invited reviews: carcinogenic and systemic health effects associated with arsenic exposure--a...

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2003 31: 575Toxicol PatholPaul B. Tchounwou, Anita K. Patlolla and Jose A. Centeno

ReviewA Critical−−Invited Reviews: Carcinogenic and Systemic Health Effects Associated with Arsenic Exposure

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Toxicologic Pathology, 31:575–588, 2003Copyright C© by the Society of Toxicologic PathologyISSN: 0192-6233 print / 1533-1601 onlineDOI: 10.1080/01926230390242007

Invited Reviews

Carcinogenic and Systemic Health Effects Associated with ArsenicExposure—A Critical Review

PAUL B. TCHOUNWOU,1 ANITA K. PATLOLLA,1 AND JOSE A. CENTENO2

1Molecular Toxicology Research Laboratory, NIH-Center for Environmental Health, School of Science and Technology,Jackson State University, Jackson, Mississippi, USA and

2Environmental and Toxicologic Pathology, Department of Armed Forces Institute of Pathology, Washington, DC, USA

ABSTRACT

Arsenic and arsenic containing compounds are human carcinogens. Exposure to arsenic occurs occupationally in several industries, includingmining, pesticide, pharmaceutical, glass and microelectronics, as well as environmentally from both industrial and natural sources. Inhalation isthe principal route of arsenic exposure in occupational settings, while ingestion of contaminated drinking water is the predominant source ofsignificant environmental exposure globally. Drinking water contamination by arsenic remains a major public health problem. Acute and chronicarsenic exposure via drinking water has been reported in many countries of the world, where a large proportion of drinking water is contaminatedwith high concentrations of arsenic. General health effects that are associated with arsenic exposure include cardiovascular and peripheral vasculardisease, developmental anomalies, neurologic and neurobehavioural disorders, diabetes, hearing loss, portal fibrosis, hematologic disorders (anemia,leukopenia and eosinophilia) and multiple cancers: significantly higher standardized mortality rates and cumulative mortality rates for cancers of theskin, lung, liver, urinary bladder, kidney, and colon in many areas of arsenic pollution. Although several epidemiological studies have documentedthe sources of exposure and the global impact of arsenic contamination, the mechanisms by which arsenic induces health effects, including cancer,are not well characterized. Further research is needed to provide a better understanding of the pathobiology of arsenic-induced diseases and to betterdefine the toxicologic pathology of arsenic in various organ systems. In this review, we provide and discuss the underlying pathology and nature ofarsenic-induced lesions. Such information is critical for understanding the magnitude of health effects associated with arsenic exposure throughoutthe world.

Keywords. Arsenic pollution; human exposure; molecular mechanisms; systemic health effects; carcinogenicity.

INTRODUCTION

Arsenic is a ubiquitous element detected in low con-centrations in virtually all environmental media. Arseniccompounds represent a concern to environmental and oc-cupational health when their presence in the environmentincreases due to natural or anthropogenic sources (2). Morethan 80% of arsenic compounds are used to manufactureproducts with agricultural applications such as insecticides,herbicides, fungicides, algicides, sheep dips, wood preserva-tives, dye-stuffs, and medicines for the eradication of tape-worms in sheep and cattle (109). Arsenic compounds havebeen used for at least a century in the treatment of syphilis,yaws, amoebic dysentery, and trypanosomaiasis. In 1887,Hutchinson first described skin cancer in patients treated witharsenic-containing medication for psoriasis and other skinconditions (69, 70). Arsenical drugs are still used in treatingcertain tropical diseases such as African sleeping sicknessand amoebic dysentery, and in veterinary medicine to treat

Address correspondence to: Dr. Paul B. Tchounwou, NIH-Center forEnvironmental Health, Jackson State University, 1400 Lynch Street, Box18540, Jackson, MS 39217; email: [email protected]

parasitic diseases, including filariasis in dogs and black headin turkeys and chickens (109). Recently, arsenic has been usedas an anticancer agent in the treatment of acute promeylocyticleukemia, and its therapeutic action has been attributed to theinduction of programmed cell death (apoptosis) in leukemiacells (128).

A large number of people are exposed to arsenic chroni-cally throughout the world. Exposure to arsenic occurs viathe oral route (ingestion), inhalation, dermal contact, and theparenteral route to some extent (2). Arsenic is found natu-rally, its concentrations in air in remote locations (away fromhuman releases) range from 1 to 3 ng/m3, whereas concentra-tions in cities may range from 20 to 100 ng/m3. In water, theconcentrations of arsenic are usually less than 10 µg/L, al-though higher concentrations can occur near natural mineraldeposits or man made sources. Natural levels of arsenic in soilusually range from 1 to 40 mg/kg, but pesticide applicationor waste disposal can produce much higher values. Arsenicis also found in many foods at concentrations ranging from20 to 140 ng/kg (2).

Diet, for most individuals is the largest source of exposure,with an average intake of about 50 µg per day from food.Intake from air, water, and soil are usually much smaller,

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576 TCHOUNWOU ET AL TOXICOLOGIC PATHOLOGY

but exposure from these media may become significant inareas of arsenic contamination. Workers who produce oruse arsenic compounds in such occupations as vineyards,ceramics, glass-making, smelting, pharmaceuticals, refiningof metallic ores, pesticide manufacturing and application,wood preservation, or semiconductor manufacturing can beexposed to substantially higher levels of arsenic (58).

Hazardous waste sites (HWS) constitute another possiblesource of human exposure to arsenic. This element has beenidentified at 781 sites of the 1,300 HWS that have been pro-posed for inclusion on the national priority list (59). Exposureat these sites may occur by a variety of pathways, includingof dusts in air, ingestion of contaminated water or soil, orthrough the food chain.

Analyzing the toxic effects of arsenic is complicated be-cause the toxicity varies according to its oxidation state, itssolubility (95, 161) and in many different inorganic and or-ganic compounds. Several studies have indicated that thetoxicity of arsenic depends on the exposure dose, frequencyand duration, the biological species, age, and gender, as wellas on individual susceptibilities, genetic and nutritional fac-tors (26). Most cases of human toxicity from arsenic havebeen associated with exposure to inorganic arsenic. Inor-ganic trivalent arsenite (AsIII) is 2–10 times more toxic thanpentavalent arsenate (AsV) (76). Gallium arsenide (GaAs)is another inorganic arsenic compound of potential humanhealth concern because of its widespread use in the micro-electronics industry (110). Contamination with high levelsof arsenic is of concern because arsenic can cause a numberof human health effects, including cancer (112). Interest inthe toxicity of arsenic has been heightened by recent reportsof large populations in West Bengal, Bangladesh, Thailand,Inner Mongolia, Taiwan, China, Mexico, Argentina, Chile,Finland, and Hungary that have been exposed to high con-centrations of arsenic in their drinking water and are dis-playing various clinico-pathological conditions, the majoreffects being skin alterations and skin cancer besides car-diovascular and peripheral vascular disease, developmentalanomalies, neurologic and neurobehavioural disorders, di-abetes, hearing loss, portal fibrosis, hematologic disorders(anemia, leukopenia, and eosinophilia), and carcinoma (23,101). Several epidemiological studies have reported a strongassociation between arsenic exposure and increased risks ofboth carcinogenic and systemic health effects (112). In thispaper, we provide and discuss important information aboutthe molecular mechanisms of arsenic toxicity, as well as thehealth effects associated with arsenic exposure.

MECHANISMS OF ARSENIC TOXICITYAND CARCINOGENICITY

One of the mechanisms by which arsenic exerts its toxiceffect is through impairment of cellular respiration by theinhibition of various mitochondrial enzymes, and the uncou-pling of oxidative phosphorylation. Most toxicity of arsenicresults from its ability to interact with sulfhydryl groups ofproteins and enzymes, and to substitute phosphorous in a va-riety of biochemical reactions (51). Arsenic in vitro reactswith protein sulfhydryl groups to inactivate enzymes, suchas dihydrolipoyl dehydrogenase and thiolase, thereby pro-ducing inhibited oxidation of pyruvate and betaoxidation offatty acids (12).

Tests for genotoxicity have indicated that arsenic com-pounds inhibit DNA repair, and induce chromosomal aber-rations, sister-chromatid exchanges, and micronuclei forma-tion in both human and rodent cells in culture (11, 57, 73,164) and in cells of exposed humans (159). The mechanismof genotoxicity is not known, but may be due to the abilityof arsenate to inhibit DNA replicating or repair enzymes, orthe ability of arsenate to act as a phosphate analog (88). Re-version assays with Salmonella typhimurium fails to detectmutations that are induced by arsenic compounds. Althougharsenic compounds are generally perceived as weak mutagensin bacterial and animal cells, they exhibit clastogenic proper-ties in many cell types in vivo and in vitro (57, 72, 73, 164).In the absence of animal models, in vitro cell transforma-tion studies become a useful means of obtaining informationon the carcinogenic mechanisms of arsenic toxicity. Arsenicand arsenical compounds are toxic to and induce morpho-logic transformations of Syrian hamster embryo (SHE) cellsas well as mouse C3H10T1/2 cells and BALB/3T3 cells (79,82, 146). Based on the comet assay, it has been reportedthat arsenic trioxide induces DNA damage in human lym-phocytes (132). Arsenical compounds have also been shownto induce gene amplification, arrest cells in mitosis, inhibitDNA repair, and induce expression of the c-fos gene and theoxidative stress protein heme oxygenase in mammalian cells(49, 107, 108, 127). They have been implicated as promotersand comutagens for a variety of toxic agents (68).

The major metabolic pathway for inorganic arsenic in hu-mans is methylation. This pathway of arsenic metabolismand excretion is presented in Figure 1. Most of the inorganicarsenic [As (III) and As (V)] is metabolized to monomethy-larsonic acid [MMA (V)] and dimethylarsinic acid [DMA(V)] before excretion in the urine. Methylation of arsenic in-volves a two-electron reduction of pentavalent [eg, As (V) &MMA (V)] to trivalent [eg, As (III) & MMA (III)] arsenicspecies followed by the transfer of a methyl group from amethyl donor, such as S-adenosylmethionine (35, 112, 149).This methylation mechanism has been widely accepted, andthe metabolites MMA (V) and DMA (V) have been con-sistently observed in human urine. A key intermediate forthe methylation of MMA (V) to DMA (V) is the MMA (III)species. Several studies have indicated the presence of MMA(III) species in rat liver cytosol and hepatocytes, and demon-strated the important effects of the methylated trivalent ar-senic species in biological systems (5, 89, 120, 142–145,174, 175).

The generally held view of arsenic carcinogenesis in thepast was that arsenite was the most likely cause of carcino-gensis and that methylation of arsenic species was a detox-ification pathway. Several authors thought that methylationof arsenic was of great importance in minimizing arsenic’stoxicity and/or carcinogenicity (75). The present view of ar-senic carcinogenesis is that there are many possible chemicalforms of arsenic that may be causal in carcinigenesis and thatmethylation of arsenic may be a toxification, not a detoxifica-tion, pathway. A great amount of evidence has accumulated,in a short period of time about toxification pathway of methy-lated arsenic.

