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7 Summary and Conclusions CHEMISTRY The compound of arsenic produced in largest quantity is arsenic trioxide. It is a by-product of the copper-smelting industry. Arsenic exhibits oxidation states of III and V and forms a great variety of inorganic and organic compounds. In addition to arsenic trioxide, some widely encountered inorganic compounds are arsenic pentoxide, arse- nous acid, arsenic acid, tetraarsenic tetrasulfide (realgar), arsenic trisulf~de (orpiment), and arsenic pentasulfide. Some of the more common organic compounds are methanearsonic acid, cacodylic acid, methyldihydroxyarsine, dimethylhydroxyarsine, trimethylarsine, and trimethylarsine oxide. Some aromatic arsenic derivatives with veteri- nary and medicinal uses are arsanilic acid, 3-nitro-4-hydroxyphenyl- arsonic acid, 4-nitrophenylarsonic acid, and 3-nitro-4-ureidophenyl . . arsenic ac~a. Cationic species of As(III) are probably not present in aqueous solution. Arsenous acid likely exists as As(OH)3. The fact that the hydroxides of iron(II), iron(III), chromium(III), and aluminum strongly adsorb or form insoluble precipitates with arsenites and arsenates is important in the control of arsenic pollution. The ability of various molds and bacteria to convert arsenic compounds to various methyl 216

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Summary and Conclusions 217 ated arsines is well known. Because the methylated arsines are spar- ingly soluble in water, volatile, and sensitive to air, they are returned to the environment as methanearsonates, cacodylates, and trimethylar- sine oxide. Arsenic-sulfur bonds are less subject to hydrolysis than arsenic-oxygen bonds, and the formation of arsenic-sulfur bonds with sulfur-containing biologic molecules is considered to be of great impor tance. DISTRIBUTION Arsenic is ubiquitous in the environment and is found in all living organisms. Natural sources include a variety of sulfur-containing min- erals, of which arsenopyrite is the most common. The amounts of arsenic in soil and water depend largely on the geologic inputs from mineral weathering processes, whereas the amounts in indigenous plants and animals reflect species differences. Some species of marine plants, such as algae and seaweed, and marine organisms, such as crustaceans and some fish, often contain naturally high concentrations of arsenic. Man-made sources of arsenic are generally by-products of the smelt- ing of nonferrous metal ores, primarily copper and to a lesser degree lead, zinc, and gold. In the United States, the sole producer and refiner of arsenic trioxide is the copper smelter of the American Smelting and Refining Company in Tacoma, Washington. Major imports of arsenic come from Sweden, the world's leading producer. The largest use of arsenic is in the production of agricultural pes- ticides, in the categories of herbicides, insecticides, desiccants, wood preservatives, and feed additives. Arsenic trioxide was the raw mate- rial for the older inorganic pesticides, including lead arsenate, calcium arsenate, and sodium arsenite. The newer major organic arsenical pesticides include three herbicides, monosodium and disodium methanearsonate and cacodylic acid, and four feed additives that are substituted phenylarsonic acids. Arsenic has several minor uses primarily as an additive in metallurgic applications, in glass production, as a catalyst in several manufacturing processes, and in medicine. Arsenical drugs are still used in treating tropical diseases, such as African sleeping sickness and amebic dysentery, and are used in veterinary medicine to treat parasitic diseases, such as heartworm (filariasis) in dogs and blackhead in turkeys and chickens. The major arsenic residues resulting from use of agricultural pes- ticides and fertilizers are found in soils and to a lesser degree in plants

