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Page 27 3 Chemistry and Analysis of Arsenic Species in Water, Food, Urine, Blood, Hair, and Nails In this chapter, the subcommittee describes the chemistry of arsenic and its analysis in water and biological materials. The chapter is divided into four sections. The first section, Arsenic Compounds in Water and Food, provides the reader with general information on the various arsenic species that are now known to be present in food and water and that could be of concern in assessing normal human exposure (i.e., nonoccupational exposure) to arsenic. However, it should be emphasized that many unidentified arsenic species are probably present in the environment, including many in living organisms. It is not an easy task to detect and identify low concentrations of arsenicals, and methods to do so have been developed only in recent years. The second section, Relevant Chemical Considerations, provides a brief account of arsenic's chemistry that is relevant to considerations of toxicity and carcinogenicity. In the third section, Analysis of Arsenic Compounds, general methods that have been used to analyze arsenic and its species are outlined. The results of applying these methods to the analysis of water and food, respectively, are presented in the sections Arsenic in Water and Arsenic in Food. A separate section discusses the application of these methods to the analysis of arsenic in urine, blood, hair, and nails. Summary Of Arsenic Compounds In Water And Food Table 3-1 lists the most important arsenic compounds and species known to be present in water and food consumed by humans. The identified compounds that are not listed are (1) the volatile arsines MexAsH3-x
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Page 28 TABLE 3-1 Some Arsenic Compounds and Species Known to be Present in Water and Food Consumed by Humans Name Abbreviation Chemical Formula Arsenous acid As(III) H3AsO3 Arsenic acid As(V) H3AsO4 Oxythioarsenic acid H3AsO3S Monomethylarsonic acid MMA CH3AsO(OH)2 Methylarsonous acid MMA(III) CH3As(OH)2[CH3AsO]n Dimethylarsinic acid DMA (CH3)2AsO(OH) Dimethylarsinous acid DMA(III) (CH3)2AsOH[((CH3)2As)2O] Trimethylarsine TMA (CH3)3As Trimethylarsine oxide TMAO (CH3)3AsO Tetramethylarsonium ion Me4As+ (CH3)4As+ Arsenocholine AsC (CH3)3As+CH2CH2OH Arsenobetaine AsB (CH3)3As+CH2COO- Arsenic-containing ribo- Arsenosugar X-XVa sides Arsenolipidb aArsenosugar R X Y X (CH3)2As(O)- -OH -OH XI (CH3)As(O)- -OH -OPO3HCH2CH(OH)CH2OH XII (CH3)2As(O)- -OH -SO3H XIII (CH3)2As(O)- -OH -OSO3H XIV (CH3)2As(O)- -NH2 -SO3H XV (CH3)3As+- -OH -OSO3H bArsenolipid R X Y (CH3)2AsO- -OH -OPO3HCH2CH(OPalm)CH2OPalm
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Page 29 (Me =CH3, x = 0-3) produced naturally by the action of microorganisms on available arsenicals (Cullen and Reimer 1989); (2) the ethylmethylarsines EtxAsMe3-x (Et=C2H5, x = 1-3) found in natural gas (Irgolic et al. 1991); (3) phenylarsonic acid, C6H5AsO(OH)2, found in shale oil and retort water (Fish et al. 1982); and (4) the undoubtedly numerous arsenicals not yet discovered. The structures of the arylarsenicals that are approved as animal-food additives are shown in Figure 3-1. 4-Hydroxy-3-nitrophenylarsonic acid (3-NHPAA) and p-arsanilic acid (p-ASA) are approved for poultry and swine. 4-Nitrophenylarsonic acid (4-NPAA) and p-ureidophenylarsonic acid (p-UPAA) are approved only for controlling blackhead disease in turkeys (Ledet and Buck 1978; Adams et al. 1994). Melarsoprol, a related arylarsenical, is still the drug of choice for treating secondary trypanosomiasis in humans in rural Africa (Berger and Fairlamb 1994). FIGURE 3-1 Structures of arylarsenicals approved as animal-food additives. 