MMA (III) has been found in urine of humans exposedto arsenic without (5) and with concomitant treatment withchelators (6). Some of the biological activities that MMA(III) is known to possess in various experimental systems



Vol. 31, No. 6, 2003 ARSENIC EXPOSURE AND HEALTH EFFECTS 577

FIGURE 1.—Metabolism of arsenic in the liver: AsV → AsIII (Reduction); AsIII → AsV (Oxidation); AsIII → MMAsV (Methylation); SAM (S-Adenosyl-methionine); SAH (S-Adenosylhomocysteine); GSH (Glutathione reduced); GSSG (Glutathione oxidized).

include enzyme inhibition (89, 144), cell toxicity (120), andgenotoxicity (96). MMA (III) is an excellent choice as a causeof arsenic carcinogenesis.

DMA (III) has been detected in human urine of arsenic-exposed humans administered a chelator (81). In a study ofhamsters given arsenate (130), substantial hepatic concentra-tions of trivalent MMA and DMA were found in addition tothe expected pentavalent MMA and DMA. The capacity toseparate the trivalent forms of the methylated arsenic speciesfrom the pentavalent forms has just been developed (37, 81,130). Wei et al (167) demonstrated DMA to be a carcinogen

for the rat urinary bladder and suggested that DMA exposuremay be relevant to the carcinogenic risk of inorganic arsenicin humans. Diverse genetic alterations observed in DMA-induced urinary bladder tumors imply that multiple genesare involved in stages of DMA-induced tumor development(167).

Few data are currently available on the tissue concentra-tions of trivalent methylated species. Some of the biologicalactivities that DMA (III) is known to possess in various ex-perimental systems include enzyme inhibition (89, 144), celltoxicity (120), genotoxicity, and clastogenecity (81).




Trimethylarsinic acid [TMA (III)] may be produced fromtrimethylarsine oxide [TMAO] by reduction. Data from onegroup suggest that only rats may have relatively high levelsof TMAO in their urine. A molecule of TMA (III) possessesno ionizable hydroxyl groups to limit the ability of the triva-lent arsenic species to interact with DNA. TMA (III) mayexist in higher concentrations in rat tissues than in humantissues. Interaction of novel information on the formation,fate, and actions of the methylated arsenicals in humans andother species will reduce some of the uncertainties in the riskassessment for arsenic.

Exposure to arsenic is considered a major public healthconcern, particularly because of its clear carcinogenicpotential (112). However, the molecular mechanism by whichand the dose at which it causes cancer are still unclear. Inrisk assessment of environmental arsenic, it is important toknow and to utilize both the mode of carcinogenic actionand the shape of the dose-response curve at low environ-mental arsenic concentrations. Although much progress hasbeen recently made in the area of arsenic’s possible mode(s)of carcinogenic action, a scientific concensus has not yetbeen reached. Kitchin (75) in his review discussed 9 dif-ferent possible modes of action of arsenic carcinogenesis:induced chromosomal abnormalities (49, 88, 94, 166), oxida-tive stress (3, 53, 90, 98, 165, 171, 172), altered DNA repair(1, 67, 88), altered DNA methylation patterns (97, 179, 180),altered growth factors (47, 136, 160), enhanced cell prolifer-ation (8, 17, 121, 165, 170), promotion/progression (33, 55,104), suppression of p53 (14, 20, 54, 65, 129), gene amplifi-cation (83). Presently, 3 modes (chromosomal abnormality,oxidative stress, and altered growth factors) for arsenic car-cinogenesis have a degree of positive evidence, both in ex-perimental systems (animal and human cells) and in humantissues. The remaining possible modes of carcinogenic ac-tion for arsenic (progression of carcinogenesis, altered DNArepair, p53 suppression, altered DNA methylation patternsand gene amplification) do not have as much evidence, par-ticularly from in vivo studies with animals, in vitro studieswith human cells, or with human data from case or popu-lation studies. Thus, the mode-of-action studies suggest thatthe arsenic might be acting as a cocarcinogen, a promoter, ora progressor of carcinogenesis (112).

Various hypotheses have been proposed to explain thecarcinigenicity of inorganic arsenic (75). Nevertheless,molecular mechanisms by which this arsenical induces can-cer are still poorly understood. Results of previous studiesindicated that inorganic arsenic does not act through classicgenotoxic and mutagenic mechanisms, but rather may be atumor promoter that modifies signal transduction pathwaysinvolved in cell growth and proliferation (136). Inorganic ar-senic (III) has been shown to modulate expression and/orDNA-binding activities of several key transcription factors,including nuclear factor kappa B (10), tumor suppressor 53(p53) (129), and activating protein-1 (AP-1) (18, 22, 137).Mechanisms of AP-1 activation by trivalent inorganic ar-senic include stimulation of the mitogen-activated proteinkinase (MAPK) cascade with a consequent increase in theexpression and/or phosphorylation of the two major AP-1constituents, c-Jun and c-Fos (136).

In another study, Trouba et al (151) concluded that long-term exposure to high levels of arsenic might make cells more

susceptible to mitogenic stimulation and that alterations inmitogenic signaling proteins might contribute to the carcino-genic actions of arsenic. Collectively, several studies (27, 122,162) have demonstrated that arsenic can interfere with cellsignaling pathways (eg, the p53 signaling pathway) that arefrequently implicated in the promotion and progression of avariety of tumor types in experimental animal models and ofsome human tumors.

Clinical trials have found that arsenic has therapeutic valuein the treatment of acute promyelocytic leukemia, and thereis interest in exploring its effectiveness in the treatment of avariety of other cancers (106, 140). In acute promyelocyticleukemia, the specific molecular event critical to the forma-tion of malignant cells is known. The study by Puccetti et al(123) found that forced overexpression of BCR-ABL sus-ceptibility in human lymphoblasts cells resulted in greatlyenhanced sensitivity to arsenic-induced apoptosis. They alsoconcluded that arsenic is a tumor specific agent capable of in-ducing apoptosis selectively in acute promyelocytic leukemiacells. Several studies showed that arsenic induces apop-tosis through alterations in other cell signaling pathways(4, 135). In addition to acute peomyelocytic leukemia, arsenicis thought to have therapeutic potential for myeloma (36). Insummary, numerous cancer chemotherapy studies in cell cul-tures and in patients with acute promyelocytic leukemia andmyeloma demonstrate that arsenic can lead to cell-cycle ar-rest and apoptosis in malignant cells.

Alterations in gene expression via hypo or hypermethyla-tion of CpG sites in DNA have been reviewed (54, 77, 180).An important mechanism for altering gene expression in re-sponse to both endogenous and exogenous signals, includingtoxins is altering nuclear transcription factor activities eitherdirectly or via specific cell-signaling pathways that regulatethem (74). Several studies have examined p53 gene expres-sion and mutation in tumors obtained from subjects with ahistory of arsenic ingestion. The p53 participates in manycellular functions, cell-cycle control, DNA repair, differen-tiation, genomic plasticity and programmed cell death (52,80, 86). The tumor suppressor protein p53 is one componentof the DNA damage response pathway in mammalian cells.Some of these normal cellular functions of p53 can be mod-ulated and sometimes inhibited by interactions with eithercellular proteins (eg, mdm2) or oncoviral proteins of certainDNA viruses. Several different studies support the hypothe-sis that arsenic can modulate gene expression in humans andexperimental models (91, 119, 157).

SYSTEMIC HEALTH EFFECTS

On the basis of epidemiological studies, ingestion of inor-ganic arsenic is implicated in noncarcinogenic health effectsin various organs or systems including cardiovascular, der-mal, reproductive, neurological, respiratory, hepatic, hema-tological, renal, and gastrointestinal.

Dermatologic Effects: Chronic arsenic exposure causesa characteristic pattern of noncarcinogenic dermal effects thatbegins with spotted hyper-pigmentation and may later includepalmar and plantar hyperkeratosis (101). Arsenic contami-nation of well water in Argentina, Chile, India, Taiwan, andThailand has caused cutaneous skin lesions such as keratosis,and both hyperpigmentation, and hypopigmentation (101).




The mechanisms for those latter dichotomous effects wouldbe unique and interesting. Characteristic skin lesions of ar-senic toxicity may be used as an indicator of high exposureand are distinctive in contrast to other clinical manifestationsof arsenic intoxication. Several studies have investigated ad-verse health effects associated with ingestion of arsenic ingroundwater in the Gangetic plain of West Bengal, India andneighboring Bangladesh, where over the past decade morethan 30 million people might have been consuming waterwith arsenic concentrations in excess of 50 µg/L. This studyshowed a higher prevalence rate of arsenic skin lesions inmales than females, with a clear dose-response relationship(31).

Mazumder et al (101) conducted a cross-sectional surveyof the prevalence of hyperpigmentation and palmar-plantarkeratosis in a region of West Bengal, India with ground-water arsenic concentrations ranging from nondetectable to3,400 µg/L. This study found that males were more affectedthan females for both hyperpigmentation and palmar-plantarkeratosis. Several studies found an association between skinlesions and arsenic ingestion in India and Inner Mongolia(156).

Cardiovascular Effects: Epidemiological studies haveshown that the cardiovascular system is particularly sen-sitive to long-term ingestion of arsenic in drinking water.Noticeable effects include hypertension and increased car-diovascular disease mortality (113). Rahman et al (125) con-ducted a cross-sectional evaluation of blood pressure in 1,595adults (above 30 years of age) who resided all their life in arural area of Bangladesh. The area had a high level of arsenicexposure resulting from the use of contaminated groundwaterfor drinking water; wells were drilled because of microbialcontamination of surface water. At the time of this study nosubjects were taking antihypertensive medication. The diet,lifestyle, and socioeconomic status of all subjects were simi-lar. The study found that increasing arsenic in drinking waterincreased the incidence and severity of hypertension (125).

An increased risk of coronary heart disease has been re-lated to long-term exposure to inorganic arsenic. Blackfootdisease patients have been reported to have increased mor-tality from ischemic heart disease (ISHD) (28). Arsenic is amajor risk factor for what is known as blackfoot disease, thatis peripheral atherosclerosis resulting in dry gangrene andspontaneous amputation of affected extremities. The diseasewas named for its most striking clinical feature blackish dis-coloration of the feet or hands (154). A recent study hasreported a biological gradient between cumulative arsenicexposure through consuming artesian well water and lethalischemic heart disease (ISHD) in Taiwan (24). Environmen-tal exposure to inorganic arsenic through drinking water hasbeen associated with increased mortality from cardiovasculardisease in Chile (176) and Japan (155), and from cardiovascu-lar disease among chimney sweeps, copper smelter workers,and glass blowers exposed to arsenic in their working envi-ronments (66).

In India, individuals exposed to elevated inorganic arseniclevels in drinking water showed a range of health effectsincluding peripheral vascular disease, noncirrhotic portal fi-brosis, nasal septum perforation, bronchitis, and polyneu-ropathy. In Taiwan, skin pigmentation changes and hyperker-

atoses were the most sensitive indicators of inorganic arsenicexposure (101).

