTPA specifics but not given Quantitative microscopic analysis skinof tumours included not confirmedbut as papillomas at termination Skin lesions only Incomplete reporting makes independent statistical analysis impossible Comments NR NR Significance b in b

b

b

2.5 TPA ~3/mouse, 2.5 TPA b in arsenic ~7/mouse + 2.5 TPA Macroscopic skin papillomas/ mouse: in none control or arsenic alone, intermediate in alone (~0.5/mouse), TPA arsenic + TPA Incidence tumours of Macroscopic skin papillomas/ mouse: 0 in control, As alone, alone;and 1.25 TPA maximalAs + 1.25 TPA ~5/ mouse, “4-fold higher”“4-fold (~2.1/mouse)

throughout throughout

/mouse in a

ad libitum ad libitum Groups: control, As alone, TPA, As + TPA 20/group acetone topical to shaved dorsal skin twice/wk, 5 and 6 Week Dosing regimen Animals/group at start 0.02%0 or As in drinking- water, experiment 2.50 or µg TPA 0.02%0 or As in drinking- water, experiment 0, 1.25, 2.5 in µg TPA/mouse acetone topical to shaved dorsal skin twice/wk, 5 and 6 Week Groups: control, As alone, 1.25 2.5 As + 1.25 TPA, TPA, TPA, As + 2.5 TPA 20/group

. (1997) . (1998) et al et al

Table 3.12 Studies where Studies concurrently arsenicals with given other no effect carcinogenesis agents enhance while having 3.12 Table experimentalalone in animals Duration Reference 14 wk Germolec 24 wk Germolec Species, strain (sex) homozygousMouse, (F) Tg.AC homozygousMouse, (F) Tg.AC

73 IARC MONOGRAPHS – 100C

Survival and unremarkable bw Small control groups Age start, at 3wk Purity, NR Age, 3 wk Survival and unremarkable bw Specific quantitative microscopic analysis skin of tumours reportednot confirmed but as primarily squamous cell carcinomas at termination Experiment 1 shows clear arsenic dose–response in enhancement through 5.0 mg/L various by criteria Comments ] e ] f < 0.01 all < 0.01 groups vs < 0.01 < 0.01 < 0.01 < 0.01 P P P P P [ alone UVR [ Significance

: 2.4 d d

Macroscopic analysis– Time to first occurrence: + As UVR earlier than UVR Microscopic analysis– tumoursTotal all mice: + UVR)53 (UVR), (As 127 Highly invasive squamous cell carcinoma: UVR), (26%; 14/53 As64/127 (50%; + UVR) volume: UVRTumour smaller than As + UVR Skin (tumours): Macroscopic and microscopic analysis–0/5, and (control 0/5 As alone) (UVR), 5.4 (1.25 As (UVR), + UVR), (1.25 5.4 (5.0 As (2.5 As + UVR), 11.1 7.21 As+ UVR), + UVR) 6.8 (10.0 Experiment 2: Skin tumours/mouse: 3.5 (UVR), + UVR) (As 9.6 Skin tumour incidence: and As (control alone 0/10 0/10, both experiments) Incidence tumours of Experiment 1: Skin tumours/mouse 3x/ c

2 ) 3x/ c ) 3x/wk UVR c 2

solar irradiation UVB, (85% 2 starting 3 wk after As until termination Groups: control, As alone, UVR alone, As + UVR 5–15; 5 controls5–15; wk starting 3 wk after As to termination Experiment 2: mg/L10.0 sodium arsenite in drinking-water from onset plus topical kJ/m 1.7 solar irradiation (UVR < 1% UVC, 4% UVA, remainder UVC, UVA, 4% < 1% visible; termed UVR Dosing regimen Animals/group at start mg/L0, 10 sodium arsenite in drinking-water throughout experiment plus topical 1.7 kJ/ m Experiment 0, 1.25, 2.50, 1: 5.00, mg/L 10.0 sodium arsenite in drinking-water from onset plus topical kJ/m 1.0 0 or wk, starting 3 wk after As to termination

BR (hairless) (hairless) BR hr . (2001) . (2004)

et al et al

Table 3.12 (continued) 3.12 Table Rossman Duration Reference (F) 29 wk Species, strain (sex) Mouse, Crl: SKl- Mouse, SKl (hairless), (NR) 29 wk Burns

74 Arsenic and arsenic compounds

-XSC added-XSC as

-XSC Purity-XSC > 99% Age start, at 8 wk Purity, NR Survival unremarkable Small group sizes Quantitative microscopic skin tumour incidence or multiplicity not reported though histologically confirmed Age start, at 3 wk Sodium arsenite, purity (NR), p Comments Survival and unremarkable bw Small control groups Vitamin E and p antioxidants Specific quantitative microscopic analysis skin of tumours not reported but random sampling tumours/group) confirmed(10 primarily squamous cell carcinomas at termination untreatedNo control arsenic or alone groups included