3-NHPAA, roxarsone, 4-hydroxy-3-nitrophenylarsonic acid; p-ASA, p-arsanilic acid; 4-NPAA, 4-nitrophenylarsonic acid; p-UPAA, p-unridophenylarsonic acid As(III) (pKa (negative logarithm of equilibrium constant for dissociation) = 9.23, 12.13, 13.4), As(V) (pKa = 2.22, 6.98, 11.53), MMA (pKa = 4.1, 8.7), DMA (pKa = 6.2), TMA, and TMAO are usually associated with the terrestrial environment, As(III) and As(V) being dominant in water. Unidentified species ("hidden species" not detected by using hydride generation; see section Hidden Arsenic Species), however, can reach up to 22% of total arsenic in river water (Sturgeon et al. 1989), and methylarsenicals can reach up to 59% of total arsenic in lake water (Anderson and Burland 1991). The recent discoveries of AsB, AsC, and Me4As+ in mushrooms (Byrne et al. 1995; Kuehnelt et al. 1997a,b); arsenosugar X in algae (Lai et al. 1997); and oxythioarsenic acid and methylarsenic(III) species MMA(III) and DMA(III) in water (Bright et al. 1994; Hasegawa 1996, 1997; Schwedt and Reickoff 1996a,b) extend the range of identified species. In the marine environment, all the compounds shown in Table 3-1, except
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Page 30 the oxythioarsenate, have been identified. The most important arsenic compounds in seawater are the inorganic species As(III) and As(V). Those species are usually associated with much lower concentrations of DMA and MMA. In fish, the principal arsenic species is AsB, which is regarded as being ubiquitous. The telost fish Silver Drummer, however, does not contain any AsB, and its principal arsenic species is TMAO (Edmonds et al. 1997). Small amounts of AsC, DMA, MMA, As(V), TMAO, Me4As+, and arsenosugars also are found in marine animals (e.g., Larsen et al. 1993a), although the last two arsenic species can be important in some bivalves. High concentrations of unknown arsenicals have been identified in the abalone (Edmonds et al. 1997). Marine algae contain arsenosugars, principally X-XIII, and 15 arsenosugars have been identified to date. In addition, marine algae contain small amounts of inorganic arsenic and DMA (Francesconi and Edmonds 1997). High concentrations of inorganic arsenic (38-61% of total arsenic) are found in some marine algae, notably Sargassum muticum and Hizikia fusiforme (Morita and Shibata 1990; Francesconi and Edmonds 1997). The arsenolipid (Table 3-1) is a minor component of the brown alga Undaria pinnatifida, an edible seaweed known as Wakame (Shibata et al. 1992), but lipid-soluble arsenicals can reach high concentrations in some species. Relevant Chemical Considerations Is Arsenic Similar to Phosphorus? Arsenic is situated in the Periodic Table in Group 15 (old Group V) below nitrogen and phosphorus. The oxidation state of arsenic in compounds found in the environment is either III or V (Table 3-1), and much of the chemistry of those compounds results from the easy conversion between those two states. The two-electron reduction of arsenate As(V) to arsenite As(III) is favored in acidic solution (E° (standard reduction potential) = 0.56 volts), whereas the reverse is true in basic solution (Eº = -0.67 volts) (Latimer and Hildebrand 1951). In contrast, phosphorus(V) compounds are difficult to reduce. Another major difference between arsenic and phosphorus is the stability of the esters of phosphoric acid to hydrolysis, allowing the existence of, for example, DNA and adenosine 5'-triphosphate (ATP). Esters of As(V) acids are easily hydrolyzed; the half-life in neutral pH is about 30 min. If As(V)OR has a good leaving group such as -P(V) or C(O)R', the half-life falls to seconds. Enzymes can accept arsenate to incorporate into other compounds, such as ATP, but the analogues formed hydrolyze immediately. Thus, arsenate uncouples oxidative metabolism from ATP biosynthesis. That phenome-