Reproductive and Developmental Effects: Whereas ar-senic exposure has been associated with a number of adversehealth outcomes, relatively little attention has been directedtoward the potential impact of arsenic on human reproduc-tive system, despite studies in both humans and experimen-tal animals demonstrating that arsenic and its methylatedmetabolites cross the placenta (34). Evidence from humanstudies suggests the potential for adverse reproductive im-pacts among the offspring of employees and nearby residentsof a Swedish copper smelter where arsenic exposure weredocumented (114–117). Female workers gave birth to lowerweight infants than women who resided outside the smelterarea, and the difference was greater if the mothers workedin the more highly exposed jobs (117). An incremental trendin the rates of spontaneous abortions was observed with in-creasing occupational and residential exposure (115, 117).Congential malformations appeared to be more frequent ifthe expectant mother was employed in highly exposed jobsduring pregnancy (116). In Bulgaria, the incidence of tox-emia of pregnancy and the mortality from congential malfor-mations were significantly higher in an area near a smelterwith environmental contamination from various metals thanthe national rates (178). Studies of populations exposed toarsenic from drinking water have found increased rates ofspontaneous abortions and stillbirths in Hungary (16) andArgentina (21). In the United States, three studies reportedadverse reproductive effects, including increases in mortal-ity from congential cardiovascular anomalies (39, 181) andspontaneous abortions (9). A study in Texas found an increasein the rates of stillbirths in relation to residential exposuresfrom an arsenic pesticide factory (71).

Neurological Effects: In the past, studies of arsenic in-duced neurological effects have generally focused on centralnervous system effects following acute, high-dose intoxica-tion, and on the peripheral neuropathy that occurs followingchronic exposure (112). Two studies have focused on sub-tle cognitive effects in children following chronic exposureto arsenic. Siripitayakunkit et al (138) investigated the as-sociation between environmental arsenic exposure and theintelligence (IQ) of children in the Ronpiboon district ofThailand, where shallow artesian wells were contaminatedwith arsenic. To prove a significant association between ar-senic and growth, head-hair arsenic concentrations and per-formance on the Weschler Intelligence Scale Test for children(WISTC) in 529 schoolchildren were analysed in a cross-sectional evaluation. High arsenic levels measured in hairaffect height but not weight. Only 2 epidemiological studieson the effects of arsenic on children’s growth exist in the lit-erature. In these studies males were more susceptible than fe-males, and stature was more affected than weight (118, 134).Anorexia, malabsorption, and weight loss may be presentbecause of low-dose arsenic ingestion (105). Two follow-upstudies of arsenic-poisoned Japanese victims, found that thevictim group showed retarded growth from the age of oneyear to school age with average height of the victims lessthan that of a same-age group (173).

A cross-sectional study in San Luis Potosi, Mexico (19) ex-amined the impact of arsenic, lead and under-nutrition on the




neuropsychological performance of school children aged 6 to9 years. Subjects included 41 children living within 1.5 Kmof a smelter complex (Morales Zone) with increasing arsenicand lead concentrations, and 39 children living 7 Km up-wind from smelter (Martinez Zone). The geometric mean to-tal arsenic concentration in urine was higher in the Moraleschildren than in the Martinez children. Maternal and pater-nal educational attainment, socioeconomic status was lowerin the Martinez group. Neuropsychological performance wasassessed using the Weschler Intelligence Scale for children,Revised version, for Mexico (WISC-RM). The Morales chil-dren scored significantly lower than the Martinez children onthe full-scale IQ test and other neuropsychological subscores(19).

Respiratory Effects: Noncancer respiratory effects havebeen reported in populations exposed to arsenic in drinkingwater (112), but the database is sparse. Mazumder et al (102)recently reported an association between arsenic ingestion indrinking water and the prevalence of respiratory disorders.Respiratory effects in West Bengal were first noted in 1995when 57% of the 156 patients who lived in arsenic-affectedvillages reported having chronic cough (100). Moreover, epi-demiological studies in Chile have previously suggested anassociation between arsenic and nonmalignant respiratory ef-fects. The survey data collected from 1968 to 1972 in Antofa-gasta, Chile, Zaldivar, and Ghai (177) reported that the preva-lence of cough among 398 children correlated with meandrinking water arsenic concentrations.

Zaldivar (176) also reported that the prevalence ofbronchiectasis was 23-fold greater among children witharsenic-induced skin-lesions living in Antofagasta comparedto children living in the rest of Chile. A 1976 cross-sectionalsurvey in Antofagasta examined 144 school children witharsenic-induced skin-lesions, and bronchopulmonary diseaseoccurred 2.5 times more often in these children compared tochildren with normal skin (15). In a study, Smith et al (139)found high relative rates for chronic obstructive pulmonarydisease (COPD) mortality among young men and women liv-ing in the same arsenic-exposed region in Chile that includesAntofagasta. A few occupational studies conducted in the1950s in Sweden have also reported nonmalignant respira-tory effects in copper smelter workers exposed to airbornearsenic. In one of the clinical study of copper smelter work-ers cited by Gerhard et al (46), a syndrome characterizedby lesions of the mucous membranes of the upper respiratorysystem, emphysema, and decreased pulmonary function, wasdescribed (45).

The relationship between ingested arsenic and nonmalig-nant respiratory effects has so far only been reported fromChile (30), India (93), and Bangladesh (103). Studies fromarsenic-affected regions in Taiwan, Chile, and Argentinashow marked increases in lung cancer mortality. The char-acteristic feature of arsenic is that it seems to increase bothmalignant and nonmalignant respiratory disease followingingestion.

Milton et al (103) reported an association between chronicarsenic ingestion and chronic bronchitis in a small cross-sectional study of 94 individuals in Bangladesh with arsenic-associated skin lesions. Chronic bronchitis was defined asa history of cough productive of sputum on most days for

at least 3 consecutive months for more than 2 successiveyears, combined with the presence of chest rhonchi and orcrepitations on physical examination. Males were at greaterrisk for chronic bronchitis than the females.

Hepatotoxic Effects: Hernandez-Zavala et al (60) studiedliver function in individuals from three towns in the regionof Lagunera, Mexico. They determined the serum activityof aspartate aminotransferase (SAT) and alanine aminotrans-ferase (ALT) as indicators of hepatocellular injury and thatof gamma-glutamyl-transpeptidase (GGT) and alkaline phos-phatase (ALP) as indicators of cholestasic injury. The mainfindings of this study were predominantly conjugated hy-perbilirubinemia and increased serum ALP activity whichwere related to the concentration of total arsenic in urine,suggesting the presence of cholestasis in arsenic exposedindividuals.

Armstrong et al (7) also observed increased concentra-tions of total bilirubins in serum samples from 7 individu-als ingested with arsenic via drinking water. Furthermore,histological examination of livers of individuals chronicallyexposed to high arsenic concentrations has revealed the pres-ence of portal tract fibrosis, which occasionally causes por-tal hypertension and bleeding from esophageal varices (99).In a study by Santra et al (131), bilirubin or alkaline phos-phatase increases were not a characteristic finding in patientswith firm hepatomegaly attributed to chronic arsenicosis inWest Bengal, India. In that study, liver biopsy results frompatients with clinical diagnosis of chronic arsenic poison-ing revealed mild portal fibrosis, and cirrhosis. Clinical ev-idence of portal hypertension (eg, esophageal varices) wasuncommon.

Hematologic Effects and Diabetes: Hernandez-Zavalaet al (61) studied the activities of some enzymes of theheme biosyntheis pathway and their relationship with theprofile of urinary porphyrin excretion in individuals ex-posed chronically to arsenic via drinking water in RegionLagunera, Mexico. The more evident alterations in hememetabolism observed were: small but significant increasesin porphobilinogen deaminase (PBG-D) and uroporphyrino-gen decarboxylase (URO-D) activities in peripheral blooderythrocytes; increases in the urinary excretion of total por-phyrins, mainly due to coproporphyrin III (COPROIII) anduroporphyrin III (UROIII); and increases in the COPRO/URO and COPROIII/COPROI ratios. No significantchanges were observed in uroporphyrinogen III synthetase(UROIII-S) activity. The direct relationships between en-zyme activities and urinary porphyrins, suggest that the in-creased porphyrin excretion was related to PBG-D, whereasthe increased URO-D activity would enhance coproporphyrinsynthesis and excretion at the expense of uroporphyrin. Noneof the human studies available have reported the markedporphyric response and enzyme inhibition observed inrodents.

The main concern of arsenic on the endocrine system is theassociation between arsenic exposure and diabetes mellitus.As part of an ecological study examining multiple causes ofmortality in the area of Southwestern Taiwan where black-foot disease is endemic, Tsai et al (152) examined mortal-ity from diabetes mellitus in 4 townships, where artesianwell water containing arsenic had been consumed from the




early 1900s until the mid-to-late 1970s. Diabetes mellituswas listed as the underlying cause of death for 188 males and343 females.

Tseng et al (153) reported a prospective cohort study ex-amining the incidence of diabetes mellitus in three villagesfrom the arsenic endemic area of Southwestern Taiwan. Thestudy population consisted of three villages where artesianwell water (0.70 to 0.93 mg/L As) was used for drinkingand cooking until the mid-to-late 1970s. The population wassubjected to a follow-up examination that includes fastingblood glucose and an oral glucose tolerance test. The re-sults of this study show an association between long-termarsenic exposure and diabetes mellitus, as found in the pre-vious prevalence study. The prevalence of diabetes mellituswas 2-fold higher in Southwestern area of Taiwan than inTaipei city and the Taiwan area in general (78).

A dose-response relation between cumulative arsenic ex-posure and the prevalence of diabetes mellitus was alsodemonstrated after adjustment for multiple risk factors (78).Rahman and Axelson (124) carried out a case-control studyon Swedish copper smelter workers. Using the death recordsfor 1960–1976, they compared three arsenic exposure cate-gories with an unexposed group. They observed an increasedrisk of dying from diabetes mellitus with increasing arsenicexposure. In a similar study carried out among art glass work-ers, indications of a relationship between arsenic exposureand diabetes mellitus have also been reported (126). In acommunity-based survey of diabetes mellitus in Bangladesh,Rahman et al (125) observed a dose-response trend betweenthe prevalence of diabetes mellitus and the arsenic level indrinking water.

Renal Effects: The kidneys are the major route of ar-senic excretion, as well as a major site of conversion of pen-tavalent arsenic into the more toxic and less soluble triva-lent arsenic. Sites of arsenic damage in the kidney includecapillaries, tubules, and glomeruli (133, 141, 168). As inother organs, capillary damage seems to be a basic eventleading to other cellular manifestations. Glomerular arteri-oles dilate, permitting hematuria. Damaged proximal tubu-lar cells lead to proteinuria and casts in the urine. Mito-chondrial damage is also prominent in tubular cells (105).Oliguria is a common manifestation, but if acute arsenic poi-soning is sufficiently severe to produce shock and dehydra-tion, there is real risk of renal failure, although dialysis hasbeen effective in overcoming this complication (48). Acutecortical necrosis is an uncommon severe renal manifesta-tion, but benefits from dialysis (46). Arsine-induced hemol-ysis is likely to cause acute tubular necrosis with partial orcomplete renal failure, requiring hemodialysis for removal

TABLE 1.—Mortality ratios or incidence of lung cancer in case-control studies on arsenic.