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218 ARSENIC and animals living on contaminated soils. The highest pesticide resi- dues occur primarily in orchard soils that received large applications of lead arsenate. Large accumulations of arsenic also occur in soils around smelters. Two important closely related effects measurable in plants are arsenic residues and phytotoxicity. Some soils that received massive applications of arsenate are currently incapable of supporting plant growth. Arsenic in air has three major sources: smelting of metals, burning of coal, and use of arsenical pesticides. Two known acute incidents of arsenic pollution from smelters have occurred in the United States. The most serious air-pollution problem, however, is associated with manufacturing processes and occupational hazards to workers. Some arsenic in water results from industrial discharges. Several endemic poisonings of water supplies have been reported. Safe disposal of arsenic wastes still constitutes a major administra- tive and technologic problem. The major sources of arsenical wastes are residues in empty pesticide containers; surplus pesticides stored by government agencies, manufacturers, state and municipal facilities, and users; and soil contaminated by extensive use of arsenical pes- ticides. Recommended procedures for management of arsenical wastes are recycling and reuse (preferred), long-term storage, recovery of other metals and long-term storage of arsenic trioxide, and disposal in landfill sites. Several arsenic cycles have been proposed to interrelate the source, emission, movement, distribution, and sinks of various forms in the environment. Arsenic is continuously cycling in the environment, owing to oxidation, reduction, and methylation reactions. Man's ac- tivities can alter the distribution of arsenic in finite geographic areas or in selected components of the environment, but man has little control over the natural processes. METABOLISM Arsenic compounds must be in a mobile form in the soil solution in order to be absorbed by plants. Except for locations around smelters or where the natural arsenic content is high, the arsenic taken up is distributed throughout the plant body in less than toxic amounts. In nature, arsenic absorption by plants from the air is negligible. Although smelter fumes and dusts may deposit on plant leaves, there is no evidence that arsenic from this source is taken into plants. Translocation of arsenicals in plants is demonstrated by the fact that

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Summary and Conclusions 219 arsenical solutions applied to foliage of some weeds results in the killing of root tissue. Metabolic experiments with radiolabeled organic arsenic compounds have indicated that these compounds or metabo- lites thereof form complexes with some plant constituents. Bacteria and fungi can metabolize inorganic arsenic salts to form methylated derivatives. Algae can biosynthesize complex organic ar- senicals that are associated with the lipid fraction of these microor- ganisms. Mollusks and crustaceans can contain rather high concentra- tions of arsenic, but there appears to be no relationship between their arsenic content and the collection date or geographic location; this suggests that industrial pollution is not a factor. Fish also can contain arsenic, which apparently is derived from their diet. The arsenic that occurs naturally in seafood is metabolized quite differently from inor- ganic arsenic. The form of arsenic in shrimp, for example, is not retained by the human body and is rapidly excreted. The rat has a unique arsenic metabolism that renders it unsuitable for metabolic studies with arsenic compounds. This rodent stores arsenic in the hemoglobin of its red cells, which release the arsenic only when they break down. The resulting very slow excretion led to the belief that arsenic is a cumulative poison. Trivalent sodium arsenite seems to be almost entirely oxidized to pentavalent sodium arsenate in vivo. Evidence of the opposite process i.e., the in vivo reduction of arse- nate to arsenite is much less clear. Arsenic in normal urine of man, dog, and cow is principally in the methylated form. When the dog and cow are fed large doses of trivalent or pentavalent inorganic arsenic, about half the arsenic appears in the urine as methylated derivatives. This methylation process is true detoxification, inasmuch as methanearsonates and cacodylates are only one two-hundredth as toxic as sodium arsenite. EFFECTS ON ANIMALS AND PLANTS A number of different factors can influence the toxicity of arsenicals, including chemical form, physical form, mode of administration, species, and criterion of toxicity. Several reports have suggested that arsenic can exert biologic effects at concentrations below those gen- erally considered "safe," but the physiologic significance of such findings is not known. The trivalent forms of arsenic apparently exert their toxic effect chiefly by reacting with the sulfhydryl groups of vital cellular enzymes. Pyruvate dehydrogenase seems to be a particularly vulnerable site in

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220 ARSENIC metabolism, because it contains the dithiol lipoic acid that is especially reactive with trivalent arsenicals. The biochemical basis of the toxic action of pentavalent arsenic compounds is known with less certainty, but such arsenicals may well compete with phosphate in phosphoryla- tion reactions to form unstable arsenyl esters that spontaneously hydrolyze and thereby short-circuit energy-yielding bioenergetic pro- cesses. The use of phenylarsonic animal feed additives as recommended is beneficial and does not constitute a human or animal health hazard. Animal losses and excessive arsenical residues in poultry and pork tissues occur only when the arsenicals are fed at excessive dosages for long periods. The mechanism of action of phenylarsonic animal feed additives remains obscure, and these compounds are for the most part absorbed and excreted without metabolic change. Toxicoses caused by the phenylarsonates are manifested by an entirely different syndrome from those caused by the inorganic and aliphatic organic arsenicals. The latter produce the typical signs and lesions usually associated with arsenic poisoning, whereas the former are less toxic and produce demyelination and gliosis of peripheral and cranial nerves. Poisoning of forage-eating livestock by inorganic and aliphatic or- ganic arsenical compounds, especially those used as herbicides and defoliants, has been reported. Most cases result from accidental or careless contamination of forage that becomes accessible to livestock. The large-scale use of arsenicals in the United States has caused some scientists to suspect that the use of these compounds may have a deleterious effect on wildlife. However, there is little evidence to confirm such suspicions in the scientific literature. Wildlife kills that have been attributed to arsenic compounds were all associated with misuse of the compounds in question. But several laboratory studies have shown that wild species are generally more sensitive to arsenic poisoning than many domestic species; therefore, some ecologic vigi- lance is appropriate. Most data on the effects of arsenicals on aquatic organisms, particu- larly on freshwater organisms, were collected in short-term, direct- lethality studies. Practically nothing is known about the sublethal long-term effects of arsenic, singly or in combination with other pollutants, on aquatic organisms. Although early workers were not able to demonstrate any adaptation in animals to toxic concentrations of inorganic arsenic, some recent work has suggested that there may be a rather limited adaptive re- sponse to inorganic arsenicals under some conditions.

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Summary and Conclusions 221 Abnormal physiologic responses have been noted in animals ex- posed to arsenic trioxide aerosols at concentrations considerably below currently accepted air-quality standards. Unfortunately, these experiments were carried out with the rat, which has a unique ability to accumulate arsenic and is therefore a poor animal model for studying arsenic metabolism. It is difficult to draw valid conclusions about the public-health or environmental implications of these investigations. High concentrations of arsenicals have been shown to decrease the ability of mice to resist viral infection, presumably by inhibiting inter- feron formation or action. However, low concentrations of arsenicals appear to enhance the antiviral activity of interferon. Arsenic is known to protect partially against the effects of selenium poisoning over a wide variety of conditions. Arsenic decreases the toxicity of selenium by enhancing its biliary excretion, thus clearing it from the liver, the primary target organ in selenosis. Preliminary results have suggested a role for arsenic as a nutri- tionally essential trace element. Improved methods in trace-element research such as the use of ultrapure water, highly refined diets, and plastic animal housing apparently have enabled nutritionists to un- cover a function for arsenic in normal metabolism. The biologic effects of arsenic compounds on microorganisms ap- pear to be mediated very much by the same mechanisms as in mam- mals. However, some microorganisms have a substantial ability to adapt to toxic concentrations of arsenicals. This adaptation seems in most cases to be due to decreased permeability of the microorganism to ~__~....~_ _ arsenic. Arsenicals clearly can be toxic to plants, but the biochemical basis of such toxicity is less understood than that of the toxicity of arsenicals to animals. As in animals, arsenates are generally less toxic to plants than arsenites. One of the first symptoms of plant injury by sodium arsenite is wilting caused by loss of turgor, whereas the symptoms due to arsenate do not involve rapid loss of turgor, at least through the early expression of toxicity. The chvtotoxicity of organic arsenical herbicides is characterized by . my--or-- ~ - ~ . a relatively slow kill; the first symptoms are usually chloros~s, cessa- tion of growth, and gradual browning followed by dehydration and death. Several variables can influence the response, including stage of growth, senescence, moisture availability, temperature, light intensity, and insect or mechanical wounding of foliage before treatment. Arsenic can interact with several plant nutrients in either soils or nutrient solutions. Phosphate can increase or decrease the toxicity of arsenicals, depending on the experimental conditions. The toxicity in