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Page 31 non is believed to account for some of the toxicity of arsenate (Dixon 1997; see Chapter 7). Many As(III) compounds are formulated as RAsX or (R2As)2X (X = 0, S). In the solid state, some of those compounds can be polymeric (e.g., (CH3AsO)3 and (CH3AsS)3), but CH3As(OH)2 and (CH3)2AsOH seem to exist in dilute aqueous solution (Hasegawa 1996, 1997). Affinity Of Arsenic For Sulfur The affinity of arsenic for sulfur is revealed in any list of natural arsenic-containing minerals. Many are sulfides and include As4S4 (realgar), As4S6 (orpiment), and FeAsS (arsenical pyrites, mispickel). That affinity also has been invoked to account for the toxicity of As(III) compounds through the interaction with protein thiols, as shown in Equation 3-1 in Figure 3-2 (see also Chapter 7). Such binding to proteins might inhibit the function of such enzymes as pyruvate dehydrogenase and 2-oxoglutarate dehydrogenase (Knowles and Benson 1983a,b; Dixon 1997). FIGURE 3-2 Affinity of arsenic for sulfur. BAL, British Anti-Lewisite (dimercaprol). The action of dimercaprol, British Anti-Lewisite (BAL), in aiding the elimination of arsenic species from humans, is believed to result from the displacement of bound arsenic from a protein because of the formation of a more stable complex (Equation 3-2). However that action does not necessarily mean that the initial postulate of Equation 3-1 is correct. Binding of the arsenic to BAL could restore the function of an enzyme regardless of how the arsenic was originally bound. Li and Pickart (1995) pointed out that little evidence supports the proposal that the binding of As(III) compounds to
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Page 32 enzymes is solely or even predominantly that represented in Equation 3-1. Li and Pickart (1995) found that the binding of phenylarsenoxide, (C6H5AsO)n, (which is possibly C6H5As(OH)2 in dilute aqueous solution) to Arg [Arginine]-tRNA protein transferase does not involve vicinal thiols. However, Cys [Cysteine]-31 and Cys-184 seem to be implicated in lecithin-cholesterolacyl transferase (Jauhiainen et al. 1988). The reduction of As(V) compounds by thiols has been well documented (Cullen et al. 1984), but sulfhydryl groups in enzymes do not always affect the reduction (Dixon 1997), presumably because this reductive interaction with sulfhydryl groups requires that more than one sulfhydryl group reach the same arsenic atom (i.e., reduction is a two-electron process). The As(III)-sulfur bond is much more resistant to hydrolysis than the As(III)-oxygen moiety (Sagan et al. 1972; Zingaro and Thomson 1973). Biomethylation of Arsenic Endogenous thiols probably play a critical role in the metabolic conversion of As(III) and As(V) species. It is likely that glutathione (GSH) acts as a reducing agent for As(V) species; the resulting As(III) species can then accept a methyl group from S-adenosylmethionine (SAM) to produce the methylarsenic(V) species in an oxidative-addition reaction, as illustrated in Figure 33 (Cullen and Reimer 1989). This cycle of reduction followed by oxidative addition of a methyl group can be continued, and the end product seems to depend on the organism. This cycle is based on the pioneering studies of Challenger (1951). The end products can be trimethylarsine oxide or trimethylarsine for fungi, the tetramethylarsonium ion for clams, and probably DMA for humans (Cullen and Reimer 1989; Cullen et al. 1994) (see Chapter 5). FIGURE 3-3 Biomethylation of arsenic: SAM as methyldonor, GSH as reducing agent. GSH, glutathione.
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Page 33 SAM is probably the source of the adenosyl group that is found in the arsenosugars (Francesconi and Edmonds 1997). The As(III) derivatives seem to have the unique ability to accept all three groups that are attached to sulfur in SAM, as illustrated in Figure 3-4. FIGURE 3-4 Reaction of As(III) derivatives with SAM. SAM, S-adenosylemthionine.