< 0.05 < 0.05 < 0.01 (UVR < 0.01 vs UVR (UVR < 0.01 + As P vs + BA BA) (As P vs + BA BA) (As P + As) P vs UVR + As + either ) Significance d

b -XSC). p -XSC) % large papillomas of mm) (≥ 3 total papillomas: 0, 65 0, 16, Macroscopic skin tumours/ mouse: 0, 2.0, 0, 3.2 Macroscopic skin tumours/ mouse: 3.60 (UVR 7.00 alone), (UVR 3.27 (UVR + As), + As + Vitamin 3.40 (UVR E), + As + p Incidence tumours of

c

/mL i UVR 2

h (10 mg/kg diet) (10 mg/kg from g -XSC

above. -XSC 3x/wk starting 3 wk after As to termination. Groups: UVR alone, UVR + As, UVR + As + Vitamin E, UVR + As + p onset. 1.0 kJ/m Topical 25 µL topical once/wk 2 wk for Sodium arsenate 25 0 or mg/L drinking-water 25 wk for Groups: Control, BA, As, BA + As 10/group 10; 3010; controls (UVR) Dosing regimen Animals/group at start 0, 5 mg/L sodium arsenite in drinking-water from onset; diet unsupplemented with or added vitamin IU/ E (62.5 kg diet; basal IU/kg) 49.0 or p Treatment withTreatment 2 mg BA

. (2001) et al

BR (hairless) (hairless) BR hr -test. t . (2005)

(methylene)selenocyanate synthetic a organoselenium compound. . (2005) bis

et al et al -tetradecanoyl-13-acetate.

O

Some control groups are not discussed for the sake of brevity (UVR + Vitamin E and UVR + Estimated from graphical presentation. descriptive No statistics included. Data included descriptive statistics. Using Dunnett’s multiple comparison test and not including arsenic alone and untreated control groups UVR as defined in Rossman Using Student’s Using

1,4-Phenyl 12-

Table 3.12 (continued) 3.12 Table Duration Reference (F) Duration, NR Uddin Species, strain (sex) Mouse, Crl: SKl- Mouse, Swiss-bald hairless (M) 25 wk Motiwale

9,10-dimethyl-1,2-benzanthracene. a b c d e f g h i F, female;F, M, male; NR, not reported; wk, week or weeks

75 IARC MONOGRAPHS – 100C of age, although arsenic treatment alone had no In a comprehensive study, rats were given an effect, it markedly increased the multiplicity of initial pretreatment with a mixture of organic squamous cell carcinoma when combined with carcinogens (including diethylnitrosamine, TPA compared to TPA alone (Waalkes et al., N-methyl-N-nitrosourea, 1,2-dimethylhydra- 2008; see Table 3.13). zine, N-butyl-N-(4-hydroxybutyl)nitrosamine, Prenatal sodium arsenite exposure via and N-bis(2-hydroxypropyl)nitrosamine) by maternal drinking-water when combined with various routes, no treatment for 2 weeks and then postnatal topical TPA exposure increased the DMAV (at four levels) in the drinking-water for liver tumour incidence and multiplicity in an 24 weeks, rats developed an increased incidence arsenic-dose-related fashion (female offspring), of tumours of urinary bladder with the combined and lung tumours (male offspring) compared carcinogen treatment and arsenical (Yamamoto to controls; effects not seen with TPA or arsenic et al., 1995). alone (Waalkes et al., 2004). Prenatal arsenic In another study in rats, N-butyl-N-(4- exposure followed by postnatal diethylstilbestrol hydroxybutyl)nitrosamine in the drinking- increased uterine carcinoma, vaginal carcinoma, water was used as an initiator for 4 weeks urinary bladder total proliferative lesions, and followed by four levels of DMAV for 32 weeks, liver tumours in female offspring compared to and the combined treatment increased urinary controls; effects not seen with diethylstilbestrol bladder hyperplasia, papilloma, and carcinoma, or arsenic alone. In female offspring, prenatal but the arsenical treatment alone had no effect arsenic exposure followed by postnatal tamox- (Wanibuchi et al., 1996). ifen administration similarly increased urinary bladder total proliferative lesions (Waalkes et al., 3.6 Gallium arsenide 2006a). In male offspring, prenatal arsenic exposure A single study (NTP, 2000) was judged to followed by postnatal diethylstilbestrol increased provide evidence for the carcinogenicity of the liver tumour response and urinary bladder gallium arsenide in rodents. In this report, total proliferative lesions effects when compared B6C3F1 mice and F344 rats were exposed via to controls; effects not seen with diethylstilbestrol inhalation to various levels of gallium arsenide or arsenic alone. In male offspring, prenatal particulate for up to ~2 years, and the tumour arsenic exposure followed by postnatal tamox- response was assessed in various tissues (see ifen increased liver tumour response, urinary Table 3.14). bladder total tumours, and urinary bladder total proliferative lesions (Waalkes et al., 2006b). 3.6.1 Mouse 3.5.2 Rat No treatment-related tumours were observed, but in both males and females, dose-related Rats that underwent partial hepatectomy increases in the incidence in lung epithelial alve- followed by diethylnitrosamine injection and olar hyperplasia were reported. one week later by oral administration of sodium arsenite in the drinking-water for approximately 3.6.2 Rat 24 weeks showed an increased incidence of renal tumours, but arsenic treament alone had no In female rats, dose-related responses were effect Shirachi( et al., 1983). reported for the incidence of lung alveolar/ bronchiolar tumours and atypical hyperplasia

76 Arsenic and arsenic compounds

to

Litters culled 4 d postpartum at than more no 8 pups pregnant10 mice used to randomly derive each group Maternal water consumption and unaltered body Offspringweaned at 4 wk Offspringbw unalteredby arsenic All skin tumours were histopathologically diagnosed for stage and number per animal Some mice killed were because of tumour burden during experiment werebut not lost to observation Only skin tumours reported Age, 4 wk (offspring) Purity, NR Comments