Study Location Exposure Number of cases Study outcome

Ferreccio et al (43) Northern Chile Individual 40+ year average arsenic conc. 151 cases Age and sex adjusted odd ratios∗from public water 419 controlssupply records0–10 µg/L10–29 µg/L 1.6 (0.5–5.3)30–49 µg/L 3.9 (1.2–12.3)50–199 µg/L 5.2 (2.3–11.7)200–400 µg/L 8.9 (4.0–19.6)

∗Odd ratios were used to estimate relative risks of exposure to various concentrations of arsenic in drinking water relative to a reference concentration of 0–10 ug/L.

of the hemoglobin-bound arsenic (44, 148). Recovery mayleave interstitial fibrosis and thickened glomerular basementmembranes.

Gastrointestinal Effects: The effects of oral ingestion byaccident or with suicidal or homicidal intent, the direct ef-fects on the gastrointestinal tract have been prominent andduly noted by several authors (38, 50, 62, 133, 141, 158). Al-though arsenic may produce direct irritant effects on gastroin-testinal tissues with which it comes in contact, the greatestdegree of damage is produced by local submucosal capillarydamage from absorbed arsenic (32). The vascular damage isthought to be the cause of submucosal vesicles, whose rupturecan create grossly visible erosions and major fluid and pro-tein loss. Nausea and vomiting can be severe, as can colickyabdominal pain and marked diarrhea. If sufficiently severe,the acute gastroenteritis can lead to circulatory collapse withrenal damage and shutdown.

Arsenic poisoning from lesser doses of arsenic may man-ifest as dry mouth and throat, heartburn, nausea, abdominalpains and cramps, and moderate diarrhea. Chronic low-dosearsenic ingestion may be without symptomatic gastrointesti-nal irritation or may produce a mild esophagitis, gastritis,or colitis with respective upper and lower abdominal dis-comfort. Anorexia, malabsorption, and weight loss may bepresent (105).

CARCINOGENIC HEALTH EFFECTS

Carcinogenesis is a multistage process involving the in-appropriate activation of normal cellular genes to becomeoncogenes, eg, ras, and the inactivation of other cellulargenes called tumor suppressor genes (56). The prototypictumor suppressor genes are well suited as a molecular linkbetween the causes of cancer, ie, carcinogenic chemicaland physical agents and certain viruses, and the develop-ment of clinical cancer. The crucial differences between nor-mal and cancer cells stem from discrete changes in specificgenes controlling proliferation and tissue homeostasis (56).Progress in the fields of molecular carcinogenesis and molec-ular epidemiology increases our ability to assess cancer risk.Because regulatory decisions based on cancer risk assess-ments have significant public health and economic con-sequences, the scientific basis of risk assessment contin-ues to be, and should continue to be, actively investigated(111).

Long-term exposure to arsenic affects the gastrointestinaltract, circulatory system, skin, liver, lung, kidneys, nervoussystem, and heart. Evidence from epidemiological studiesclearly shows that exposure to inorganic arsenic increasesthe risk of cancer. In workers exposed by inhalation, the




TABLE 2.—Mortality ratios or incidence of bladder cancer in epidemiological studies on arsenic (Cohort studies).

Study Location Exposure Number of cases Study outcome

Chiou et al (29) NE Taiwan Conc. of arsenic in Incidence rate Relative riskhousehold well H2O

≤10 µg/L 37.6 (3) 1.510–50 µg/L 4.8 (3) 2.250.1–100 µg/L 66.4 (2) 4.8>100 µg/L 134.1 (7)

Lewis et al (87) Utah Cumulative arsenic exposure during Male Female Male Femaleresidence in study towns

<1.000 ppb-yr 3 2 0.36 1.181.000–4.998 ppb-yr — —>5,000 ppb-yr 0.95 1.10

All 0.42 0.81(0.08–1.23) (0.10–2.93)

Chiou et al (30) SW Taiwan Cumulative arsenic Incidence rate Relative risk<0.1 mg/L × yr 4 1.00.1–19.9 mg/L × yr 7 2.1 (0.6–7.2)≥20 mg/L × yr 9 5.1 (1.5–17.3)

Average arsenic<0.05 mg/L 6 1.00.05–0.70 mg/L 7 1.8 (0.6–5.3)≥0.71 mg/L 7 3.3 (1.0–11.1)

predominant carcinogenic effect is an increased risk of lungcancer (40, 85), when exposure occurs orally, the main car-cinogenic effect is increased risk of skin cancer. In addition toskin cancer, increased risk of several internal cancers (mainlyof liver, kidney, lung, colon, and bladder) have been reportedwith arsenic exposure (147).

In a region of Northern Chile with a history of increasedconcentrations of arsenic in drinking water, Ferreccio et al(43) conducted a case control study of incident lung can-cer in eight public hospitals in regions I, II and III from1994 through 1996 and frequently matched hospital controls(Table 1). The study identified 152 cases and 419 controls.Historical exposure to arsenic in drinking water for each re-spondent was estimated by linking residential history infor-mation on arsenic concentrations in public water supplies for40+ years. Odds ratios were used to estimate relative risks ofexposure to various concentrations of arsenic in drinking wa-ter relative to a reference concentration of 0–10 µg/L. Odd ra-tios were calculated using unconditional logistic regression,adjusted for age, socioeconomic status, smoking and work-ing in a copper smelter. An association between lung cancerincidences and arsenic concentrations in drinking water wasfound.

TABLE 3.—Mortality ratios or incidences of bladder cancer in epidemiological studies on arsenic (Ecological studies).

Number of cases Study outcome (SMR)a

Study Location Exposure Females Males Females Males

Tsai et al (152) Blackfoot endemic area of SW Taiwan Arsenic endemic area 295 312 14.07 (12.51–15.78)b 8.92 (7.96–9.96)b

17.65 (5.70–19.79)c 10.50 (9.37–11.73)c

Smith et al (139) Region II Northern Chile 5-year average, 420 µg/L average 64 93 8.2 (6.3–10.5) 6.0 (4.8–7.4)Hopenhayn-Rich Cordoba Province, Argentina County group

et al (63, 64) Low 39 113 1.21 (0.9–1.6) 0.80 (0.7–1.0)Medium 24 93 1.58 (1.0–2.4) 1.42 (1.1–1.7)High 27 131 1.82 (1.2–2.6) 2.14 (1.8–2.5)

Wu et al (169) Southwest Taiwan Average arsenic<0.30 ppm 30 23 25.6 22.60.30–0.59 ppm 36 36 57.0 61.0≥0.60 ppm 30 26 111.3 92.7

Chen et al (25) Southwest Taiwan Blackfoot disease endemic area 165 167 20.09 (17.0–23.2) 11.00 (9.3–12.7)aStandardized mortality ratios.bRegional rate.cNational rate.

Two studies of arsenic exposure and cancer in Chile arealso documented. The first, an ecological cohort study, usedcommunity estimates of arsenic in water and age-specific in-gestion rates (42). This study found an association betweenarsenic in drinking water at 50 µg/L and skin cancer as wellas 4 internal cancers. The second, a case control study, foundan association between bladder cancer and arsenic exposure,as reflected in significant changes in odds ratios with an es-timated lifetime cumulative exposure to arsenic (42).

A prospective cohort study of 8,102 persons was carriedout in the Lanyang basin of northeastern Taiwan (29), a re-gion where arsenic-contaminated shallow wells were used fordrinking water over the past 50 years (Table 2). Relative riskswere calculated using subjects with exposures <10 µg/L asa reference population. The outcome of the study was a rel-ative risk of total urinary tract cancer incidence (includingkidney, bladder and urethral), specifically of the most com-mon cell type of urinary cancer, transitional cell carcinoma(29).

In the United States, a retrospective cohort mortality studywas conducted in Utah based on community estimates ofarsenic exposure (Table 2). The results of this study indicatedan association between inorganic arsenic and certain cancers




TABLE 4.—Mortality ratios of incidents of lung cancer in epidemiological studies on arsenic (Ecological studies).

Number of cases Study outcome (SMR)a

Study Location Exposure Females Males Females Males

Tsai et al (152) Black foot endemic area Arsenic endemic area 471 699 4.13 (3.77–4.52)b 3.1 (2.88–3.34)b

of SW Taiwan 3.5 (3.19–3.84)c 2.64 (2.45–2.84)c

Smith et al (139) Region II 5-year average 154 554 3.1 (2.7–3.7) 3.8 (3.5–4.1)Northern Chile 420 µ/L average

Hopenhayn-Rich et al (63, 64) Cordoba province, County groupArgentina Low 194 826 1.24 (1.06–1.62) 0.92

Medium 138 914 1.34 (1.12–1.58) 1.54High 156 708 2.16 (1.83–2.52) 1.77

Wu et al (169) Southwest Taiwan Average arsenic<0.30 ppm 43 53 36.1 49.160.30–0.59 ppm 40 62 60.82 100.67≥0.60 ppm 38 32 122.16 104.08

Chen et al (25) Southwest Taiwan Blackfoot disease endemic area 233 322 4.13 3.20aStandardized mortality ratios.bRegional rate.cNational rate.

as well as noncancer effects. The most predominant types ofcancer that were found in the population were bladder andother urinary organ cancers. Males were affected more thanthe females (87).

A case-control study of skin cancer, in Hungary found anincreased risk of basal cell carcinoma associated with el-evated levels of atmospheric arsenic from coal combustion.This was particularly apparent in cases diagnosed before 1982as compared to cases diagnosed after 1986. In addition, thesame investigators reported that basal cell carcinomas wereassociated with elevated occupational exposure to airbornearsenic (1).

According to an epidemiological study from a blackfootdisease-endemic area of Taiwan, a high mortality was foundin males and females for skin, liver, lung, bladder, kidney,and nasal cancers, and possibly other sites. The outcomes ofthis study corroborate the results of several other studies sug-gesting a relationship between arsenic exposure and cancersof the internal organs (152). Arsenic has also been implicatedas a bladder carcinogen in separate studies from Argentina,Chile, and Taiwan (13, 63) (Table 3). In addition, the resultsof a study in Cordoba, Argentina add to the evidence that ar-senic ingestion increases the risk of kidney cancers (64). Theassociation between carcinoma of the lung and inhaled ar-senic is well established (Table 4); more studies have shownthat ingested inorganic arsenic may also be an etiologicalfactor in the development of lung cancer (152).

Significant excess mortality from cancers of the diges-tive tract has been observed among copper smelter workersin Anaconda, Montana, with a standardized mortality ratioof 1.3 (41); only a slight excess in mortality from digestivetract cancer was observed among smelter workers in Tacoma,Washington (163). Increased mortality from stomach cancerhas been reported among copper smelter workers in Swedenwith a standardized mortality ratio of 1.7 (92), and amongMoselle vinters with a standardized mortality ratio of 2.4(150). Colon cancer mortality has also been significantly as-sociated with chronic exposures to inorganic arsenic amongcopper smelter workers in Tacoma, Washington, with a sig-nificant standardized mortality ratio of 2.1 for those who em-ployed before respirators were implemented in the smelter(41), and among smelter workers in Japan with a standard-ized mortality ratio of 5.1 (25).