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Page 34 The As(III) species that are intermediates in the biotransformation of arsenic might well be toxic (Hocking and Jaffer 1969; Sheridan et al. 1973; Cullen et al. 1989b) (see Chapter 7). For example, glutathione reductase (GR) is a key enzyme in the metabolism of GSH and is inhibited by the methylarsenic(III) and As(III) species (Delnomdedieu et al. 1994). The action of GR is critical in maintaining the redox status of cells. Some Geochemical Considerations: Absorption and Redox As(III) exists in most natural water as As(OH)3 (pKa = 9.2) and is more mobile than As(V) because it is less strongly absorbed on most mineral surfaces than the negatively charged As(V) oxyanions (H3AsO4; pKa = 2.22, 6.98, 11.53). Iron(III) oxy species are well known to have a high affinity for As(V) (Waychunas et al. 1993; Lumsdon et al. 1984), and As(III) also seems to be adsorbed on some iron(III) surfaces (Sun and Doner 1996). Little is known about the adsorption of As(III) on the terrestrially abundant aluminum oxides and aluminosilicate minerals. Activated alumina has a twofold higher affinity for As(V) than for As(III) at pH 7 (Ghosh and Yuan 1987); negligible removal of As(III) from drinking water is achieved by coagulation with alum (Hering et al. 1997). Kaolinite and montmorillonite also have higher affinities for As(V) than for As(III) (Frost and Griffin 1977). Abiotic oxidation of As(III) is enhanced in the presence of the clay minerals kaolinite and illite, a process that results in strongly bound As(V) species (Manning and Goldberg 1997; Scott and Morgan 1995). Thus, long-term modeling of arsenic mobility in soils and aquifers must consider the effects of pH and mineral conditions, which will influence both adsorption and abiotic oxidation of As(III). Little is known about the adsorption behavior of the organic arsenic species listed in Table 3-1 in spite of the use of the methylarsenicals MMA and DMA and their salts as pesticides, herbicides, and defoliants (Vallee 1973; Nriagu and Azcue 1990). Microbial Activity and Arsenic Mobilization Direct microbial reduction of arsenate to the more mobile arsenite is known for bacterial, algal, and fungal species (Cullen and Reimer 1989; Silver et al. 1993; Diorio et al. 1995). Microbial activity has been implicated in arsenic mobilization from sediments. Iron-reducing bacteria might cause arsenate dissociation from sediment that is solid as a consequence of iron
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Page 35 oxide dissolution (Lovley et al. 1991). Sulfate-reducing bacteria produce hydrogen sulfide, which might promote arsenate reduction. In recent years, some arsenate-respiring bacteria have been isolated; those include the dissimilatory arsenate-reducer strain MIT-13 (Ahmann et al. 1994) and Chrysiogenes arsenatis native to gold-mine waters (Macy et al. 1996). Ahmann et al. (1997) showed that arsenic-rich anoxic sediments from the Halls Brook storage area are mobilized by native microbial activity. In particular, strain MIT-13 is likely to catalyze that activity. In related experiments, Ahmann et al. (1997) found that microbial activity catalyzed rapid dissolution of arsenic, as As(III), from Fe(II) and Fe(III) arsenates. Free Radical and Peroxy Species It has been suggested that the observed tumor promotional activity of DMA might be due to the action of active oxygen-containing species, such as the dimethylarsenic peroxyl radical (CH3)2As-O-O (Rin et al. 1995; Yamanaka et al. 1996) (see Chapter 7). In fact, not much is known about peroxy species of arsenic, but the proposed As(III) species does not seem to be a plausible entity. Phenylarsonic acid, C6H5AsO(OH)2, can act as an oxygen-transfer agent by reacting with peroxide to form the intermediate peroxy acid C6H5AsO(OH)(OOH) (Jacobson et al. 