< 0.05 (all TPA groups < 0.05 (all TPA < 0.05 (all TPA groups < 0.05 (all TPA with (trend < 0.01 As < 0.05 (all TPA + As < 0.05 (all TPA with (trend < 0.01 As P alonevs control;vs TPA + TPA) 85As P vs control; all As + TPA alonegroups vs TPA P in mice) TPA-treated P groups vs control or TPA alone) P in mice) TPA-treated Significance – a ), 17 (42.5 As 17 ), b

a Squamous cell carcinomas/ mouse: + TPA), 11 (85 As + TPA) (85 11 + TPA), 0.5 (control), 0.9 (42.5 As), 0.12 0.12 0.9 (42.5 As), 0.5 (control), (TPA 17 As), (85 0.04 (control), 0.06 0.04 (42.5 (control), As), 1.31 0.57 (TPA), As), 0.04 (85 As (85 1.49 (42.5 As + TPA), + TPA) Incidence of mice with squamous more 3 or cell carcinomas: 0/49 (control), 0/47 (42.5 As), (42.5 As), 0/47 (control), 0/49 TPA), (2%; 1/47 As), (85 0/48 42.5 (19%; As9/48 + TPA), As 85 (29%; + TPA) 14/49 Incidence tumours of Skin (tumours): Papillomas/mouse ,

c

a

ad libitum

TPA, 2 µg/0.1 mLTPA, acetone, topical twice/wk, applied to shaved dorsal skin, 4–40 wk of exposure) wk TPA of age (36 Offspring (M, F): groups Without TPA: (0, 42.5, (0, Without TPA: ppm 85 arsenic) 42.5, (0, With TPA: ppm 85 arsenic) 50/group Dosing regimen Animals/group at start Maternal exposure: 0, 42.5, arsenic ppm 85 in drinking-water, gestation Day 8–18 Offspring exposure:

) . (2008)

et al postpartum -tetradecanoyl-13-acetate. O Manuscript included descriptive statistics. Because initial analysis of tumours showed no gender-based differences between similarly treated groups of males andfemales, theywere pooled for final assessment and are reported 12-

Table 3.13 Studies where Studies before arsenic given another no effect carcinogenesis enhances agent while having alonein 3.13 Table animals experimental Duration Reference Waalkes Species, strain (sex) (M, F) Mouse, Tg.AC Homozygous 40 wk ( a b c as such. Initial groups were made up of 25 M and 25 F mice. bodybw, weight; female; F, M, male; NR, not reported; vs; versus; wk, week or weeks

77 IARC MONOGRAPHS – 100C

Comments Purity > 98% Age start, at 6 wk MMAD, µm 0.9–1.0 GSD, 1.8–1.9 µm Chamber controls used No reducedNo with bw treatment increasesNo in tumour incidence Survival unaltered Purity > 98% Minimal decrease in body weight high at dose in second yr Survival unaltered increasesNo in tumour incidence in males Age start, at 6 wk MMAD, µm 0.9–1.0 GSD, 1.8–1.9 µm Chamber controls used

≤ 0.01 (high ≤ 0.01 dose) (trend) ≤ 0.01 ≤ 0.05 (high dose) ≤ 0.01 (trend) ≤ 0.01 ≤ 0.01 (high ≤ 0.01 dose) ≤ 0.05 (mid-dose) ≤ 0.01 (high ≤ 0.01 dose) (mid-dose) ≤ 0.01 ≤ 0.01 (high ≤ 0.01 dose) (mid-dose) ≤ 0.01 (high ≤ 0.01 dose) (trend) ≤ 0.01 (high ≤ 0.01 dose) (trend) ≤ 0.01 P P P P P P Significance P P NS P P NS P P NS P P NS NS NS

4/50 (8%), 6/49 (12%), 6/50 6/50 (12%), 6/49 4/50 (8%), b

(adenomas or carcinomas): (adenomas or carcinomas): 15/50 7/50 (4%), 2/50 0/50, 0/50, (adenomas): (6%), 3/50 0/49, (2%), 1/50 (adenomas): a a a a (12%), 13/49 (27%) Mononuclear cell leukaemia: 22/50 (44%), 21/50 (42%), 18/50 (36%), 33/50 33/50 (36%), 18/50 (42%), 21/50 (44%), 22/50 (66%) Males Lung (atypical hyperplasias): (4%), 2/49 0/50, (36%) 18/50 (10%), 5/50 Lung Incidence tumours of Females Lung (epithelial alveolar hyperplasias):2/50 (86%) 43/50 (54%), 27/50 (10%), 5/50 (4%), Lung Lung (carcinomas): 0/50, 0/50, 2/50 (4%), Lung (4%), 2/50 0/50, (carcinomas): 0/50, 3/50 (6%) 7/50 (14%), 4/50 (8%), 4/50 (8%), 6/50 (12%) 6/50 4/50 (8%), 4/50 (8%), (14%), 7/50 Males (26%) 13/50 (32%), 16/50 (28%), 14/50 (30%), (14%) Lung (adenomas or carcinomas): 0/50, 0/50, (18%) 9/50 4/50 (8%), 2/50 (4%) 2/50 0/49, Lung (4%), (carcinomas): 2/50 1/50 (2%) (4%), Lung carcinomas): or (adenomas (6%), 3/50 (6%) 3/50 (10%), 5/50 0/49, Lung (epithelial alveolar hyperplasias):4/50 (90%) 45/50 (78%), 39/50 (18%), 9/50 (8%), Lung Adrenal medulla: Females Lung

3

3

0, 0.1, 0.5, mg/m 1.0 0, 0.1, Dosing regimen Animals/group at start mg/m 1.0 0.1, 0, 0.01, 6 h/d, 5 d/wk 50/group/sex 6 h/d, 5 d/wk 50/group/sex

1

All tumours were benign pheochromocytoma except one which was malignant in the low-dose group. All lung tumours were of avelolar/bronchiolar origin.

