Arsenic, Its Clinical andEnvironmental SignificanceJ. Thomas Hindmarsh*

Departments of Pathology, Laboratory Medicine, and Biochemistry,University of Ottawa and the Ottawa Hospital, Ottawa, Ontario, Canada

Arsenic is ubiquitous and exposure can occur from natural and anthropogenic sources.Human exposure occurs from air, food, and drinking water. Airborne exposure is smallexcept in polluted locations. Food exposure can be significant but, particularly in fish andshellfish, it is mostly in organic forms that are relatively nontoxic. Drinking water remainsthe most significant source worldwide, and large numbers of people are subject to seriousexposure from this source in India, Bangladesh, China, and Mongolia. Toxicity consistsmostly of neuropathy, skin lesions, vascular damage, and carcinogenesis. Vascular lesionsare the result of endarteritis (blackfoot disease). This appears to be more prevalent indeveloping rather than developed countries and may be related to nutritional deficiencies.Skin cancer is the most clearly associated malignancy related to arsenic exposure fromdrinking water; however, bladder, lung, liver, and kidney tumors also appear to be related.Whereas the toxicity of drinking water levels of >200mg/L is well established, the toxicitybelow 100mg/L is not clearly defined, and this remains one of the most important enigmasin arsenic toxicology today. J. Trace Elem. Exp. Med. 13:165–172, 2000.© 2000 Wiley-Liss, Inc.

Key words: arsenic; hair analysis; water analysis; toxicity; carcinogenesis; neuropathy; naturalanthropogenic

INTRODUCTION

Arsenic (As) is a metalloid belonging to group VA of the periodic table (N, P, As,Sb, Bi). It can exist in three oxidation states: metalloid (0), trivalent (−3 or +3), andpentavalent (+5). In general, the toxicity of arsenic compounds obey the followingorder: arsines > arsenites > arsenates > organic > elemental. The structure of somearsenic compounds related to human toxicity are shown in Table I. A lethal humandose of arsenic trioxide is∼100–200 mg.

TOXICOLOGY

Trivalent arsenic compounds can inhibit various enzymatic pathways includingglycolysis and the tricarboxylic acid cycle by binding to sulfydryl groups of enzymes.Pentavalent compounds can uncouple mitochondrial oxidative phosphorylation. Their

*Correspondence to: Dr. J. Thomas Hindmarsh, Ottawa Hospital, General Campus, 501 Smyth Road,Ottawa, Ontario K1H 8L6.

Received 7 January 1999; Accepted 30 September 1999

The Journal of Trace Elements in Experimental Medicine 13:165–172 (2000)

© 2000 Wiley-Liss, Inc.

PROD #298-009

route of entry is usually through the gastrointestinal tract or the lung [1]. They aretransported in the blood from which they are rapidly cleared [2]. The metabolism anddetoxification of arsenic have been extensively studied by Vahter [3,4]. Early tissuedistribution is to the liver and kidney, but after 24 hours, little remains in these organsand the greatest amounts can then be found in the skin, hair, and nails. Inorganicarsenicals are mostly detoxified by methylation and are excreted in the urine in theform of monomethylarsenate and dimethylarsenite, by which route 60–70% is ex-creted in 48 hours [5,6]. However, after prolonged exposure to arsenic, urine levelsmay remain elevated longer [7]. Thus blood and urine levels are of no value inidentifying exposure retrospectively (several weeks previously) and hair levels shouldbe used for this purpose. Urine levels, however, are useful for monitoring ongoingexposure such as may occur in smelter workers. Arsenic compounds have beenreported to induce hepatic metallothioneine production [8].

Fish and shellfish may contain considerable amounts of arsenic but in a relativelynontoxic form (arsenobetaine, arsenocholine, arsenosugars) [9]. These are rapidlyexcreted in the urine [10,11] and can cause confusion when urine arsenic levels arebeing used to identify potentially toxic arsenic exposure. Therefore, in these circum-stances, urine arsenic should be speciated to specifically identify which compoundsare present [12]. Whereas exposure to inorganic arsenic compounds is reflected in hairarsenic levels, fish arsenic is not deposited in the hair [11,13].