There was no apparent increase in stomach cancer mortal-ity among residents in the area of endemic blackfoot diseasein Taiwan, but significantly increased colon cancer mortality,with a standardized mortality ratios of 1.6 for men and 1.7for women, was observed in the area (25).

CONCLUSIONS

Integration of the available scientific information on ar-senic indicates that geogenic and anthropogenic contamina-tion of natural resources represents a major public healthproblem in many countries of the world. Exposure to arsenicoccurs via ingestion, inhalation, and dermal contact. Suchexposure has been associated with a significant number ofsystemic health effects in various organs and tissue systemsincluding skin, lung, liver, kidney, bladder, gastrointestinaltract, respiratory system, and hematopoetic system. Evidencefrom recent studies has linked arsenic consumption in drink-ing water with two non-cancer health conditions (hyperten-sion and diabetes mellitus) that are a major cause of morbidityand mortality. A small number of studies have investigatedthe relationship between arsenic exposure in humans and ad-verse reproductive effects, including studies of populationsin Chile and Bangladesh exposed to increased concentra-tions of arsenic in drinking water. There is some evidencefrom these studies that arsenic increases stillbirths, sponta-neous abortions, preterm births, and infant mortality. Find-ings from a large prevalence study in West Bengal, a smallprevalence study in Bangladesh, and an ecological mortalitystudy in the area of Southwestern Taiwan where arsenic is en-demic indicated an association between arsenic ingestion andnon-cancer respiratory effects. Two recent investigations ofneurocognitive function in young schoolchildren suggest thatarsenic exposure might be associated with an (IQ) adverse ef-fect. Experiments in animals and in vitro have demonstratedthat arsenic has many biochemical and cytotoxic effects at lowdoses of human exposure. Those effects include induction ofoxidative damage, altered DNA methylation and gene ex-pression; changes in intracellular levels of mdm2 protein andp53 protein; inhibition of thioredoxin reductase; inhibition ofpyruvate dehydrogenase; altered colony-forming efficiency;induction of protein-DNA cross-links; induction of apop-tosis; altered regulation of DNA-repair genes, thioredoxin,




glutathione reductase, and other stress-response pathways;stimulation or inhibition of normal human keratinocyte pro-liferation, depending on the concentration; and altered func-tion of the glucocorticoid receptor. Additionally, the evidenceof carcinogenicity in humans is very strong, especially forcancer of the skin, lung, liver, kidney, and bladder.

Further epidemiological studies are highly recommendedto investigate the dose-response relationship btween arsenicingestion and noncancer endpoints. Because of the very largepopulations exposed, these endpoints are common causes ofmorbidity and mortality, even small increases in relative riskat low doses of arsenic exposure could be of considerablepublic-health significance. Such information is also impor-tant in developing a comprehensive risk assessment and man-agement program for arsenic.

ACKNOWLEDGEMENTS

This research was supported by a grant from the NationalInstitutes of Health (Grant No. 1G12RR13459) through theRCMI-Center for Environmental Health at Jackson State Uni-versity. We thank Dr. Jennie Hunter-Cevera, President of theUniversity of Maryland Biotechnology Institute, and othermembers of the External Advisory Board for their technicaladvice on this project.

REFERENCES

1. Abernathy CO, Liu YP, Longfellow D, Aposhian HV, Beck B, Fowler B,Goyer R, Menzer R, Rossman T, Thompson C, Waalkes M (1999). Arsenic:Health effects, mechanisms of actions and research issues. Environ HealthPerspect 107: 593–597.

2. Agency for Toxic Substances and Disease Registry (ATSDR) (2000).Toxicological Profile for Arsenic TP-92/09. Center for Disease Control,Atlanta, Georgia.

3. Ahmad S, Kitchin KT, Cullen WR (2000). Arsenic species that causerelease of iron from ferritin and generation of activated oxygen. ArchBiochem Biophys 382: 195–202.

4. Alemany M, Levin J (2000). The effects of arsenic trioxide on humanmegakaryocyticleukemia cell lines with a comparison of its effects onother cell lineages. Leuk Lymphoma 38(1–2): 153–163.

5. Aposhian HV, Gurzau ES, Le XC, Gurzau A, Healy SM, Lu X, Ma M,Yip L, Zakharyan RA, Maiorino RM, Dart RC, Tircus MG, Gonzalez-Ramirez D, Morgan DL, Avram D, Aposhian MM (2000a). Occurrenceof monomethylarsonous acid in urine of humans exposed to inorganicarsenic. Chem Res Toxicol 13(8): 693–697.

6. Aposhian HV, Zheng B, Aposhian MM, Le XC, Cebrian ME, Cullen W,Zakharyan RA, Ma M, Dart RC, Cheng Z, Andrewes P, Yip L, O’MalleyGF, Maiorino RM, Van Voorhies W, Healy SM, Titcomb A (2000b).DMPS-arsenic challenge test II. Modulation of arsenic species, includingmonomethylarsonous acid (MMA (III)), excreted in human urine. ToxicolAppl Pharmacol 165: 74–83.

7. Armstrong CW, Stroube R, Rubio T (1984). Outbreak of fatal arsenicpoisoning caused by contaminated drinking water. Arch Environ Health39: 276–279.

8. Arnold LL, Cano M, St. John M, Eldna M, Van Gemert M, Cohen SM(1999). Effects of dietary dimethylarseinic acid on the urine and urotheliumof rats. Carcinogenesis 20: 2171–2179.

9. Aschengrau A, Zierler S, Cohen A (1989). Quality of community drinkingwater and the occurrence of spontaneous abortion. Arch Environ Health44: 283–290.

10. Barchowsky A, Dudek EJ, Treadwell MD, Wetterhahn KE (1996). Arsenicinduces oxidant stress and NFκB activation in cultured aortic endothelialcells. Free Radic Biol Med 21: 783–790.

11. Barrett JC, Lamb PW, Wang TC, Lee TC (1989). Mechanisms ofarsenic-induced cell transformation. Biol Trace Elem Res 21: 421–429.

12. Belton JC, Benson NC, Hanna ML, Taylor RT (1985). Growth inhibitionand cytotoxic effects of three arsenic compounds on cultured Chinesehamster ovary cells. J Environ Sci Health 20A: 37–72.

13. Biggs ML, Haque R, Moore L, Smith A (1998). Arsenic-laced water inChile. Science 281: 785.

14. Boonchai W, Walsh M, Cummings M, Chenevix-Trench G (2000). Ex-pression of p53 in arsenic-related and sporadic basal cell carcinoma. ArchDermatol 136: 195–198.

15. Borgono JM, Vicent P, Venturino H, Infante A (1977). Arsenic in thedrinking water of the city of Antofagasta: epidemiological and clinicalstudy before and after the installation of a treatment plant. Environ HealthPerspect 19: 103–105.

16. Borzsonyi M, Bereczky A, Rudnai P, Csanady M, Horvath A (1992). Epi-demiological studies on human subjects exposed to arsenic in drinkingwater in Southwest Hungary. Arch Toxicol 66: 77–78.

17. Brown J, Kitchin KT (1996). Arsenite, but not cadmium, induces ornithinedecarboxylase and heme oxygenase activity in rat liver: Relevance to ar-senic carcinogenesis. Cancer Lett 98: 227–231.

18. Burleson FG, Simeonova PP, Germolec DR, Luster MI (1996). Dermato-toxic chemical stimulate of c-jun and c-fos transcription and AP-1 DNAbinding in human keratinocytes. Res Commun Mol Pathol Pharmacol 93:131–148.

19. Calderon J, Navarro ME, Jimenez-Capdeville ME, Santos-Diaz MA,Golden A, Rodriguez-Leyva I, Borja-Aburto V, Diaz- Barriga F (2001).Exposure to arsenic and lead and neuropsychological development in Mex-ican children. Environ Res 85(2): 69–76.

20. Castren K, Ranki A, Welsh JA, Vahakangas KH (1998). Infrequent p53mutations in arsenic-related skin lesions. Oncol Res 10: 475–482.

21. Castro JA (1982). Efectos carcinogenicos, mutagenicos y teratogenicosdel arsenico. Acta Bioquim Clin Latinoam 16: 3–17.

22. Cavigelli M, Li WW, Lin A, Su B, Yoshioka K, Karin M (1996). The tu-mor promoter arsenite stimulates AP-1 activity by inhibiting a JNK phos-phatase. EMBO J 15: 6269–6279.

23. Chappell W, Beck B, Brown K, North D, Thornton I, Chaney R, Cothern R,Cothern CR, North DW, Irgolic K, Thornton I, Tsongas T (1997). Inorganicarsenic: A need and an opportunity to improve risk assessment. EnvironHealth Perspect 105: 1060–1067.

24. Chen CJ, Chiou HY, Chiang MH, Lin LJ, Tai TY (1996). Dose-response re-lationship between ischemic heart disease mortality and long-term arsenicexposure. Arterioscler Thromb Vasc Biol 16: 504–510.

25. Chen CJ, Chuang YC, Lin TM, Wu HY (1985). Malignant neoplasmsamong residents of a blackfoot disease-endemic area in Taiwan: High-arsenic artesian well water and cancers. Cancer Res 45: 5895–5899.

26. Chen CJ, Lin LJ (1994). Human carcinogenicity and atherogenicity in-duced by chronic exposure to inorganic arsenic. In: Arsenic in the Envi-ronment; Part II: Human Health and Ecosystem Effects, Nriagu JO (ed).John Wiley & Sons, New York, pp 109–131.

27. Chen NY, Ma WY, Huang C, Ding M, Dong Z (2000a). Activation ofPKC is required for arsenite-induced signal transduction. J Environ PatholToxicol Oncol 19(3): 297–306.

28. Chen CJ, Wu MM, Lee SS, Wang JD, Chen SH, Wu HY (1988). Athero-genicity and carcinogenicity of high-arsenic artesian well water: multiplerisk factors and related malignant neoplasms of blackfoot disease. Athe-riosclerosis 8: 452–460.

29. Chiou HY, Chiou ST, Hsu YH, Chou YL, Tseng CH, Wei ML, Chen CJ(2001). Incidence of transitional cell carcinoma and arsenic in drinkingwater: a follow-up study of 8,102 residents in an arseniasis-endemic areain Northeastern Taiwan. Am J Epidemiol 153(5): 411–418.

30. Chiou Hy, Hsueh YM, Liaw KF, Horng, SF, Chiang MH, Pu YS, Lin JS,Huang CH, Chen CJ (1995). Incidence of internal cancers and ingestedinorganic arsenic: a seven-year follow-up study in Taiwan. Cancer Res 55:1296–1300.

31. Chowdhury UK, Biswas BK, Chowdhury TR, Samanta G, Mandal BK,Basu GC, Chanda CR, Lodh D, Saha SC, Mukherjee SK, Roy S, Kabir S,




Quamruzzaman Q, Chakraborti D (2000). Groundwater arsenic contam-ination in Bangladesh and West Bengal, India. Environ Health Perspect108(5): 393–397.