(M, F) wk M for 105 (2000) NTP 106 wk F 106 for Table 3.14 Studies of Studies experimental cancer in exposure) exposed animals arsenide gallium to (inhalation 3.14 Table Species, strain (sex) B6C3F Mouse, Rat, F344 (F) Duration Reference 105 wk (2000) NTP a b d, day or days; female; F, h, hour or hours; M, male; NS, not significant; wk,week weeks;or yearyr, or years

78 Arsenic and arsenic compounds of the alveolar epithelium. In male rats, though traditional bioassays for arsenicals for adult treatment-related tumours were not observed, a rodents were frequently negative in their final dose-related increase in the incidence of atyp- evaluations.] ical hyperplasia of the lung alveolar epithelium Inhalation of gallium arsenide causes lung occurred. Atypical hyperplasia of the lung alve- and adenal tumours in rats but not in mice. olar epithelium is considered potentially preneo- In multiple studies, initiating, promoting or . In the female rats, dose-related increases co-carcinogenic activity was demonstrated in the in the incidence of adrenal medulla pheochro- urinary bladder, skin, female reproductive tract, mocytomas and an increase in mononuclear cell kidney, lung, liver and thyroid after exposure to leukaemia at the highest dose were also reported inorganic arsenicals or DMAV in drinking-water (NTP, 2000). or by transplacental exposure.

3.6.3 Hamster 4. Other Relevant Data Another study using intratracheal instilla- tion of gallium arsenide in hamsters (Ohyama et al., 1988) was judged inadequate due to critical 4.1 Absorption, distribution, design flaws (short duration, small groups, etc.) metabolism, and excretion with no indication of tumours. Most inorganic arsenic compounds are readily absorbed after oral exposure (about 80–90% for 3.7 Synthesis soluble compounds, and a smaller percentage for less soluble compounds), less well absorbed Oral administration of sodium arsenate and after inhalation (better for small particulates DMAV induced lung tumours in mice. Calcium and soluble arsenicals), and least well absorbed arsenate induced lung tumours in hamsters by after dermal exposure NRC,( 1999; IARC, 2004). oral and intratracheal administration. Pre- and Large airborne arsenic-containing particulates postnatal exposure in mice to arsenic trioxide, that are deposited in the upper airways may also through subcutaneous injections (maternal be absorbed in the intestine if they are later swal- and postnatal), induced lung tumours in the lowed. Hamsters exposed to gallium arsenide offspring. Transplacental exposure via maternal by the oral route or by intratracheal instillation oral exposure in mice to sodium arsenite during showed the presence of AsIII in blood and urine, gestation induced lung, liver, ovary and adrenal but the majority of the gallium arsenide was tumours in the offspring in several studies, and excreted in faeces, indicating that absorption was the uterus in one study. Early life transplacental limited by its insolubility. Absorption was about and perinatal exposure to sodium arsenite 30 times higher after intratracheal installation appears to be a time of particular sensitivity in than by the oral route (Carter et al., 2003). terms of carcinogenesis. The transport of AsV is thought to take place Oral exposure to DMAV induced urinary via phosphate transporters (Csanaky & Gregus, bladder tumours in several studies in rats and 2001). The sodium-coupled phosphate trans- among studies in mice, only one showed nega- porter NaPi-IIb may be responsible in part for tive results. Oral trimethylarsine induced liver the intestinal and hepatic uptake of AsV (Villa- tumours in rats. Chronic oral exposure to MMAV Bellosta & Sorribas, 2008). AsIII enters the cell did not produce tumours in rats and mice. by 9 and 7 (Liu et al., 2004), [The Working Group considered that previous