1979a,b). One compound that was formulated as (CH3)2As-S-S-As(CH3)2, close in structure to the proposed peroxyl radical, turned out to have the structure (CH3)2As(S)-S-As(CH3)2, which has arsenic in two oxidation states (Camerman and Trotter 1964). On that basis and because of the ease of oxidation of DMA(III), (CH3)2As(O)-O or even (CH3)2As(O)-O-O might be more likely candidates for active oxygen-containing species. Related antimony peroxy species have been isolated and characterized (Dodd et al. 1992). Analysis Of Arsenic Compounds The discovery by Scheele in 1775 that arsenic compounds could react under reducing conditions to produce a volatile gas, arsine (AsH3) (Partington 1962), provided a tool to counteract the use of arsenic, usually as the oxide As2O3, for homicide; that use had reached epidemic proportions during the Middle Ages. The discovery led to the development of the Marsh test for arsenic, in which arsine is volatalized out of the reaction mixture and is detected, for example, by decomposition to an arsenic mirror. Alternatively, in the Gutzeit modification, the arsine is brought into contact with a filter
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Page 36 paper soaked with either silver nitrate or mercuric halide to produce a colored deposit. Both procedures can be made semiquantitative. They are the first applications of an analytical method now referred to as ''hydride generation" that is widely applicable to the analysis of elements that form volatile hydrides when treated with an appropriate reducing agent, usually sodium borohydride (Vallee 1973). In older studies, zinc and hydrochloric acid were used as reducing agents. The Gutzeit method was used in a recently published Japanese study (Tsuda et al. 1995) in which well water was found to contain arsenic in the parts-per-million rangethe measurements were made in 1959. A variation of this method, Natelson's method (Natelson 1961), was used in the early study of arsenic in the well water of Taiwan (Tseng et al. 1968). That method uses colorimetric detection and is said to detect arsenic at 40 µg/L. Arsine produced from arsenate and arsenite is sometimes reacted with silver diethyldithiocarbamate solution to produce a red solution of undetermined chemical nature that can be measured colorimetrically (Vallee 1973; Irgolic 1994; see also Table 3-3). The colorimetric method is easy to use, is inexpensive in terms of equipment and operator costs, and is commonly used by the water-supply industry. For example, Saha (1995) used the colorimetric method for his work on the wells of Bengal, and the method was used in the Lane County, Oregon, study (Morton et al. 1976); however, it has limitations with regard to sensitivity and arsenic speciation. Total-arsenic determination commonly involves oxidation of the sample, by using digestion or ashing, with a mixture of chemicals, including HNO3-H2SO4-H2O2 or HNO3-H2SO4-HCIO4 for wet digestion and MgO-MgNO3 for dry ashing (Irgolic et al. 1995). The arsenic is then determined by using one of a number of methods ranging from hydride generation (colorimetric or spectroscopic detection or neutron activation) to spectrophotometry (e.g., graphite-furnace atomic absorption (GFAA) or inductively coupled plasmaatomic emission spectrometry (ICP-AES)). Hydride Generation with Speciation The commonly used hydride-generation method that is currently applied to the determination of arsenic species is outlined in Figure 3-5. Volatile arsines are produced from a range of inorganic and methylarsenicals in both oxidation states. The four arsines, AsH3 and MexAsH3-x (x = 1-3) are produced from their appropriate precursors and are then quantified following separation if necessary. Bramen and Foreback (1973) and Andreae (1977) were among the first to use this method for arsenic speciation in natural systems.