32. Clarkson TW (1991). Inorganic and organometal pesticides. In: Handbookof Pesticide Toxicology, Hayes WJ Jr, Laws ER Jr (eds). Academic Press,San Diego, pp 545–552.

33. Clayson DB, Kitchin KT (1999). Interspecies differences in response tochemical carcinogens. In: Carcinogenicity: Testing, Predicting, and In-terpreting Chemical Effects, Kitchin K (ed). Marcel Dekker, New York,pp 837–880.

34. Concha G, Vogler G, Lezeano D, Nermell B, Vahter M (1998). Exposureto inorganic arsenic metabolites during early human development. ToxicolSci 44: 185–190.

35. Cullen WR, McBride BC, Reglinski J (1984). The reduction of trimethy-larsine oxide to trimethylarsine by thiols: a mechanistic model for thebiological reduction of arsenicals. J Inorg Biochem 21: 45–60, 179–194.

36. Deaglio S, Canella D, Baj G, Arnulfo A, Waxman S, Malavasi F (2001).Evidence of an immunologic mechanism behind the therapeutic effects ofarsenic trioxide on myeloma cells. Leuk Res 25(3): 237–239.

37. Del Razo LM, Styblo M, Thomas DJ (2000). Determination of trivalentmethylated arsenic species in water, cultured rat hepatocytes, and humanurine. 4th International Conference on Arsenic Exposure and Health Ef-fects, Poster 10. San Diego, California, USA.

38. Ellenhorn MJ, Barceloux DG (1988). Medical Toxicology: Diagnosis andTreatment of Human Poisoning. Elsevier, New York, pp 1012–1016.

39. Engel RE, Smith AH (1994). Arsenic in drinking water and mortality fromvascular disease: an ecological analysis in 30 counties in the United States.Arch Environ Health 49: 418–427.

40. Enterline PE, Henderson VL, Marsh GM (1987). Exposure to arsenic andrespiratory cancer: a reanalysis. Am J Epidemiol 125: 929–938.

41. Enterline PE, Marsh GM (1982). Cancer among workers exposed to ar-senic and other substances in a copper smelter. Am J Epidemiol 116: 895–911.

42. Ferreccio C, Gonzalez C, Milosavlijevic V, Marshall G, Sancha AM(1998). Lung cancer and arsenic exposure in drinking water: a case controlstudy in Northern Chile. Cad Saude Publica 14: 193–198.

43. Ferreccio C, Gonzalez C, Milosavlijevic V, Marshall G, Sancha AM, SmithAH (2000). Lung cancer and arsenic concentrations in drinking water inChile. Epidemiology 11(6): 673–679.

44. Fowler BA, Weissberg JB (1974). Arsine poisoning. N Engl J Med 291:1171–1174.

45. Gerhardsson L, Brune D, Nordberg GF, Wester PO (1988). Multielementalassay of tissues of deceased smelter workers and controls. Sci Total Environ74: 97–110.

46. Gerhardt RE, Hudson JB, Rao RN, Sobel RE (1978). Chronic renal insuf-ficiency from cortical necrosis induced by arsenic poisoning. Arch InternMed 138: 1267–1269.

47. Germolec DR, Spalding T, Boorman GA, Wilmer JL, Yoshida T,Simeonova PD, Bruccoleri A, Kayama F, Gaido K, Tennant R, Burleson F,Dong W, Lang RW, Luster MI (1997). Arsenic can mediate skin neoplasiaby chronic stimulation of keratinocyte-derived growth factors. Mutat Res386: 209–218.

48. Giberson A, Vaziri ND, Mirahamadi K, Rosen SM (1976). Hemodialysisof acute arsenic intoxication with transient renal failure. Arch Intern Med136: 1303–1304.

49. Gonsebatt ME, Vega L, Salazar AM, Montero R, Guzman P, Blas J, DelRazo LM, Garcia-Vargas G, Albores A, Cebrian ME, Kelsh M, Ostrosky-Wegman P (1997). Cytogenetic effects in human exposure to arsenic. MutatRes 386: 219–298.

50. Gorby MS (1988). Arsenic poisoning. West J Med 149: 308–315.51. Goyer RA (1996). Toxic effects of metals. In: Cassarett & Doull’s

Toxicology—The Basic Science of Poisons, Klaassen CD (ed). McGrawHill, New York, pp 691–736.

52. Greenblatt MS, Bennett WP, Hollstein M, Harris CC (1994). Mutationsin the p53 tumor suppressor gene: clues to cancer etiology and molecularpathogenesis. Cancer Res 54: 4855–4878.

53. Gurr J, Liu F, Lynn S, Jan K (1998). Calcium-dependent nitric oxide pro-duction is involved in arsenite-induced micronuclei. Mutat Res 416: 137–148.

54. Hamadeh HK, Vargas M, Lee E, Menzel DB (1999). Arsenic disruptscellular levels of p53 and mdm2: a potential mechanism of carcinogenesis.Biochem Biophys Res Commun 263(2): 446–449.

55. Hanahan D, Weinberg RA (2000). The hallmarks of cancer. Cell 100:57–70.

56. Harris CC (1996). p53 tumor suppressor gene: at the crossroads of molec-ular carcinogenesis, molecular epidemiology, and cancer risk assessment.Environ Health Perspect 104(suppl 3): 435–439.

57. Hartmann A, Speit G (1994). Comparative investigations of the Geno-toxic effects of metals in the single cell gel assay and the sister-chromatidexchange test. Environ Mol Mutagen 23: 299–305.

58. Hartwig A, Groblinghoff UD, Beyersmann D, Natarajan AT, Filon R,Mullenders LHF (1997). Interaction of Arsenic (III) with nucleotide exci-sion repair in UV-irradiated human fibroblasts. Carcinogenesis 18: 399–405.

59. Hazardous Chemicals Data (HAZDAT) (1992). Agency for Toxic Sub-stances and Disease Registry. Atlanta, Georgia.

60. Hernandez-Zavala A, Del Razo LM, Aguilar C, Garcia-Vargas GG, BorjaVH, Cebrian ME (1998). Alteration in bilirubin excretion in individualschronically exposed to arsenic in Mexico. Toxicol Lett 99(2): 79–84.

61. Hernandez-Zavala A, Del Razo LM, Garcia-Vargas GG, Aguilar C, BorjaVH Albores A, Cebrian ME (1999). Altered activity of heme biosynthesispathway enzymes in individuals chronically exposed to arsenic in Mexico.Arch Toxicol 73(2): 90–95.

62. Hindmarsh JT, McCurdy RF (1986). Clinical and environmental aspectsof arsenic toxicity. CRC Crit Rev Clin Lab Sci 23: 315–347.

63. Hopenhayn-Rich C, Biggs ML, Fuchs A, Bergoglio R, Tello EE, Nicolli H,Smith AH (1996). Bladder cancer mortality associated with arsenic indrinking water in Argentina. Epidemiology 7: 117–124.

64. Hopenhayn-Rich C, Biggs ML, Smith A (1998). H. Lung and kidney cancermortality associated with arsenic in drinking water in Cordoba, Argentina.Int J Epidemiol 27: 561–569.

65. Hsu CH, Yang SA, Wang JY, Lin SR (1999). Mutational spectrum of p53gene in arsenic-related skin cancers from the blackfoot disease endemicarea of Taiwan. Br J Cancer 80: 1080–1086.

66. Hsueh YM, Wu WL, Huang YL, Chiou HY, Tseng CH, Chen CJ (1998).Low serum carotene level and increased risk of ischemic heart dis-ease related to long-term arsenic exposure. Atherosclerosis 141: 249–257.

67. Hu Y, Su L, Snow ET (1998). Arsenic toxicity is enzyme specific and itsaffects on ligation are not caused by the direct inhibition on DNA repairenzymes. Mutat Res 408: 203–218.

68. Huang SC, Lee TC (1998). Arsenite inhibits mitotic division and perturbsspindle dynamics in HeLa S3 cells. Carcinogenesis 19: 889–896.

69. Hutchinson J (1887a). Arsenic cancer. Br Med J 2: 1280–1281.70. Hutchinson J (1887b). On some examples of arsenic-keratosis of the skin

and of arsenic-cancer. Trans Pathol Soc Lond 39: 352–363.71. Ihrig MM, Shalat SL, Baynes C (1998). A hospital-based case-control

study of stillbirths and environmental exposure to arsenic using an atmo-spheric dispersion model linked to a geographical information system.Epidemiology 9: 290–294.

72. Jacobson Kram D, Montalbano D (1985). The reproductive effects as-sessment group’s report on the mutagenicity of inorganic arsenic. EnvironMutagen 7: 789–804.

73. Jha AN, Noditi M, Nilsson R, Natarajan AT (1992). Genotoxic effects ofsodium arsenite on human cells. Mutat Res 284: 215–221.

74. Kaltreider RC, Davis AM, Lariviere JP, Hamilton JW (2001). Arsenicalters the function of the glucocorticoid receptor as a transcription factor.Environ Health Perspect 109(3): 245–251.

75. Kitchin KT (2001). Recent advances in arsenic carcinogenesis: modes ofaction, animal model systems, and methylated arsenic metabolites. ToxicolAppl Pharmacol 172: 249–261.

76. Kosnett MJ (1994). Arsenic. In: Poisoning and Drug Overdose, Olson KK(ed). Appleton & Lange, Norwalk, Connecticut, pp 87–89.




77. Kuo TT, Hu S, Lo SK, Chan HL (1997). p53 expression and proliferativeactivity in Bowen’s disease with or without chronic arsenic exposure. HumPathol 28(7): 786–790.

78. Lai MS, Hsueh YM, Chen CJ, Shyu MP, Chen SY, Kuo TL, Wu MM, TaiTY (1994). Ingested inorganic arsenic and prevalence of diabetes mellitus.Am J Epidemiol 139: 484–492.

79. Landolph JR (1989). Molecular and cellular mechanisms of transformationof C3H/10T1/2C18 and diploid human fibroblasts by unique carcinogenic,nonmutagenic metal compounds. A review. Biol Trace Elem Res 21: 459–467.

80. Lane DP, Benchimol S (1990). p53: oncogene or anti-oncogene. GenesDev 4: 1–8.

81. Le XC, Lu X, Ma M, Cullen WR, Aposhian HV, Zheng B (2000). Speci-ation of key arsenic metabolic intermediates in human urine. Anal Chem72: 5172–5177.

82. Lee TC, Oshimura M, Barrett JC (1985). Comparison of arsenic-inducedcell transformation, cytotoxicity, mutation and cytogenetic effects inSyrian hamster embryo cells in culture. Carcinogenesis 6(10): 1421–1426.

83. Lee TC, Tanaka N, Lamb PW, Gilmer TM, Barrett JC (1988). Inductionof gene amplification by arsenic. Science 241: 79–81.

84. Lee-Feldstein A (1983). Arsenic and respiratory cancer in man: follow-upof an occupational study. In: Arsenic: Industrial, Biomedical, and Envi-ronmental Perspectives, Lederer W, Fensterheim R (eds). Van Nostrand-Reinhold, New York, pp 245–254.

85. Lee-Feldstein A (1986). Cumulative exposure to arsenic and its relation-ship to respiratory cancer among copper smelter employee. J Occup Med28: 296–302.