79 IARC MONOGRAPHS – 100C

III although another major pathway for the uptake As(SG)3 + SAM → MMA (SG)2 III III III III of As and MMA (see below) is probably via MMA (SG)2 + SAM → DMA (SG) hexose permeases (Rosen & Liu, 2009). Because Scheme 2: The use of As(SG) (tri-glutathione AsV is rapidly reduced to AsIII once it enters the 3 complex) as a substrate for cell (Carter et al., 2003), the faster rate of cellular III V (Hayakawa et al., 2005). Each of the glutathione uptake of As , compared with As , may be part (GSH) complexes can also decompose to yield of the explanation for the greater of GSH and MMAIII or DMAIII, which can then AsIII (Bertolero et al., 1987; Dopp et al., 2004). form MMAV and DMAV, respectively. However, the much higher chemical reactivity of AsIII, compared to that of AsV is the major expla- Neither reaction scheme necessarily goes to nation. Some data suggests that glyceraldehyde completion in vivo. 3-phosphate dehydrogenase (GAPDH) func- Evidence shows that exposure to arsine V tions as a cytosolic As reductase in vivo (Németi gas (AsH3) results in the same metabolites as et al., 2006), although there are other candidate described above, but arsenobetaine found in for this reaction (Aposhian et al., 2004). seafood does not get metabolized in humans AsIII can react with cellular glutathione (GSH), (Crecelius, 1977; Luten et al., 1982; Le et al., either spontaneously or enzymatically, to form 1993, 1994; Buchet et al., 1996; Schmeisser et al., 2006). Information is not currently available on the tri-glutathione complex As(SG)3 (Leslie et al., 2004; Rey et al., 2004). the other organo-arsenic compounds in seafood AsIII is metabolized by stepwise methylation, (Lai et al., 2004). V mainly in the liver. Although some details of Dimethylthioarsinic acid (DMMTA ) and V inorganic arsenic metabolism remain uncertain dimethyldithioarsinic acid (DMDTA ) can be III (Aposhian & Aposhian, 2006), it is clear that formed from DMA in red blood cells, and the arsenic (+3 ) methyl- possibly in other cells (Naranmandura et al., transferase (AS3MT) is involved (Thomas et al., 2007; Suzuki et al., 2007). These compounds have 2007). Two schemes have been proposed for the been observed in the urine of arsenic-exposed methylation. individuals (Raml et al., 2007). They may have been misidentified as MMAIII and DMAIII in Reduction: AsV + → AsIII most studies (Hansen et al., 2004). Oxidative methylation: AsIII + SAM → Most organisms detoxify inorganic arsenic monomethylarsonate (MMAV) by cellular effluxRosen ( & Liu, 2009). In fibrob- Reduction: MMAV + thiol → MMAIII lasts and other non-methylating cells, protection Oxidative methylation: MMAIII + SAM → against arsenic takes place by specific mecha- dimethylAsV (DMAV) nisms for As(SG)3 efflux catalysed by multidrug- Reduction: DMAV + thiol → DMAIII resistance-associated protein-transport ATPases MRP1 and MRP2, and maybe others (Kala et al., Scheme 1: Inorganic arsenic metabolic 2000; Leslie et al., 2004). These efflux pumps pathway in mammals. AsIII methylation is cata- lysed by AS3MT using S-adenosylmethionine may also remove methylated arsenic–glutathione (SAM) as a methyl and thioredoxin (or, (As–GSH) complexes. less efficiently, other such as The rat is not a good model for the human or ) as a reductant. MMAIII: mono- in studying the toxicokinetics of arsenic because methylarsonous acid; MMAv: monomethyl- rat haemoglobin has a much higher affinity for arsonic acid; DMAIII: dimethylarsinous acid; trivalent arsenic species compared with human DMAv: dimethylarsinic acid haemoglobin (Lu et al., 2004). In mice, chronic

80 Arsenic and arsenic compounds exposure (12 weeks) to AsV via drinking-water of trivalent arsenicals also cause DNA strand led to total tissue arsenic accumulation in the breaks and/or alkali-labile sites (Kligerman et al., following ranking: kidney > lung > bladder > 2003; Klein et al., 2007). In mice, DMAV causes > > skin > blood > liver (Kenyon et al., 2008). lung-specific DNA damage attributed to the

Monomethylated arsenic species (MMAs) DMA peroxy radical (CH3)2AsOO (Yamanaka & predominated in the kidney, and dimethylated Okada, 1994), which can also induce DNA strand arsenic species (DMAs) predominated in the lung. breaks and DNA–protein crosslinks in cultured Urinary bladder and skin had about equal ratios cells (Tezuka et al., 1993). of inorganic arsenic and DMAs. The proportions Gallium arsenide and other arsenicals are not of different arsenic species in urinary bladder mutagenic in the (NTP, 2000; IARC, tissue did not match those in urine. 2004). There was no increase in frequency of In a study of intratracheal instillation of micronucleated erythrocytes in mice exposed gallium arsenide, although substantial levels of to gallium arsenide by inhalation for 14 weeks arsenic were detected in blood and urine, no (NTP, 2000). gallium was detected except for the amount that Despite the fact that low (non-toxic) concentra- was left in the lung Carter( et al., 2003). tions of trivalent arsenicals cause oxidative DNA Human exposure to arsenic is mainly via damage such as 8-hydroxy-2′-deoxyguanosine, drinking-water. Trivalent arsenicals are elimi- which is expected to cause G→T transversions, nated via the bile, and pentavalent arsenicals are neither AsIII, MMAIII nor DMAIII are significant mainly eliminated by urinary excretion (Gregus point (Rossman, 2003; Klein et al., et al., 2000; Kala et al., 2000; Csanaky & Gregus, 2007). This may be due to the efficient removal 2002). Most population groups exposed mainly of oxidative DNA lesions (Fung et al., 2007; via drinking-water excrete 60–70% DMAs and Pu et al., 2007b). At toxic concentrations, AsIII 10–20% MMAs, the remainder 10–30% being increased large-deletion mutations in human/ inorganic compounds (Vahter, 2000). [The hamster hybrid cells through a mechanism Working Group noted that this study did not mediated by reactive species (Hei et al., include thiolated compounds, which had not yet 1998). MMAIII and DMAIII are weakly mutagenic been discovered.] Interindividual differences in in mouse lymphoma L5178Y cells, but only at methylation patterns may reflect genetic poly- toxic concentrations, and yield mostly deletions morphisms in AS3MT, and/or variability in the (Moore et al., 1997; Kligerman et al., 2003). activities of different reductants (Thomas et al., Using a transgenic cell line that readily detects 2007). deletions as well as point mutations, statistically significant mutagenesis was never observed for III III III 4.2 Genetic and related effects DMA , and was only seen for As or MMA at toxic concentrations. MMAIII yielded a mutant Arsenicals do not react directly with DNA, fraction about 4-fold over background at 11% but cells treated with low concentrations of triva- survival, and 79% of these mutants were dele- lent arsenicals show increased oxidative DNA tions (Klein et al., 2007). damage (Wang et al., 2002; Schwerdtle et al., AsIII, MMAIII, and DMAIII can induce 2003; Shi et al., 2004; Ding et al., 2005; Wang chromosomal aberrations in vitro (Oya-Ohta et al., 2007a). AsIII and MMAIII are equally potent et al., 1996; Kligerman et al., 2003). Statistically inducers of oxidative DNA damage in human significant increases in chromosomal aber- urothelial cells, where they are equally toxic rations occur only at toxic doses (Klein et al., (Wang et al., 2007a). Cytotoxic concentrations 2007), except as a secondary effect of genomic