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222 ARSENIC some species grown on arsenic-contaminated soils could be reduced by foliar or soil application of zinc or iron. EFFECTS ON MAN The past medicinal use of inorganic arsenic preparations has provided the basis for reasonably clear definition of the consequences of chronic systemic arsenic exposure specifically, characteristic hyperkeratosis and, less frequently, irregularities in pigmentation, especially on the trunk. Association of these features with other, less common disor- ders, such as arterial insufficiency and cancer, in exposed populations must be regarded as supportive evidence of a causal function of arsenic. It should also be noted that many studies of populations ''at risk" have failed to evaluate cutaneous changes adequately. Proper examination of the skin of people subjected to chronic low-dose arsenic exposure has the potential for providing valuable information related to the dose and duration of exposure necessary to cause changes in given populations. In a word, these benign skin lesions may be regarded as sensitive indexes of exposure to an agent that has potentially serious consequences. The present generation of physicians has not used arsenic and has little direct knowledge of its toxic manifestations. Thus, the ''index of suspicion" of the average practitioner may be relatively ineffective in diagnosing isolated cases of arsenic toxicity. There is also considerable reason to believe that, judiciously used, arsenic may have therapeutic value. The time may be ripe to rediscover an old remedy with modern analytic techniques. Several occupational and nonoccupational episodes of arsenic toxic- ity have occurred. Two of the best characterized and yet least known nonoccupational episodes occurred in Japan in 1955. One involved tainted powdered milk; the other, contaminated soy sauce. In the former, 12,131 cases of infant poisoning were recorded, with 130 deaths. Evidence of severe damage to health, including retarded growth and brain dysfunction, was found in a followup study 15 years later. Experimental teratogenic effects of arsenic compounds have been reported, but none of the studies has been sufficiently exhaustive to allow accurate assessment of the human hazard. For example, the doses that were administered to achieve effects far exceeded likely environmental exposure, and accurate no-effect doses were generally not determined.

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Summary and Conclusions 223 There is some evidence that arsenicals can be mutagenic in humans: An increased incidence of chromosomal aberrations was observed in phytohemagglutinin-stimulated lymphocyte cultures prepared from psoriasis patients who had been previously treated with arsenic. There is strong epidemiologic evidence that inorganic arsenic is a skin and lung carcinogen in man. Skin cancer has occurred in associa- tion with exposure to inorganic arsenic compounds in a variety of populations, ~nc~uo~ng patients treated with Fowler's solution, Taiwanese exposed to arsenic in artesian-well water, workers engaged in the manufacture of pesticides, and vintners using arsenic as a pesticide. The Taiwan data demonstrated a gradient of incidence with degree of exposure and age. All these populations had a patho- gnomonic sequence of skin changes leading to cancer. Lung cancer has been observed to be associated with inhalation exposure to arsenic in copper smelters, workers in pesticide- manufacturing plants, Moselle vintners, and Rhodesian gold miners. Two of the three smelter studies showed a gradient in the incidence of lung cancer with the degree of arsenic exposure; one of these studies also suggested that sulfur dioxide may be a carcinogenic cofactor for the lung. Although hemangioendothelioma has been reported occasionally in people who have been exposed to arsenic, the case for arsenic as a liver carcinogen is not clear. The absence of a useful animal model is a serious handicap to the study of arsenic as a skin carcinogen and is probably due to metabolic differences between humans and the animals tested so far. The failure to induce skin cancer in test animals is perhaps not surprising, inas- much as neither melanosis nor keratosis has been duplicated in animals and these effects appear to be inseparably linked to the tumorigenic action of arsenic in the skin of man. The carcinogenicity of arsenic for the lung in animals has not yet been evaluated by inhalation studies. MEASUREMENT The preparation of material for the determination of arsenic requires the usual care to ensure that the portion of the sample submitted for analysis truly represents the whole. Special hazards related to arsenic compounds are the possible loss of arsenous oxide by volatilization and the rapid adsorption of some arsenic compounds from solution onto the walls of storage vessels. If total arsenic is to be measured in plant or animal tissue or in coal,