ARSENIC EXPOSURE

Arsenic is ubiquitous, being the twentieth most common element in the earth’scrust. Thus it is found in soil, rocks, water, and air. Trace amounts are, therefore,found in all plants and animals. The global arsenic cycle showing natural and an-thropogenic sources of arsenic is represented in Figure 1. Natural sources of arsenic,provided they remain undisturbed, present little threat to humans. Soil and surfacewater are “self cleansing.” Both organic and inorganic arsenic species react with ironand clay particles in soil to form insoluble complexes. Soil with a high iron contentand thus a high redox potential, favours the oxidation of arsenite to arsenate, whichforms very stable complexes [14]. Surface waters usually have high Eh and relativelylow pH values due to interaction with atmospheric oxygen and carbon dioxide. Thuspentavalent arsenic usually predominates. The presence of iron either dissolved or

TABLE I. Arsenic Compounds

Arsenic trioxide As2O3

Arsenous acid H3AsO3

Arsenite H2AsO31−, HAsO3

2−, AsO33−

Arsenic pentoxide As2O3

Arsenic acid H3AsO4

Arsenate H2AsO41−, HAsO4

2−, AsO43−

Arsanilic acid C6H4NH2AsO(OH)2Arsenobetaine (CH3)3As+CH2COOHDimethylarsinic acid (CH3)2AsO(OH)Methylarsonic acid CH3AsO(OH)2

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Fig. 1. The global arsenic cycle illustrating the fate of arsenic in the various environmental compartments. Reproduced from Piver [36], withpermission.

suspended readily forms insoluble salts with arsenate and arsenite, which settle out assediments. Lake Michigan, for example, has a dissolved arsenic content of only0.5–2.4mg/L; yet its sediment has a value of 7–29mg/g [14]. Groundwater, however,may not exhibit this self-cleansing action because of its usually lower Eh and higherpH. Thus weathering of arsenic-bearing minerals may release the more toxic arseniteinto this compartment. Iron cleansing can also occur in this compartment, althoughthis is much less prevalent than in surface water [14].

Anthropogenic sources present a greater hazard. Leaching of solubilized arsenicfrom waste-rock tailings can enter the surface water as can the discharges fromelectrical generators burning soft brown coal, which can also contaminate the air [15].Also, deep wells tapping groundwater sources can become naturally contaminated asoutlined above (whether this source should be considered natural or anthropogenic isacademic; it is classified here as anthropogenic). Recent extensive agricultural de-velopment with a heavy reliance on new water wells that have become heavily arseniccontaminated has led to extensive chronic arsenic poisoning in countries such asBangladesh, India (Bengal), and China (Inner Mongolia) [16].

HISTORICAL USES OF ARSENIC

Arsenic was once extensively used as a pesticide and fungicide. This role is nowlargely filled by chlorinated hydrocarbons. Fowler’s solution, first described by Dr.Thomas Fowler of Shropshire, England, in 1785, was widely used as a tonic andtreatment for psoriasis and asthma throughout the nineteenth and twentieth centuries,until 1950 when its use was discontinued; prolonged use caused chronic arsenicpoisoning. Arsenic compounds were extensively used as growth promoters for agri-cultural animals prior to the use of antibiotics for this purpose. The mechanism of thisaction is unknown and probably initiated the hypothesis that arsenic is an essentialtrace element. However, it does not fit the criteria outlined by Underwood for essen-tiality [17] and has never been demonstrated to be part of an essential physiologicalprocess in humans. Thus the claim for essentiality is probably unfounded. Arsenicwas extensively used in the nineteenth century as a pigment particularly for wallpaperand this could produce chronic arsenic poisoning [18]. In 1954, the American Am-bassador to Italy, Clare Booth Luce, suffered from chronic arsenic poisoning derivedfrom the paint on the ceiling of her nineteenth-century villa in Rome, promoting anextensive Secret Service investigation at that time looking for a more sinister cause[19]. Arsenic was extensively used as a homicidal poison in medieval times, up to themiddle of the nineteenth century, when its popularity declined probably due to theMarsh test for its detection becoming widely available at that time. The claim thatNapoleon Bonaparte was deliberately poisoned with arsenic is almost certainly un-founded; he died of a carcinoma of the stomach [20].

CURRENT USES OF ARSENIC

Current uses of arsenic compounds are in the glass industry as a clarifier, as a woodpreservative (copper arsenite), in the production of semiconductors (gallium arse-nide), as a desiccant and defoliant in agriculture, and as a byproduct of the smeltingof nonferrous metals, particularly gold and copper. Thus persons at risk from arsenic

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poisoning include those working and living downwind from smelters and those drink-ing water from contaminated wells. Places where well water is contaminated includeTaiwan (southwest coast), South America (Argentina and Chile), India (Bengal),Mexico, Bangladesh, China (Inner Mongolia) [16], Alaska, and some parts of thesouthwestern United States [21].

ARSENIC POISONING

Acute

The clinical features of a large ingested dose of arsenic include abdominal pain,vomiting, and severe diarrhea. Severe shock rapidly appears despite fluid replace-ment, and acute renal tubular necrosis and acute respiratory distress syndrome fre-quently occur. If the subject survives, protracted severe peripheral neuropathy iscommon [1].