81 IARC MONOGRAPHS – 100C instability in long-term, low-dose treatment Waalkes, 2008). Alterations of DNA methyla- protocols (Sciandrello et al., 2004). An analysis tion, along with histone modification, were seen of micronuclei induced by AsIII in human fibro- in cells treated with AsIII and MMAIII (Jensen blasts shows that at lower (relatively non-toxic) et al., 2008; Zhou et al., 2008). Global DNA doses, AsIII acts as an by interfering hypomethylation, along with hypermethylation with spindle function and causing micronuclei of specific genes, was demonstrated in several with centromeres, but at high (toxic) doses, it AsIII-transformed cells (Benbrahim-Tallaa et al., acts as a clastogen, inducing micronuclei without 2005a; Liu & Waalkes, 2008). Oxidative damage centromeres (Yih & Lee, 1999). Aneuploidy is seen to DNA has been shown to cause changes in after treatment with AsIII concentrations lower DNA methylation (Cerda & Weitzman, 1997), than those that cause chromosomal aberrations suggesting a mechanism by which AsIII may (Yih & Lee, 1999; Ochi et al., 2004; Sciandrello induce this effect. Changes in DNA methyla- et al., 2002, 2004). Aneuploidy associated with tion patterns could also result from altered SAM disruption of spindle tubulin has been reported pools or downregulation of DNA methyltrans- in other cells treated with arsenicals (Huang & ferases (Hamadeh et al., 2002; Benbrahim-Tallaa Lee, 1998; Kligerman & Tennant, 2007; Ramírez et al., 2005a; Reichard et al., 2007; Liu & Waalkes, et al., 2007). Disrupted mitotic spindles and 2008). Altered DNA methylation has also been induced persistent aneuploidy were maintained observed in arsenic-exposed humans (Chanda even 5 days after AsIII removal (Sciandrello et al., et al., 2006; Marsit et al., 2006). 2002). Humans exposed to high concentrations Although not a , AsIII can enhance of inorganic arsenic in drinking-water also show the mutagenicity of other agents (Rossman, increased micronuclei in lymphocytes, exfoli- 2003; Danaee et al., 2004; Fischer et al., 2005). ated bladder epithelial cells and buccal mucosa Co-mutagenesis may occur by interference with cells, and sometimes chromosomal aberra- both nucleotide-excision repair and base-exci- tions and sister chromatid exchange in whole- sion repair (Hartwig et al., 2002; Rossman, 2003; blood lymphocyte cultures (Basu et al., 2001). Danaee et al., 2004; Wu et al., 2005; Shen et al., Micronuclei and chromosomal aberrations are 2008). Nucleotide-excision repair was blocked in also induced in mice after intraperitoneal treat- human fibroblasts with the following potency: ment with AsIII (IARC, 2004). MMAIII > DMAIII > AsIII (Shen et al., 2008). AsIII Long-term low-dose treatment of human is not a very effective inhibitor of DNA-repair osteosarcoma cells with AsIII (but not MMAIII) enzymes (Snow et al., 2005). Rather, it appears resulted in increased mutagenesis and trans- to affect DNA-damage signalling events that formation as a secondary effect of genomic control DNA repair. One of these is poly(ADP- instability (Mure et al., 2003). In Chinese ribose) polymerase (PARP) (Hartwig et al., 2003; hamster V79–13 cells grown in the presence of Qin et al., 2008). PARP-1, the major PARP, is low concentrations of AsIII, genomic instability involved in base-excision repair by interacting (measured by chromosomal aberrations in later with DNA-repair protein XRCC1, DNA poly- generations) followed earlier changes in DNA merase β, and DNA ligase III. This might explain methylation and aneuploidy (Sciandrello et al., the inhibition of the ligation step of base-excision 2002, 2004). Other studies report gene ampli- repair by AsIII (Li & Rossman, 1989). MMAIII and fication Lee( et al., 1988; Rossman & Wolosin, DMAIII are more effective PARP inhibitors than 1992), and changes in gene expression, e.g. by is AsIII (Walter et al., 2007). The inhibition of DNA methylation changes (Liu et al., 2006b; PARP (and other proteins such as XPA) may be Klein et al., 2007; Reichard et al., 2007; Liu &

82 Arsenic and arsenic compounds mediated by the displacement of (Zn) at Zn preventing blockage of the cell cycle after geno- fingers Schwerdtle( et al., 2003; Qin et al., 2008). toxic insult by a second agent were discussed Another important signal pathway affected by above. In addition, low concentrations of AsIII AsIII is that mediated by tumour-suppressor gene in the absence of a second agent can also stimu- Tp53. AsIII was shown to prevent the activation of late cell proliferation in vitro (Germolec et al., the protein and the downstream expression 1997; Trouba et al., 2000; Vogt & Rossman, 2001; of p21 after genotoxic insult Vogt( & Rossman, Benbrahim-Tallaa et al., 2005b; Komissarova 2001; Tang et al., 2006; Shen et al., 2008). This et al., 2005), and in vivo (Germolec et al., 1998; has the effect of overriding the growth arrest at Burns et al., 2004; Luster & Simeonova, 2004). G1 (normally an opportunity for DNA repair The concentration-dependent increase in prolif- to take place before DNA replication) in cells eration of human keratinocytes after 24 hours of with DNA damage, and might explain part of treatment with arsenicals followed the potency the co-mutagenic effect Vogt( & Rossman, 2001; trend: DMAIII > MMAIII > AsIII (Mudipalli et al., Hartwig et al., 2002; Mudipalli et al., 2005). p53 2005). AsIII upregulates pro-growth proteins is also required for proficient global nucleotide- such as cyclin D1, c-myc, and E2F-1 (Trouba excision repair (Ferguson & Oh, 2005). The inhi- et al., 2000; Vogt & Rossman, 2001; Ouyang bition of thioredoxin reductase by AsIII, MMAIII et al., 2007). The increased proliferation in and DMAIII (Lin et al., 1999) would cause the mouse skin by AsIII alone (in drinking-water) is accumulation of oxidized thioredoxin, which not sufficient to induce skin cancerBurns ( et al., may be partially responsible for p53 malfunc- 2004), but may contribute to its co-carcinogen- tion, as is shown in (Merwin et al., 2002). esis with solar ultraviolet. AsIII was found to The upregulation of positive growth genes such the differentiation of skin cells, resulting as cyclin D by low concentrations of AsIII would in increased numbers of keratinocyte stem cells, also tend to drive cells to cycle inappropriately the cells that proliferate (Patterson & , 2007; (Trouba et al., 2000; Vogt & Rossman, 2001; Waalkes et al., 2008). Because tumours may arise Luster & Simeonova, 2004). from stem cells, this would increase the pool of In addition to inhibiting particular proteins, target cells for cancer of the skin. AsIII (at slightly toxic concentrations) can down- Another mechanism for arsenic-related regulate expression of some DNA repair genes carcinogenesis might be acquired resistance to (Hamadeh et al., 2002; Andrew et al., 2006; . Long-term growth of human skin Sykora & Snow, 2008). However, very low, non- cells (HaCaT) in the presence of low concentra- toxic concentrations, may have the opposite effect tions of AsIII resulted in cells with a generalized of upregulating DNA repair, concomitant with resistance to apoptosis (Pi et al., 2005). This may antioxidant defenses (Snow et al., 2005; Sykora allow the survival of cells with DNA damage, & Snow, 2008). thus facilitating tumorigenesis. Even short-term exposure to AsIII affected the apoptotic response 4.3 Co-carcinogenic and in utero to solar UV in a mouse keratinocyte cell line (Wu et al., 2005) or to UVB in normal human carcinogenic effects keratinocytes (Chen et al., 2005b). It is possible There are several non-genotoxic actions of that the loss of the P53 function partially medi- AsIII (sometimes demonstrated also for its triva- ates the reduction in apoptotic response (Chen lent metabolites) that may contribute to arsenic- et al., 2005b). induced carcinogenesis. The effects of IIIAs on Numerous studies report increased inflam- mation after AsIII exposure (NRC, 1999; Straub

83 IARC MONOGRAPHS – 100C et al., 2007). The transcription factor NF-κB is 4.4 Synthesis involved in the inflammatory response, and AsIII causes oxidant-dependent activation of In the human body, inorganic arsenic NF-κB (Barchowsky et al., 1999). Activation of compounds are converted to AsIII and AsV. AsV is the NF-κB inflammatory signalling pathway was rapidly converted to AsIII. AsIII species are more seen in infants born to AsIII-exposed mothers in toxic and bioactive than are AsV species, both Bangladesh (Fry et al., 2007). because of the greater chemical reactivity of AsIII, AsIII can disrupt the signalling of the estrogen and because AsIII enters cells more easily. receptor, glucocorticoid receptor, and of other For inorganic arsenic and its metabolites, the steroids in vivo and in vitro (Benbrahim-Tallaa evidence points to weak or non-existent direct et al., 2005b, 2007; Liu et al., 2007; Davey et al., mutagenesis, which is seen only at highly cyto- 2008). Submicromolar concentrations of AsIII toxic concentrations. On the other hand, long- stimulate the transcription of several steroid term, low-dose exposure to inorganic arsenic receptors, but slightly higher concentrations – more relevant to human exposure – is likely (1–3 µM) are inhibitory (Bodwell et al., 2006). to cause increased mutagenesis as a secondary Exposure of mice in utero to AsIII in a protocol effect of genomic instability, perhaps mediated leading to hepatocarcinogenesis resulted in by increased levels of reactive oxygen species, altered expression of numerous genes involved as well as co-mutagenesis with other agents. The in estrogen signalling or steroid metabolism, as major underlying mechanisms observed at low well as hypomethylation of estrogen receptor α concentrations include the rapid induction of (Liu & Waalkes, 2008). oxidative DNA damage and DNA-repair inhibi- Angiogenesis, which provides a blood supply tion, and slower changes in DNA-methylation to developing tumours, is stimulated by very low patterns, aneuploidy, and gene amplification. concentrations of AsIII (Mousa et al., 2007; Straub Gene amplification, altered DNA methylation, et al., 2007). This activity can be blocked by sele- and aneuploidy lead to altered gene expression, nium compounds (Mousa et al., 2007), which and genomic instability. Inhibition of DNA repair also blocks AsIII-induced co-carcinogenesis with to co-mutagenicity as well. These effects are UV and delays mutagenesis (Uddin et al., 2005). consistent with the animal carcinogenicity data, Many of these effects depend on altered in which AsIII is a transgenerational carcinogen gene expression that can result from genetic and – with exposure being present during many cell epigenetic effects discussed above. Changes in generations – and in results observed in co-carci- gene expression by AsIII can also be mediated by nogenicity studies. the alteration of miRNA patterns (Marsit et al., For bladder tumours induced by high doses 2006). Some short-term changes in gene expres- of DMAV in the rat, the mechanism is likely to sion (e.g. changes in the expression of DNA-repair involve sustained followed by stress- proteins or DNA methyltransferases) can result related cell proliferation, leading to genomic in long-term changes. Genome-wide changes in instability. gene expression and signal transduction induced Inflammation and cytotoxicity may play a by arsenicals have been reported in several publi- role in lung tumours induced by gallium arse- cations (Su et al., 2006; Kumagai & Sumi, 2007; nide in female rats. Ghosh et al., 2008).

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5. Evaluation Elemental arsenic and inorganic arsenic species share the same metabolic pathway: arse There is sufficient evidence in humans for the nate→arsenite→methylarsonate→dimethylarse carcinogenicity of mixed exposure to inorganic nite. Thus, independent of the mechanisms of the arsenic compounds, including arsenic trioxide, carcinogenic action, and independent of which arsenite, and arsenate. Inorganic arsenic of the metabolites is the actual ultimate carcin- compounds, including arsenic trioxide, arsenite, ogen, different inorganic arsenic species should and arsenate, cause cancer of the lung, urinary be considered as carcinogenic. bladder, and skin. Also, a positive association has been observed between exposure to arsenic and inorganic arsenic compounds and cancer of the References kidney, liver, and prostate. There is sufficient evidence in experimental Andrew AS, Burgess JL, Meza MM et al. (2006). Arsenic exposure is associated with decreased DNA repair in animals for the carcinogenicity of dimethylars- vitro and in individuals exposed to inic acid, calcium arsenate, and sodium arsenite. arsenic. Environ Health Perspect, 114: 1193–1198. There is limited evidence in experimental doi:10.1289/ehp.9008 PMID:16882524 Aposhian HV & Aposhian MM (2006). Arsenic toxi- animals for the carcinogenicity of sodium arse- cology: five questions. Chem Res Toxicol, 19: 1–15. nate, gallium arsenide, arsenic trioxide, and doi:10.1021/tx050106d PMID:16411650 trimethylarsine oxide. Aposhian HV, Zakharyan RA, Avram MD et al. (2004). A There is inadequate evidence in experimental review of the enzymology of arsenic metabolism and a new potential role of in the detoxi- animals for the carcinogenicity of monomethyl- cation of the trivalent arsenic species. Toxicol Appl arsonic acid and . Pharmacol, 198: 327–335. doi:10.1016/j.taap.2003.10.027 In view of the overall findings in animals, PMID:15276412 there is sufficient evidence in experimental Arnold LL, Eldan M, Nyska A e t a l . (2006). Dimethylarsinic acid: results of chronic toxicity/oncogenicity studies in animals for the carcinogenicity of inorganic F344 rats and in B6C3F1 mice. Toxicology, 223: 82–100. arsenic compounds. doi:10.1016/j.tox.2006.03.013 PMID:16677751 Arsenic and inorganic arsenic compounds Arnold LL, Eldan M, van Gemert M et al. (2003). Chronic studies evaluating the carcinogenicity of monomethyl- are carcinogenic to humans (Group 1). arsonic acid in rats and mice. Toxicology, 190: 197–219. Dimethylarsinic acid and monomethylar- doi:10.1016/S0300-483X(03)00165-3 PMID:12927375 sonic acid are possibly carcinogenic to humans ATSDR (2007). Toxicological Profile for Arsenic. Atlanta, (Group 2B). Georgia. Barchowsky A, Klei LR, Dudek EJ et al. (1999). Stimulation Arsenobetaine and other organic arsenic of reactive oxygen, but not reactive species, compounds not metabolized in humans, are not in vascular endothelial cells exposed to low levels classifiable as to their carcinogenicity to humans of arsenite. Free Radic Biol Med, 27: 1405–1412. (Group 3). doi:10.1016/S0891-5849(99)00186-0 PMID:10641735 Basu A, Mahata J, Gupta S, Giri AK (2001). Genetic toxi- The Working Group made the overall cology of a paradoxical human carcinogen, arsenic: a evaluation on ‘arsenic and inorganic arsenic review. Mutat Res, 488: 171–194. doi:10.1016/S1383- compounds’ rather than on some individual 5742(01)00056-4 PMID:11344043 Benbrahim-Tallaa L, Waterland RA, Styblo M et al. arsenic compounds, based on the combined (2005a). Molecular events associated with arsenic- results of epidemiological studies, carcino- induced of human prostatic genicity studies in experimental animals, and epithelial cells: aberrant genomic DNA methylation data on the chemical characteristics, metabo- and K-ras oncogene activation. Toxicol Appl Pharmacol, 206: 288–298. doi:10.1016/j.taap.2004.11.017 lism, and modes of action of carcinogenicity. PMID:16039940

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