86. Levin AJ, Momand J, Finlay CA (1991). The p53 tumor suppressor gene.Nature. 351: 453–456.

87. Lewis DR, Southwick JW, Oullet-Hellstrom R, Rench J, Calderon RL(1999). Drinking water arsenic in Utah: a cohort mortality study. EnvironHealth Perspect 107: 359–365.

88. Li JH, Rossman TC (1989). Inhibition of DNA ligase activity by arsenite:a possible mechanism of its comutagenesis. Mol Toxicol 2: 1–9.

89. Lin S, Cullen WR, Thomas DJ (1999). Methylarsenicals and arsinoth-iols are potent inhibitors of mouse liver thioredoxin reductase. Chem ResToxicol 12: 924–930.

90. Liu J, Kadiiska M, Liu Y, Qu W, Mason RP, Waalkes MP (2000). Acutearsenic-induced free radical production and oxidative stress-related geneexpression in mice. Toxicologist 54: 280–281.

91. Lu T, Liu J, LeCluyse EL, Zhou YS, Cheng ML, Waalkes MP(2001). Application of cDNA microarray to the study of arsenic-inducedliver diseases in the population of Guizhou, China. Toxicol Sci 59(1):185–192.

92. Luchtrath H (1983). The consequences of chronic arsenic poisoning amongMoselle wine growers: pathoanatomical investigations of post-mortem ex-aminations performed between 1960 and 1977. J Cancer Res Clin Oncol105: 173–182.

93. Madal BK, Chowdhury TR, Samanta G, Basu GK, Chowdhury PP, ChandaCR, Lodh D, Karan NK, Dhar RK, Tamili DK (1996). Arsenic in ground-water in seven districts of West Bengal, India: the biggest arsenic calamityin the world. Curr Sci 70: 976–986.

94. Mahata J, Basu A, Ghoshal S, Sarkar JN, Roy AK, Poddar G, Nandy AK,Banerjee A, Ray K, Natarajan AT, Nilsson R, Giri AK (2003). Chromo-somal aberrations and sister-chromatid exchanges in individuals exposedto arsenic through drinking water in West Bengal, India. Mutat Res 534:133–143.

95. Marafante E, Vahter M (1987). Solubility, retention, and metabolism ofintratracheally and orally administered inorganic arsenic compounds inthe hamster. Environ Res 42: 72–82.

96. Mass MJ, Tennant A, Roop B, Kundu K, Brock K, Kligerman A, DemariniD, Wang C, Cullen W, Thomas D, Styblo M (2001). Methylated arsenic(III) species react directly with DNA and are potential proximate or ulti-mate genotoxic forms of arsenic. Toxicologist 60: 358.

97. Mass MJ, Wang L (1997). Arsenic alters cytosine methylation patternsof the promoter of the tumor suppressor gene p53 in human lung cells: amodel for a mechanism of carcinogenesis. Mutat Res 386: 263–277.

98. Matsui M, Nishigori C, Toyokuni S, Takada J, Mitsuhiko A, IshikawaM, Imamura S, Miyachi Y (1999). The role of oxidative DNA damage inhuman arsenic carcinogenesis: detection of 8-hydroxy-2′-deoxyguanosinein arsenic-related Bowen’s disease. J Invest Dermatol 113: 26–31.

99. Mazumder G, Chakraborty A, Ghose A, Gupta JD, Dey SD, ChattopadhyayN (1988). Chronic arsenic toxicity from drinking tubewell water in ruralWest Bengal. Bull WHO 66: 499–506.

100. Mazumder Guha DN, Gupta Das J, Santra A (1997). Non-cancer effectsof chronic arsenicosis with special reference to liver damage. In: ArsenicExposure and Health Effects, Abernathy C, Calderon RL, Chappel WR(eds). Chapman and Hall, London, pp 112–123.

101. Mazumder DN, Haque R, Ghosh N, De BK, Santra A, Chakraborty D,Smith A (1998). Arsenic levels in drinking water and the prevalence ofskin lesions in West Bengal, India. Int J Epidemiol 27: 871–877.

102. Mazumder DN, Haque R, Ghosh N, De BK, Santra A, Chakraborti D,Smith AH (2000). Arsenic in drinking water and the prevalence of res-piratory effects in West Bengal, India. Int J Epidemiol 29(6): 1047–1052.

103. Milton AH, Hasan Z, Rahman A, Rahman M (2001). Chronic arsenicpoisoning and respiratory effects in Bangladesh. J Occup Health 43(3):136–140.

104. Moolgavkar SH (1986). Carcinogenesis modeling: from molecular biologyto epidemiology. Annu Rev Public Health 7: 151–169.

105. Morton WE, Dunnette DA (1994). Health effects of environmental arsenic.In: Arsenic in the Environment Part II; Human Health and EcosystemEffects, Nriagu JO (ed). John Wiley & Sons, Inc, New York, pp 17–34.

106. Murgo AJ (2001). Clinical trials of arsenic trioxide in hematologic andsolid tumors: overview of the National Cancer Institute Cooperative Re-search and Development Studies. Oncologist 6(suppl 2): 22–28.

107. Nakamuro K, Sayato Y (1981). Comparative studies of chromosomalaberration induced by trivalent and pentavalent arsenic. Mutat Res 88:73–80.

108. Natarajan AT, Boei JJ, Darroudi F, Van Diemen PC, Doulout F, Hande MPand Ramalho AT (1996). Current cytogenetic methods for detecting ex-posure and effects of mutagens and carcinogens. Environ Health Perspect104(Suppl.3): 455–458.

109. National Academy of Science (1977). Arsenic. Author, Washington, DC.110. National Institutes of Health (NIH) (1999). National Toxicology Program’s

Technical Report on the Toxicology and Carcinogenesis Studies of GalliumArsenide in F344/N Rats and B6C3F1 Mice. NTPTR 492. NIH publicationNo. 99-3951. Bethesda, Maryland, USA.

111. National Research Council (1994). Science and Judgement in Risk As-sessment. Assessment of Toxicology, National Academy of Sciences (eds).National Academy Press, Washington, DC, pp 56–67.

112. NRC (National Research Council) (1999). Arsenic in Drinking Water.Author, Washington, DC.

113. NRC (National Research Council) (2001). Arsenic in Drinking Water:Update. National Academy Press, Washington, DC.

114. Nordstrom S, Beckman L, Nordenson I (1978a). Occupational and envi-ronmental risk in and around a smelter in northern Sweden. I: variationsin birth weight. Hereditas 88: 43–46.

115. Nordstrom S, Beckman L, Nordenson I (1978b). Occupational and envi-ronmental risk in and around a smelter in northern Sweden. III: frequenciesof spontaneous abortion. Hereditas 88: 51–54.

116. Nordstrom S, Beckman L, Nordenson I (1979a). Occupational and envi-ronmental risk in and around a smelter in northern Sweden. V: spontaneousabortion among female employees and decreased birth weight in their off-spring. Hereditas 90: 291–296.

117. Nordstrom S, Beckman L, Nordenson I (1979b). Occupational and envi-ronmental risk in and around a smelter in northern Sweden. VI: congentialmalformations. Hereditas 90: 297–302.

118. Paigen B, Goldman LR, Magnant MM, Highland JH, Steegmann Jr, AT(1987). Growth of children living near the hazardous waste site, Lovecanal. Human Biol 59: 489–508.

119. Parrish AR, Zheng XH, Turney KD, Younis HS, Gandolfi AJ (1999). En-hanced transcription factor DNA binding and gene expression induced byarsenite or arsenate in renal slices. Toxicol Sci 50(1): 98–105.




120. Petrick JS, Ayala-Fierro F, Cullen WR, Carter DE, Aposhian HV (2000).Monomethylarsonous acid (MMAIII) is more toxic than arsenite in Changhuman hepatocytes. Toxicol Appl Pharmacol 163: 203–207.

121. Popovicova J, Moser GJ, Goldsworthy TL, Tice RR (2000). Carcinogenic-ity and co-carcinogenicity of sodium arsenite in p53+/− male mice. Tox-icologist 54: 134.

122. Porter AC, Fanger GR, Vaillancourt RR (1999). Signal transductionpathways regulated by arsenate and arsenite. Oncogene 18(54): 7794–7802.

123. Puccetti ES, Guller S, Orleth A, Bruggenolte N, Hoelzer D, OttmannOG, Ruthardt M (2000). BCR-ABL mediates arsenic trioxide-inducedapoptosis independently of its aberrant kinase activity. Cancer Res 60(13):3409–3413.

124. Rahman M, Axelson O (1995). Diabetes mellitus and arsenic exposure: asecond look at case-control data from a Swedish copper smelter. OccupEnviron Med 52: 773–774.

125. Rahman M, Tondel M, Ahmad SA, Chowdhury IA, Faruquee MH, AxelsonO (1999). Hypertension and arsenic exposure in Bangladesh. Hyperten-sion. 33(1): 74–78.

126. Rahman M, Wingren G, Axelson O (1996). Diabetes mellitus amongSwedish art glassworkers- an effect of arsenic exposure. Scand J WorkEnviron Health 22: 146–149.

127. Ramirez P, Eastmond DA, Laclette JP, Ostrosky-Wegman P (1997). Dis-ruption of microtubule assembly and spindle formation for the inductionof aneuploid cells by sodium arsenite and vanadium pentoxide. Mutat Res386: 291–298.

128. Rousselot P, Laboume S, Marolleau JP, Larghero T, Noguera ML, BrouetJC, Fermand JP (1999). Arsenic trioxide and melarsoprol induce apoptosisin plasma cell lines and in Plasma cells from myeloma patients. CancerRes 59: 1041–1048.

129. Salazar AM, Ostrosky-Wegman P, Menendez D, Miranda E, Garcia-Carranca A, Rojas E (1997). Induction of p53 protein expression by sodiumarsenite. Mutat Res 381: 259–265.

130. Sampayo-Reyes A, Zakharyan RA, Healy SH, Aposhian HV (2000).Monomethylarsonic acid reductase and monomethylarsonous acid in ham-ster tissue. Chem Res Toxicol 13: 1181–1186.

131. Santra A, Gupta Das J, De BK, Roy B and Mazumder DN (1999). Hepaticmanifestations in chronic arsenic toxicity. Indian J Gastroenterol 18(4):152–155.

132. Schaumloffel N, Gebel T (1998). Heterogeneity of the DNA damage pro-voked by antimony and arsenic. Mutagenesis 13: 281–286.

133. Schoolmaster WL, White DR (1980). Arsenic poisoning. South Med J 73:198–208.

134. Schwartz J, Angle C, Pitcher H (1986). Relationship between childhoodblood lead level and stature. Pediatrics 77: 281–288.

135. Seol JG, Park WH, Kim ES, Jung CW, Hyun JM, Kim BK, Lee YY (1999).Effect of arsenic trioxide on cell cycle arrest in head and neck cancer cell-line PCI-1. Biochem Biophys Res Commun 265(2): 400–404.

136. Simeonova PP, Luster MI (2000). Mechanisms of arsenic carcinogenicity:genetic or epigenetic mechanisms? J Environ Pathol Toxicol Oncol 19:281–286.

137. Simeonova PP, Wang S, Toriumi W, Kommineni C, Matheson J, UnimyeN, Kayama F, Harki D, Ding M, Vallyathan V, Luster MT (2000). Arsenicmediates cell proliferation and gene expression in the bladder epithelium:association with AP-1 transactivation. Cancer Res 60: 3445–3453.

138. Siripitayakunkit U, Visudhiphan P, Pradipasen M, Vorapongsathon T(1999). Association between chronic arsenic exposure and children’sintelligence in Thailand. In: Arsenic Exposure and Health effects,Chappell, WR, Abernathy CO, Calderon RL (eds). Elsevier, New York,pp 141–150.

139. Smith AH, Goycolea M, Haque R, Biggs ML (1998). Marked increase inbladder and lung cancer mortality in a region of Northern Chile due toarsenic in drinking water. Am J Epidemiol 147: 660–669.

140. Soignet S, Calleja E, Cheung NK, Pezzulli S, Vongphrachanh P, SpriggsD, Warrell RP (1999). A Phase 1 study of arsenic trioxide in patientswith solid tumors, Memorial Sloan-Kettering Cancer Center, New York,NY. Program/Proceedings Abstracts for 35th Annual Meeting of the

American Society of Clinical Oncology, Atlanta, Georgia, May 15–18,Vol. 18.

141. Squibb KS, Fowler BA (1983). The toxicity of arsenic and its compounds.In: Biological and Environmental Effects of Arsenic, Fowler BA (ed).Elsevier, New York, pp 233–269.

142. Styblo M, Del Razo LM, LeCluyse EL, Hamilton GA, Wang C, CullenWR, Thomas DJ (1999). Metabolism of arsenic in primary cultures ofhuman and rat hepatocytes. Chem Res Toxicol 12: 560–565.

143. Styblo M, Hughes MF, Thomas DJ (1996). Liberation and analysis ofprotein-bound arsenicals. J Chromatogr B 677: 161–166.

144. Styblo M, Serves SV, Cullen WR, Thomas DJ (1997). Comparative inhi-bition of yeast glutathione reductase by arsenicals and arsenothiols. ChemRes Toxicol 10: 27–33.

145. Styblo M, Yamauchi H, Thomas DJ (1995). Comparative in vitro methyla-tion of trivalent and pentavalent arsenicals. Toxicol Appl Pharmacol 135:172–178.

146. Takahashi M, Barrett JC, Tsutsui T (2002). Transformation by inorganicarsenic compounds of normal Syrian hamster embryo cells into a neoplasticstate in which they become anchorage-independent and cause tumors innewborn hamsters. Int J Cancer 99: 629–634.

147. Tchounwou PB, Wilson B, Ishaque A (1999). Important considerationsin the development of public health advisories for arsenic and arsenic-containing Compounds in drinking water. Rev Environ Health 14(4): 211–229.

148. Teitelbaum DT, Kier LC (1969). Arsine poisoning. Arch Environ Health19: 133–143.

149. Thompson DJ (1993). A chemical hypothesis for arsenic methylation inmammals. Chem-Biol Interact 88: 89–114.

150. Tokudome S, Kuratsune M (1976). A cohort study on mortality from cancerand other causes among workers at a metal refinery. Int J Cancer 17: 310–317.

151. Trouba KJ, Wauson EM, Vorce RL (2000). Sodium arsenite-induced dys-regulation of proteins involved in proliferative signaling. Toxicol ApplPharmacol 164(2): 161–170.

152. Tsai S, Wang T, Ko Y (1999). Mortality for certain diseases in areas withhigh levels of arsenic in drinking water. Arch Enivron Health 54: 186–193.

153. Tseng CH, Tai TY, Chong CK, Tseng CP, Lai MS, Lin BJ, Chiou HY,Hsueh YM, Hsu KH, Chen CJ (2000). Long-term arsenic exposure andincidence of non-insulin-dependent diabetes mellitus: A cohort study inarseniasis-hyperendemic villages in Taiwan. Environ Health Perspect 108(9): 847–851.

154. Tseng WP (1989). Blackfoot disease in Taiwan: a 30-year follow-up study.Angiology 40: 547–558.

155. Tsuda T, Nagira T, Yamamoto M (1990). An epidemiological study oncancer in certified arsenic poisoning patients in Toroku. Ind Health 28:53–62.

156. Tucker SB, Lamm SH, Li FX, Wilson R, Byrd DM, Lai S, Tong Y, LooL (2001). Relationship between Consumption of Arsenic-ContaminatedWell Water and Skin Disorders in Huhhot, Inner Mongolia. Inner Mon-golia Cooperative Arsenic Project (IMCAP) study. Final Report. Dept. ofDermatology, University of Texas, Houston, and Dept. of EnvironmentalEpidemiology, Institute of Environmental Engineering, Chinese Academyof Preventive Medicine, Beijing, China.

157. Tully DB, Collins BJ, Overstreet JD, Smith CS, Dinse GE, Mumtaz MM,Chapin RE (2000). Effects of arsenic, cadmium, chromium and lead ongene expression regulated by a battery of 13 different promoters in recom-binant HepG2 cells. Toxicol Appl Pharmacol 168(2): 79–90.

158. Vahter ME (1988). Arsenic. In: Biological Monitoring of Toxic Metals,Clarkson TW, Friberg L, Nordberg GF, Sager PR (eds). Plenum, New York,pp 303–321.

159. Vega L, Gonsebatt ME, Ostrosky-Wegman P (1995). Aneugenic effect ofsodium arsenite on human lymphocytes in vitro: an individual susceptibil-ity effect detected. Mutat Res 334(3): 365–373.

160. Vega L, Styblo M, Patterson R, Cullen W, Wang C, Germolec D (2001).Differential effects of trivalent and pentavalent arsenicals on cell prolif-eration and cytokine secretion in normal human epidermal keratinocytes.Toxicol Appl Pharmacol 172(3): 225–232.




161. Venugopal B, Lucky TD (1978). Metal Toxicity in Mammals. Plenum Press,New York.

162. Vogt BL, Rossman TG (2001). Effects of arsenite on p53, p21 and cyclinD expression in normal human fibroblasts—a possible mechanism forarsenite’s comutagenicity. Mutat Res 478(1–2): 159–168.

163. Wall S (1980). Survival and mortality pattern among Swedish smelterworkers. Int J Epidemiol 9: 73–87.

164. Wang Z, Rossman TG (1996). In: The Toxicology of Metals, vol 1, ChengLW (ed). CRC Press, Boca Raton, Florida, pp 221–243.

165. Wanibuchi H, Hori T, Meenakshi V, Ichihara T, Yamamoto S, Yano Y,Otani S, Nakae D, Konishi Y, Fukushima S (1997). Promotion of rat hepa-tocarcinogenesis by dimethylarsinic acid as assessed in rat in vivo models:a review. Mutat Res 386: 353–361.

166. Warner ML, Moore LE, Smith MT, Kalman DA, Fanning E, Smith AH(1994). Increased micronuclei in exfoliated bladder cells of individualswho chronically ingest arsenic-contaminated water in Nevada. CancerEpid Biomarker Prevent 3: 583–590.

167. Wei M, Wanibuchi H, Morimura K, Iwai S, Yoshida K, Endo G, NakaeD, Fukushima S (2002). Carcinogenicity of dimethylarsinic acid in maleF344 rats and genetic alterations in induced urinary bladder tumors. Car-cinogenesis 23(8): 1387–1397.

168. Winship KA (1984). Toxicity of inorganic arsenic salts. Adv Drug ReactAcute Poisoning Rev 3: 129–160.

169. Wu MM, Kuo TL, Hwang YH, Chen CJ (1989). Dose-response relation-ship between arsenic concentration in well water and mortality from can-cers and vascular diseases. Am J Epid 130: 1123–1132.

170. Yamamoto S, Konishi Y, Matsuda T, Murai T, Shibata M, Matsui-YuasaI, Otani S, Kuroda K, Endo G, Fukushima S (1995). Cancer induction byan organic arsenic compound, dimethylarsinic acid (cacodylic acid), inF344/DuCrj rats after pretreatment with five carcinogens. Cancer Res 55:1271–1275.

171. Yamanaka K, Hoshino M, Okanoto M, Sawamura R, Hasegawa A, OkadaS (1990). Induction of DNA damage by dimethylarsine a metabolite ofinorganic arsenics, is for the major part likely due to its peroxyl radical.Biochem Biophys Res Commun 168: 58–64.

172. Yamanaka K, Mizoi M, Kato K, Hasegawa A, Nakano M, Okada S (2001).Oral administration of dimethylarsinic acid, a main metabolite of inor-

ganic arsenics, promote skin tumorigenesis in mice. Biol Pharm Bull 24:510–514.

173. Yamashita N, Doi M, Nishio M, Hojo H, Tanaka M (1972). Recent ob-servations of Kyoto children poisoned by arsenic tainted “Morinaga DryMilk.” Jpn J Hyg 27: 364–399.

174. Zakharyan RA, Ayala-Fierro F, Cullen WR, Carter DM, Aposhian HV(1999). Enzymatic methylation of arsenic compounds VII. Monomethy-larsonous acid (MMAIII) is the substrate for MMA methyltransferaseof rabbit liver and human hepatocytes. Toxicol Appl Pharmacol 158:9–15.

175. Zakharyan RA, Aposhian HV (1999). Enzymatic reduction of arseniccompounds in mammalian systems: the rate-limiting enzyme of rabbitliver arsenic biotransformation is MMAV reductase. Chem Res Toxicol12: 1278–1283.

176. Zaldivar R (1980). A morbid condition involving cardiovascular, bron-chopulmonary, digestive and neural lesions in children and youngadults after dietary arsenic exposure. Zentralbl Bakteriol 170: 44–56.

177. Zaldivar R, Ghai GL (1980). Clinical epidemiological studies on endemicchronic arsenic poisoning in children and adults, including observationson children with high and low-intake of dietary arsenic. Zentralbl Bakte-riol. 1. Abt Originale B: Hygiene, Krankenhaushygiene, Betriebshygiene,Praventive Medizin 170: 409–421.

178. Zelikoff JT, Bertin JE, Burbacher TM, Hunter ES, Miller RK, SilbergeldEK, Tabacova S, Rogers JM (1995). Health risks associated with prenatalmetal exposure. Fundam Appl Toxicol 25: 161–170.

179. Zhao CQ, Young MR, Diwan BA, Coogan TP, Waalkes MP (1997). Associ-ation of arsenic-induced malignant transformation with DNA hypomethy-lation and aberrant gene expression. Proc Natl Acad Sci USA 94: 10907–10912.

180. Zhong CX, Wang L, Mass MJ (2001). Differentially methylated DNAsequences associated with exposure to arsenate in cultures of human cellsidentified by methylation-sensitive arbitrarily-primed PCR. Toxicol Lett122(3): 223–234.

181. Zierler S, Theodore M, Cohen A, Rothman KJ (1988). Chemical qualityof maternal drinking water and congenital heart disease. Int J Epidemiol17: 589–594.



invited reviews: carcinogenic and systemic health effects associated with arsenic exposure--a...

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