Chronic

The features of chronic arsenic poisoning are general malaise and weakness, gen-eral debility, decreased appetite, and usually profound weight loss [1]. After severalmonths of exposure, the skin usually shows the classical raindrop pigmentation anddepigmentation. Also, commonly present are the characteristic arsenic corns andhyperkeratosis on the hands and feet [22]. Hair loss is common and the nails some-times demonstrate transverse striations or Mees lines. Nervous system involvementincludes a peripheral neuropathy, sensory and motor with the former often predomi-nant particularly in the lower limbs. Mild dementia may also be present. Liver in-volvement may include noncirrhotic portal hypertension (perisinusoidal fibrosis) and/or hepatic angiosarcoma. The vascular effects may include coronary artery disease,and/or peripheral vascular disease. The latter may produce gangrene of the extremities— the so-called “Blackfoot disease,” which seems to be particularly prevalent indeveloping countries where nutritional deficiencies may be a factor in its production[23]. It has been postulated that methionine deficiency may play a role in its devel-opment as methyl donors are necessary for the detoxification of inorganic arsenic.Hematologic lesions include a normochromic normocytic anemia, and leukopenia.Erythrocyte basophilic stippling has been reported [24].

The carcinogenicity of arsenic has recently been reviewed [25,26]. Malignantlesions associated with chronic arsenic exposure include, in the skin, Bowen’s disease(intraepidermal carcinoma), basal cell carcinoma (multicentric), and squamous cellcarcinoma. Carcinoma of the lung is associated with the inhalation of arsenic dusts.However, recent reports from Southeast Asia indicate that it may also be associatedwith ingestion of arsenic contaminated water. Carcinoma of the bladder and kidney isalso associated with the ingestion of contaminated water as is hepatic angiosarcoma.

Diagnosis

The diagnosis of acute arsenic poisoning can be difficult. Blood arsenic levels aretransient; however, urine levels should be elevated provided the patient is not anuric.Hair arsenic levels can be elevated shortly after the event; in the one case of acute

Arsenic Significance 169

arsenic poisoning this author has seen, the mean hair arsenic level was 100mg/g, 25hours after the ingestion of a cup of copper acetoarsenite. The patient died 72 hoursafter the ingestion. However, the diagnosis often rests on the clinical picture andanalysis of gastric contents. If the patient succumbs and proceeds to autopsy, liverlevels can be helpful.

The diagnosis of chronic arsenic poisoning can also be problematic. Blood andurine levels are of little value unless exposure is ongoing. The best indicator is hairor nail arsenic, but it cannot be sufficiently emphasized that external contaminationmust be excluded if these parameters are to be used to support a diagnosis. Externalcontamination, perhaps from the use of arsenic trioxide as a preservative after col-lection, rather than chronic arsenic poisoning is probably the reason why increasedarsenic levels have been found in some hair samples claimed to be from NapoleonBonaparte [20]. Most investigators have used hair rather than nail arsenic because theformer is easier to obtain in sufficient quantities. It must also be emphasized thatbecause inter- and intrahair variation of arsenic levels on the same head are very large,a mean should be obtained from a minimum of 1 gram of hair derived from severalsites on the head. Analyses of individual hairs or sections of a hair are much lessreliable.

Hair arsenic derived from ingestion or external contamination cannot be differen-tiated by any known technique as they appear to be identically located in a crosssection of the hair [27]. Some authors have claimed that external contamination canbe distinguished from internal ingestion because the former is evenly distributedalong the length of the hair, whereas, in arsenic ingestion, peaks on the hair representindividual doses. However, this is not so as external contamination can also beunevenly distributed along the length of the hair [28]. The interpretation of hairarsenic levels has been extensively discussed elsewhere [27], and an approximateinterpretation is: normal <1mg/g (<3mg/g in polluted areas); chronic poisoning$ 10mg/g (can be lower); compatible with death from chronic arsenic poisoning$ 45mg/g(can be lower); external contamination up to 8,000mg/g. As can be seen, hair arseniclevels are only very approximately related to toxicity and attempts to relate themclosely to degrees of toxicity particularly in subjects drinking arsenic contaminatedwater (where hair arsenic can also be elevated due to washing in the contaminatedwater as well as from drinking it [29,30]) have been disappointing. Also, externalcontamination is often impossible to exclude. Thus the diagnosis of chronic arsenicpoisoning must rely on the characteristic clinical features of the typical skin lesions,debility, weight loss and neuropathy, and hair arsenic levels are only supportive of thediagnosis.

The toxic threshold for arsenic intake for humans is hotly debated [21]. Given thatit is a known carcinogen, some believe that any intake whatsoever is unsafe, but thisis impractical. Sto¨hrer [31] reviewing the extensive data from Taiwan [32] and else-where concluded that skin cancers, internal cancers, and noncancerous effects ofarsenic had approximately the same threshold and that these decrease sharply whenintake falls below 400mg/day; thus the disease potential above this level is wellestablished. The risks of intake less than this are unresolved and are an area of majorinterest to those responsible for determining drinking water quality. They remain anarea of considerable debate [33–35].

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