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224 ARSENIC the sample is first wet-ached with some combination of nitric, per- chloric, and sulfuric acids. Arsenic originally present in the sample at very low concentrations must often be Reconcentrated before it can be measured. If the sample is a solution, the arsenic can be coprecipitated on metallic hydroxides or precipitated with organic reagents. It can also be isolated from its original matrix by liquid-liquid extraction or by volatilization as a trihalide or as arsine. Until recently, total arsenic was usually determined calorimetrically, by either the molybdenum blue method or the silver diethyldithiocar- bamate method. Arsenic is now usually determined by atomic absorp- tion, with the sample solution introduced into a flame as an aerosol or deposited as a droplet inside a tube or on a metallic strip, which is then strongly heated. Greater sensitivity has been achieved with atomic absorption, however, by converting the arsenic to arsine and introduc- ing this gas into a heated tube. Equal sensitivity can be achieved by introducing the arsine into an arc in helium and measuring the resulting spectral emission. Low detection limits for arsenic can also be reached by neutron-activation analysis (often without chemical treatment). Electrochemical methods, such as differential pulse polarography, can achieve comparable sensitivity in the presence of natural pollutants (e.g., sludge). CONCLUSIONS Environmental contamination with and human exposure to arsenic compounds have resulted from incidents of air pollution from smelters, the improper use of arsenical pesticides, and episodes of tainted food and drink. The degree of arsenic air pollution due to smelter operations and pesticide use should decrease if currently proposed occupational and environmental standards are promulgated. The technical and eco- nomic feasibility of the changes in engineering controls or work prac- tices needed to achieve compliance with such standards, however, has yet to be determined. Although the total amount of arsenic injected into the atmosphere in the United States as a result of coal-burning is very large, the sources of such air pollution are widely dispersed, and arsenic exposure due to fossil-fuel combustion does not seem to constitute a health hazard. This contrasts with the situation in some other countries (e.g., Czechoslovakia), where the arsenic content of coal is high and high ambient-air concentrations of arsenic result. Although petroleum gen

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Summary and Conclusions 225 erally contains only small quantities of arsenic, oil from shale can contain significant amounts; therefore, if use of this fossil fuel becomes common, removal of arsenic from the oil or more careful environmen- tal monitoring of arsenic is indicated. The food supply normally contains small amounts of arsenic, but these are not considered harmful. Some seafood has appreciable natu- ral concentrations of arsenic, but in such a form that it is rapidly and completely excreted by humans after ingestion. Arsenic residues in foodstuffs due to arsenical pesticide or feed-additive use do not seem to warrant concern. There have been isolated epidemics of food poisoning due to arsenic as a result of manufacturing accidents, but they are rare. Water supplies generally contain negligible quantities of arsenic, although some cases of endemically poisoned waters have been re- ported. Industrial effluents have been shown to contain arsenic, but the self-purifying tendency of rivers and streams and improved quality of wastewater discharges should help to minimize this problem. The use of arsenical pesticides in food crops declined greatly after introduction of the chlorinated hydrocarbon and organophosphorus chemicals. However, as more and more restrictions are placed on the use of the latter two families of compounds, the use of arsenical pesticides may once again assume importance. If this occurs, more careful monitoring of arsenic in the environment and food supply would be imperative. Our greatest area of ignorance about arsenicals in the environment has to do with the ecologic cycling of arsenic compounds. Little or no quantitative information is available regarding the fate of arsenicals in the ecosphere, so it is not possible to state with certainty whether arsenic is building up in any sector of the ecosystem. For example, organic arsenicals are widely used as herbicides and desiccants, but we do not know whether such use will eventually render the soil phytotoxic, as has happened in some orchards in which lead arsenate was heavily applied. More research is needed to investigate such problems. Suitable methods for arsenic determination are available for en- vironmental analysis. However, sample-handling may present difficul- ties because of losses of arsenic compounds via sublimation? especially during air monitoring, and analytic personnel should be alerted to this possible procedural pitfall. Individual arsenic compounds can be determined only after isolation by an appropriate method, such as volatilization, paper chromatog- raphy, gas chromatography, or electrophoresis. When the nature of the

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226 ARSE~C compound is known, the quantity present can be measured by measur- ing the amount of arsenic present. The continued concern about the association between inorganic arsenic and cancer has raised questions regarding the implications of widespread dispersion of inorganic arsenicals in the environment. Clearly, the ecologic uncertainties about arsenic compounds deserve more effort and attention.