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Page 37 FIGURE 3-5 Hydride generation. Arsenic speciation by using hydride generation. UV, ultraviolet. The method involves a derivatization technique, and the number of methyl groups in the evolved arsine, MexAsH3-x, is generally the same as that in the arsenic species before reduction (Andreae 1977). The precursors to the arsines are also generally assumed to be the oxyspecies shown in Table 3-1. That is not necessarily correct. For example, in some sulfur-rich environments, the precursors to the arsines might be such compounds as MeAs(SR)2 (Bright et al. 1994, 1996). An important feature of the hydride-generation reaction is its pH dependence. All the As(III) compounds produce arsines at about pH 6 (Andreae 1977; Bright et al. 1994; Hasegawa 1997). At about pH 1, all the arsenicals are reduced to arsines. By using that difference in reactivity, As(III) and As(V) can be determined in a sample. In the absence of other confounding factors, at intermediate pHs (e.g., in acetic acid) further differentiation between species and oxidation state can be obtained (Cullen et al. 1994). When a mixture of arsines is obtained following hydride generation, the arsines must be separated before quantification can be achieved. Often, in the usual batch-type operation mode, the arsines are trapped at liquid nitrogen temperature (cryofocused) and then separated by using gas chromatography. Alternatively, the cold trapped arsines are allowed to warm up slowly, and the differences in boiling points result in sequential presentation of the four compounds to the detector. In another variation, the hydrides are trapped in cold solvent, and aliquots of the resulting solution are injected into a gas chromatograph. Many detectors have been used for the analysis of the separated arsines.
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Page 72 625/3-87/013. U.S. Environmental Protection Agency, Risk Assessment Forum, Washington, D.C. Farmer, J.G., and L.R. Johnson. 1990. Assessment of occupational exposure to inorganic arsenic based on urinary concentrations and speciation of arsenic. Br. J. Ind. Med. 47:342-348. Fish, R.H., F.E. Brinckman, and K.L. Jewett. 1982. Fingerprinting inorganic arsenic and organoarsenic compounds in in situ oil shale retort and process waters using a liquid chromatograph coupled with an atomic absorption spectrometer as a detector. Environ. Sci. Technol. 16:174179. Florêncio, M.H., M.F. Duarte, A.M. Bettencourt, M.L. Gomes, and L.F. Vilas Boas. 1997. Electrospray mass spectra of arsenic compounds. Rapid Commun. Mass Spectrom. 11:469-473. Foà, V., A. Colombi, M. Maroni, M. Buratti, and G. Calzaferri. 1984. The speciation of the chemical forms of arsenic in the biological monitoring of exposure to inorganic arsenic. Sci. Total Environ. 34:241-259. Food Additives and Contaminants Committee. 1984. Report on the Review of the Arsenic in Food Regulations. Ministry of Agriculture, Fisheries and Foods, FAC/REP/39. London: Her Majesty's Stationary Office. Francesconi, K.A. and J.S. Edmonds. 1997. Arsenic and marine organisms. Adv. Inorg. Chem. 44:147-189. Frost, R.R. and R.A. Griffin. 1977. Effect of pH on adsorption of arsenic and selenium from landfill leachate by clay minerals. Soil Sci. Soc. Am. J. 41:53-57. Gartrell, M.J., J.C. Craun, D.S. Podrebarac, and E.L. Gunderson. 1985. Pesticides, selected elements, and other chemicals in adult total diet samples, October 1979-September 1980. J. Assoc. Off. Anal. Chem. 68:862-875. GESAMP (IMO/FAO/UNESCO/WMO/WHO/IAEA/UN/UNEP). 1986. Joint Group of Experts on the Scientific Aspects of Marine Pollution. Review of Potentially Harmful Substances; Arsenic, Mercury, and Selenium. Report and Studies. GESAMP Vol. 28. Ghosh, M.M., and J.R. Yuan. 1987. Adsorption of inorganic arsenic and organoarsenicals on hydrous oxides. Environ. Progress 6:150-157. Gunderson, E.L. 1995. FDA total diet study, July 1986-April 1991, dietary intakes of pesticides, selected elements, and other chemicals. J. AOAC Int. 78:1353-1363. Harrison, W. W. and G.G. Clemena. 1972. Survey analysis of trace elements in human fingernails by spark source mass spectrometry. Clin. Chim. Acta 36:485-492. Hasegawa, H. 1996. Seasonal changes in methylarsenic distribution in Tosa
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Representative terms from entire chapter: