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6
Biomarkers of Arsenic Exposure

Assessment of arsenic exposure via drinking water is often based on the measured concentrations in the drinking water and estimations of the amount of water consumed. For estimation of population averages, default values are often used for water consumption (e.g., 2 liters of water per day for an adult person). Data on individual consumption require information on the actual amount of water each individual uses for drinking and preparation of foods and beverages, as well as information on the water sources used and the arsenic concentration in each source. Unless the consumption data are based on actual measurements over several days by the duplicate portion technique, such data are estimates, the uncertainty of which will depend on the method used.

Biological monitoring provides data on the absorbed dose for each individual studied. In this chapter, the subcommittee evaluates various biomarkers (e.g., arsenic in urine, blood, hair, and nails) as meaningful measures of the absorbed dose of inorganic arsenic. A discussion is provided on the suitability of the various biomarkers to serve as indicators of acute or chronic exposure to inorganic arsenic and the various factors (e.g., dietary intake of arsenic compounds) that can influence the indicators.

Arsenic In Urine

The concentration of total arsenic in urine has often been used as an indicator of recent exposure because urine is the main route of excretion of most arsenic species (see, e.g., Buchet et al. 1981; Vahter 1994). The halftime of inorganic arsenic in human subjects is about 4 days (see Chapter 5). However, the total urinary arsenic concentration does not provide information



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Page 177 6 Biomarkers of Arsenic Exposure Assessment of arsenic exposure via drinking water is often based on the measured concentrations in the drinking water and estimations of the amount of water consumed. For estimation of population averages, default values are often used for water consumption (e.g., 2 liters of water per day for an adult person). Data on individual consumption require information on the actual amount of water each individual uses for drinking and preparation of foods and beverages, as well as information on the water sources used and the arsenic concentration in each source. Unless the consumption data are based on actual measurements over several days by the duplicate portion technique, such data are estimates, the uncertainty of which will depend on the method used. Biological monitoring provides data on the absorbed dose for each individual studied. In this chapter, the subcommittee evaluates various biomarkers (e.g., arsenic in urine, blood, hair, and nails) as meaningful measures of the absorbed dose of inorganic arsenic. A discussion is provided on the suitability of the various biomarkers to serve as indicators of acute or chronic exposure to inorganic arsenic and the various factors (e.g., dietary intake of arsenic compounds) that can influence the indicators. Arsenic In Urine The concentration of total arsenic in urine has often been used as an indicator of recent exposure because urine is the main route of excretion of most arsenic species (see, e.g., Buchet et al. 1981; Vahter 1994). The halftime of inorganic arsenic in human subjects is about 4 days (see Chapter 5). However, the total urinary arsenic concentration does not provide information

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Page 178 on the form of arsenic absorbed. As mentioned in Chapter 3, some foods, especially those of marine origin, often have high concentrations of arsenic mainly in the form arsenobetaine, which is not metabolized in the body but is rapidly excreted in the urine (Vahter et al. 1984; Vahter 1994). Thus, ingestion of such foods results in a rapid increase in the concentration of total arsenic in the urine; that increase would invalidate urinary arsenic as an indicator of exposure to inorganic arsenic. One serving of seafood might give rise to urinary arsenic concentrations of more than 1,000 µg/L (Norin and Vahter 1981). In comparison, concentrations of 5-50 µg/L are found in the urine of subjects with no intake of seafood arsenic or excessive exposure to inorganic arsenic in drinking water or in the working environment. Certain other foods (e.g., chicken) also might contain arsenobetaine if fish meal is used as a source of protein in the feed. A better measurement of the intake of inorganic arsenic can be obtained from the concentration of inorganic arsenic and its metabolites monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) in the urine (see Chapters 3 and 5). Exposure to MMA, DMA, or both will influence the estimate, but other than occupational exposure to pesticides containing DMA, such exposure seems to be very low in most countries. However, certain types of seafood, especially seaweed and some shellfish, might contain DMA (Mohri et al. 1990; Arbouine and Wilson 1992; Yamauchi et al. 1992) or arsenosugars, which are partly metabolized in the body to DMA (Le et al. 1994; Ma and Le 1998). Thus, consumption of such foods might result in increased urinary concentrations of DMA, and those increases might be interpreted as exposure to inorganic arsenic. In fact, consumption of seafood has been shown to cause a slight increase in the concentration of metabolites of inorganic arsenic in the urine (Norin and Vahter 1981; Vahter and Lind 1986; Arbouine and Wilson 1992; Mürer et al. 1992; Larsen et al. 1993; Buchet et al. 1994). Therefore, the intake of seafood, especially seaweed, should be investigated when urinary metabolites of arsenic are to be used for evaluation of exposure to inorganic arsenic. If such food is common, people should be asked to refrain from eating seafood a couple of days before urine sampling. Reported data on average background concentrations of metabolites of inorganic arsenic (inorganic arsenic + MMA + DMA) in the urine are generally below 10 µg/L in European countries (Apel and Stoeppler 1983; Valkonen et al. 1983; Foà et al. 1984; Vahter and Lind 1986; Andrén et al. 1988; Jensen et al. 1991; Buchet et al. 1996; Trepka et al. 1996; Kristiansen et al. 1997; Kavanagh et al. 1998), somewhat higher in some parts of the United States (Smith et al. 1977; Morse et al. 1979; Binder et al. 1987), and around 50 µg/L in Japan (Yamauchi and Yamamura 1979; Yamauchi et al.

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Page 179 1992). In certain areas in the United States, an average concentration of metabolites of inorganic arsenic at 10 µg/L or less has been reported for children (Kalman et al. 1990; Pollisar et al. 1990; Gottlieb et al. 1993). Urinary arsenic concentrations among occupationally exposed subjects can reach hundreds of micrograms per liter (Cant and Legendre 1982; Vahter et al. 1986; Yamauchi et al. 1989; Hakala and Pyy 1992; Offergelt et al. 1992; Yager et al. 1997). In a population, group-average concentrations of arsenic metabolites in the urine correlate with the average concentrations of arsenic in drinking water. However, the relationship can vary considerably depending on the amount of water consumed and the amount of water used for cooking. In studies carried out in California and Nevada, a water arsenic concentration of 400 µg/L corresponded to about 230 µg/L in the urine (as total urinary arsenic), and 100 µg/L in the water corresponded to about 75 µg/L in the urine (Valentine et al. 1979). Similarly, people in Alaska where the arsenic concentration was about 400 µg/L in drinking water had on average 180 µg/L in urine, and those exposed to 50-100 µg/L (average 75 µg/L) had on average 45 µg/L (Harrington et al. 1978). Among native Andean people in northwestern Argentina where the local water contains arsenic at about 200 µg/L, the average concentration of arsenic metabolites in urine was much higher, on the average of 250-450 µg/L, mainly because fluids other than the water are generally not consumed and most of the food is prepared with the water (Vahter et al. 1995; Concha et al. 1998a,b). In northeastern Taiwan, people living in villages with arsenic concentrations of 50-300 µg/L in drinking water had an average of 140 µg/L in urine (Chiou et al. 1997). Studies have also reported a relationship between airborne concentrations of arsenic and urinary excretion of inorganic arsenic metabolites (inorganic arsenic + MMA + DMA) among workers occupationally exposed to arsenic (Smith et al. 1977; Vahter et al. 1986; Offergelt et al. 1992; Yager et al. 1997). The urinary concentrations of arsenic metabolites were found to increase steadily during the first day of the workweek (2-3 days after the end of the previous workweek), after which they reached a steady state (Vahter et al. 1986). The concentrations in the late evening were very similar to those of the following early morning, and both correlated well with the total daily excretion. Hakala and Pyy (1995) reported a significant correlation between airborne concentrations of arsenic in a copper smelter and an arsenic trioxide refinery plant and urinary concentrations of inorganic arsenic. The urinary DMA correlated poorly with airborne arsenic, apparently because of the influence of dietary arsenic compounds that resulted in increased urinary DMA. As in other studies measuring concentrations of exposure markers in the

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Page 180 urine, an important question is whether to collect 24-hr urine samples, spot urine samples, or first-morning urine samples. Ideally, the amount of arsenic excreted over a certain period of time should be assessed. Usually that is done by measuring the excretion of arsenic in all urine produced in 24 hr. However, obtaining complete 24-hr urine collections is difficult (Bingham and Cummings 1983; Johansson et al. 1998).  It requires supervision and validation. Because of those difficulties and other problems (e.g., the risk of contamination of the urine during sampling), the first-morning urine or spot urine samples are generally collected for determination of the urinary concentration of arsenic or arsenic metabolites. To evaluate the concentration properly, especially in the case of spot urine samples, the dilution of the urine has to be considered. The urine flow is highly variable, being dependent on numerous factors, such as body size, body water content, solute intake, physical activity, and diurnal variations (Diamond 1988). A short time after the consumption of large amounts of fluid, the urine is very diluted and has a low solute content. To compensate for the dilution, the concentration of arsenic can be related to the concentration of creatinine or the specific gravity. A disadvantage of using the creatinine-adjusted urinary arsenic measurement is that it is dependent on the muscle mass and thus is often quite different for men and women. Protein intake might also influence urinary creatinine concentrations. In a study of bladder-cell micronuclei in people exposed to arsenic via drinking  water in northern Chile, creatinine-adjusted urinary  arsenic measurements showed the strongest correlation with intake estimates (average daily intake over the previous 4 months), and unadjusted urinary arsenic (sum of inorganic arsenic metabolites) showed the strongest correlation with bladder-cell micronuclei (Biggs et al. 1997).  At the most, 67%  of the variation in urinary arsenic was explained by the intake estimate, probably because urinary arsenic reflected exposure over the previous 1-2 days and the intake estimate reflected the average for the previous 4 months, and the daily intake of water and water-derived food is likely to vary considerably. A comparison with 24-hr recall data was not reported. The results might also reflect the difficulties in correctly estimating the intake of water without direct measurements (i.e., by duplicate portion collections). Arsenic In Blood Most of the absorbed inorganic and organic arsenic has a short half-time in blood (see Chapter 5); arsenic concentrations in blood are increased only for a very short time following absorption. If exposure is continuous and

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Page 181 steady, as is often the case with exposure through drinking water, the blood arsenic concentration might reach a steady-state and then reflect the degree of exposure. Blood is a difficult matrix for chemical analysis (see Chapter 3), so in general, only total arsenic concentrations are reported. Partial speciation of arsenic in blood has been reported in a few cases (Zhang et al. 1996; Concha et al. 1998b). When using total arsenic in blood as an indicator of exposure to inorganic arsenic, the interference from organic arsenic compounds originating from seafood has to be considered. Furthermore, because of the low concentrations, the analytical error might be significant, unless the more-sensitive methods are used. Data on concentrations of arsenic in blood in people with no known exposure to arsenic cover quite a wide range-0.3-2 µg/L (Bencko and Symon 1977; Heydorn 1970; Kagey et al. 1977; Olguin et al. 1983; Hamilton et al. 1994; Vahter et al. 1995; Concha et al. 1998a,b). In a population in northern Argentina with no known exposure to inorganic arsenic and very little fish intake, the average blood arsenic concentration was 0.9 µg/L in children and 1.5 µg/L in adults (Vahter et al. 1995; Concha et al. 1998a,b). The average blood arsenic concentration in people in Belgium was reported to be about 0.4 µg/L; that in red blood cells was 1.8 µg/L (Versieck 1985; Versieck and Vanballenberghe 1985). In areas where consumption of seafood is common, mean blood arsenic concentrations of 5-10 µg/L have been reported (Foà et al. 1984; Yamauchi et al. 1992). Similarly, the blood arsenic concentration was much higher in people living in coastal municipalities in Norway with high fish consumption than in people living in inland areas with low fish consumption (average values 7-18 µg/L versus 1 µg/L; Blekastad et al. 1984). Heydorn (1970) sampled blood from four individuals every 4 hr to determine the arsenic content in blood. No signs of circadian variation occurred, but following a supper of flatfish, blood arsenic concentrations rapidly increased in one subject by more than an order of magnitude (18 µg/L), followed by an approximately exponential decrease with a half-time of about 8 hr. The baseline blood arsenic concentrations in the four subjects were 0.3, 1.2, 1.6, and 4.5 µg/L, respectively. In subjects exposed to arsenic via drinking water, blood arsenic concentrations are clearly increased and might reach several tens of micrograms per liter (Heydorn 1970; Valentine et al. 1979; Vahter et al. 1995). In people exposed to arsenic in drinking water (200 µg/L) in northern Argentina, arsenic concentration in blood was about 10 µg/L on average (Vahter et al. 1995; Concha et al. 1998a,b). In studies carried out in California and Nevada, an arsenic concentration of 400 µg/L in the water corresponded to about 13 µg/L in the blood, and 100 µg/L in the water corresponded to 3-4

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Page 182 µg/L in the blood (Valentine et al. 1979). Obviously, compared with urine, blood is a much less sensitive biomarker of exposure to arsenic via drinking water. Arsenic In Hair And Nails Arsenic concentrations are normally higher in hair and nails than in other parts of the body because of the high content of keratin, the SH groups of which might bind trivalent inorganic arsenic (Curry and Pounds 1977; Hopps 1977; Hostýnek et al. 1993). The concentration of arsenic in the root of the hair is in equilibrium with the concentration in the blood. Hair might be considered an excretory pathway, and once incorporated in the hair, the arsenic is not biologically available. Arsenobetaine, the major organic arsenic compound in seafood, is not accumulated in hair (Vahter et al. 1983). That implies that arsenic in hair reflects exposure to inorganic arsenic only. Experimental studies in which radiolabeled DMA was administered to mice and rats showed very low incorporation of DMA in skin and hair compared with that of inorganic arsenic (Vahter et al. 1984). However, in one study, the presence of DMA in hair and nails has been reported (Yamauchi and Yamamura 1983; Yamato 1988). Segmental hair analysis (i.e., determination of the concentration along the length of the hair) might provide valuable information on the time of acute arsenic exposure (Smith 1964; Toribara et al. 1982; Koons and Peters 1994). For example, Smith (1964) reported a case in which a single fatal ingestion of 0.8 g of arsenic trioxide gave rise to a concentration of only 0.86 mg/kg for the whole length of hair, 30 cm long. Further analysis showed that the concentration of arsenic in the first millimeter, including the root, was 90 mg/kg. In another fatal case of arsenic poisoning, centimeter segmental analysis revealed that the concentrations of arsenic varied between 28 and 226 mg/kg (Poklis and Saady 1990). The main disadvantage of using hair and nails as indicators of exposure to arsenic is that the arsenic concentrations might be influenced by external contamination via air, water, soaps, and shampoos.  That was clearly demonstrated in studies on people living in Fairbanks, Alaska, where the water contained arsenic at 345 µg/L (Harrington et al. 1978). One group of people drinking essentially only bottled water, resulting in low concentrations of arsenic in urine (average 43 µg/L), had high arsenic concentrations in hair (average 5.7 µg/g). In areas with low concentrations of arsenic in drinking water (less than 50 µg/L in water, 38 µg/L in urine), the concentration in hair was 0.4 µg/g, on average. Thus, the concentrations in hair varied by a factor

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Page 183 of 14 at similar concentrations in urine. Apparently, arsenic was bound to the hair during washing with the arsenic-rich water. As discussed in Chapter 3, methods for cleaning hair and nails externally contaminated by arsenic have been proposed. It is not clear whether such procedures can remove the arsenic that is bound to the surface of hair and nails as a result of contact with arsenic in the water. Experimental absorption and desorption experiments have shown that the amount of externally deposited arsenic removed from hair by various washing protocols is variable and virtually always incomplete (Smith 1964; Atalla et al. 1965; Bate 1966; Maes and Pate 1977; Van den Berg et al. 1968). Moreover, attempts to remove externally deposited arsenic by washing may result in removal of arsenic contained in the hair as a result of in vivo incorporation (Atalla et al. 1965; Van den Berg et al. 1968). In addition, the influence on the accumulation and external binding of arsenic by hair treatment (e.g., permanent waving and dying) is not known. Therefore, although the determination of arsenic concentrations in the hair might be useful for the detection of arsenic exposure, its use as an indicator of the degree of exposure to arsenic on an individual basis is limited. Another problem with using hair arsenic concentrations as an indicator of absorbed dose of arsenic is related to the fact that the concentration of arsenic in the hair over the head of the same person might vary considerably (Cornelis 1973). In people with no known exposure to arsenic, the concentration of arsenic in hair is generally 0.02-0.2 mg/kg (Valentine et al. 1979; Olguin et al. 1983; Narang et al. 1987; Takagi et al. 1988; Koons and Peters 1994; Wang et al. 1994; Wolfsperger et al. 1994; Vienna et al. 1995; Raie 1996; Paulsen et al. 1996; Rogers et al. 1997; Kurttio et al. 1998). The concentrations of arsenic in hair are clearly increased in people drinking water with high arsenic concentrations. For example, concentrations ranging from 3 to 10 mg/kg are reportedly common in people in areas in West Bengal that have high arsenic concentrations in drinking water (Das et al. 1995). On a group basis, a few reports indicate that the correlation between the concentration of arsenic in drinking water and the concentration in hair is fairly good, although it is not known how much of the arsenic in hair originates from arsenic in blood and how much is bound due to external contact with the water, as discussed above. The range of reported relationships is significant. In studies carried out in California and Nevada, a concentration of 400 µg/L in drinking water corresponded to about 1.2 µg/g in hair, and 100 µg/L in water corresponded to about 0.5 µg/g in hair (Valentine et al. 1979). In Alaska, an average of 400 µg/L in drinking water corresponded to 3.3 µg/g in hair (Harrington et al. 1978). In Hungary, people with drinking-water concentrations ranging from 50 to 100 µg/L had

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Page 184 an average hair concentration of 3 µg/g (Börzsönyi et al. 1992). The highest hair arsenic concentrations were found in children. In Canada, 50% of 86 individuals using well water with arsenic concentrations above 50 µg/L had hair arsenic concentrations above 1 µg/g (Grantham and Jones 1977). Of the 33 people using wells with arsenic concentrations above 100 µg/L, 94% had hair concentrations above 1 µg/g. Data on arsenic in nails are sparse, but normal values appear to range from 0.02 to 0.5 µg/g (Narang et al. 1987; Takagi et al. 1988). Several tens of micrograms per gram have been reported in cases of chronic poisoning (Pounds et al. 1979; Das et al. 1995). A single dose of arsenic can be detected at the distal tip of the nails about 100 days after exposure (Pounds et al. 1979; Pirl et al. 1983). Presumably, arsenic is deposited in the nail roots from the blood and then migrates distally as the nails grow (at about 0.12 mm a day).  As with hair, external contamination can increase the arsenic concentrations in nails. Summary And Conclusions Arsenic exposure via drinking water is often estimated from the concentrations in the drinking water, sometimes in combination with information on the consumed amounts of water via drinking and food preparation. The latter measurement might include marked uncertainties, especially concerning individual data, depending on the method used. The concentration of arsenic metabolites (inorganic arsenic, MMA, and DMA) in urine reflects the absorbed amount of inorganic arsenic and serves as a useful measurement of an individual's recent (previous day) or ongoing exposure (e.g., via drinking water). Total urinary arsenic is a less useful biomarker of exposure to inorganic arsenic, unless ingestion of certain foods, especially those of marine origin, can be excluded. Ingestion of such foods can result in a rapid increase in the concentration of total arsenic in the urine, and even small amounts of seafood can invalidate total urinary arsenic as an indicator of exposure to inorganic arsenic. Certain seafood, especially seaweed and mussels, might increase in the concentration of DMA in urine. If such exposure is common, the people under study should be asked to refrain from eating such food at least 5 days before urine sampling. This is particularly important if the exposure to inorganic arsenic is low. Because of the variations in the proportions of different arsenic metabolites in urine, the concentration of the sum of the metabolites is a better indicator of exposure than is the concentration of inorganic arsenic or DMA in urine. The exact reasons for the variations are largely unknown, but

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Page 185 probably are influenced by age, sex, health status, genetic factors, and analytical variability. Few reports have been published on urinary concentrations of arsenic metabolites in populations living in the Unites States. In the case of continuous exposure to arsenic, there is an association between the absorbed dose and the concentration in blood. Because intake of food containing organic arsenic compounds of marine origin might cause a substantial increase in the concentration of arsenic in blood and because it is difficult to speciate arsenic in this matrix, blood is not a useful biomarker of exposure to inorganic arsenic. In addition, because of the lower concentrations in blood compared with urine, blood arsenic is less sensitive as a biomarker of exposure. Also, the half-time of arsenic in blood is in the order of a few hours compared with a few days in urine. Thus, the time between the last exposure and the sampling can affect the results. Arsenic concentrations in hair and nails have often been used as indicators of exposure to inorganic arsenic. Arsenic externally deposited onto hair and nails cannot be consistently removed by washing methods nor distinguished from  arsenic present as a result of internal incorporation.  Therefore, measurement of arsenic in hair and nails will have very limited use as a quantitative biomarker of internal exposure unless the potential for external exposure can be definitively excluded. Speciation is of less importance because the major forms of organic arsenic compounds in food (i.e., arsenobetaine, arsenocholine, and arsenosugars) are not accumulated in hair or nails. In the case of acute exposure to arsenic, an advantage of the hair biomarker is that the time of exposure can be estimated by determining the arsenic concentrations along the length of a hair strand. The main disadvantage of using hair and nails as biomarkers of arsenic exposure is that it is difficult to distinguish between arsenic incorporated into the hair and nail from the systemic circulation and that bound externally (e.g., when washing with water containing arsenic). In addition to water, arsenic in dust can also contaminate hair externally. Thus, arsenic concentrations in hair and nails can be used as markers of exposure rather than markers of absorbed dose. The variation in accumulation in hair and nails between individuals is unknown. Recommendations More data are needed that tie biomarkers of absorbed dose (especially urinary concentrations of arsenic metabolites) to arsenic exposure concentrations, tissue concentrations, and the clinical evidence of arsenic toxicity. Data are particularly lacking for people living in different parts of the United States.

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Page 186 The relationship between arsenic in urine and arsenic in whole blood or serum needs to be clarified as well as between those biomarkers and arsenic in hair and nails, taking into consideration the possibility of external contamination. References Andrén P., A. Schütz, M. Vahter, R. Attewell, L. Johansson, S. Willers, and S. Skerfving. 1988. Environmental exposure to lead and arsenic among children living near a glassworks. Sci. Total Environ. 77:25-34. Apel, M., and M. Stoeppler.  1983. Speciation of arsenic in urine of occupationally non-exposed persons.  Pp. 517-520 in International Conference Heavy Metals in the Environment, Heidelberg- September 1983. Vol. 1. Edingburgh: CEP Consultants Arbouine, M.W., and H.K. Wilson. 1992. The effect of seafood consumption on the assessment of occupational exposure to arsenic by urinary arsenic speciation measurements. J. Trace Elem. Electrolytes Health Dis. 6:153160. Atalla, L.T., C.M. Silva, F.W. Lima. 1965. Activation analysis of arsenic in human hair-Some observations on the problems of external contamination. Ann. Acad. Brasil. Cien. 37:432-441. Bate, L.C. 1966. Adsorption and elution of trace elements on human hair. Int. J. Appl. Radiat. Isot. 17:417-423. Bencko, V., and K. Symon. 1977. Health aspects of burning coal with a high arsenic content: Arsenic in hair, urine, and blood in children residing in a polluted area. Environ. Res. 13:378-385. Biggs, M.L., D.A. Kalman, L.E. Moore, C. Hopenhayn-Rich, M.T. Smith, and A.H. Smith. 1997. Relationship of urinary arsenic to intake estimates and a biomarker of effect, bladder cell micronuclei. Mutat. Res. 386:185-195. Binder, S., D. Forney, W. Kaye, and D. Paschal. 1987. Arsenic exposure in children living near a former copper smelter. Bull. Environ. Contam. Toxicol. 39:114-121. Bingham, S., and J.H. Cummings. 1983. The use of 4-aminobenzoic acid as a marker to validate the completeness of 24 h urine collection in man. Clin. Sci. 64:629-635. Blekastad, V., J. Jonsen, E. Steinnes, and K. Helgeland. 1984. Concentrations of trace elements in human blood serum from different places in Norway determined by neutron activation analysis. Acta Med. Scand. 216:25-29. Börzsönyi, M., A. Berecsky, P. Rudnai, M. Csanady, and A. Horvath. 1992. Epidemiological studies on human subjects exposed to arsenic in drinking

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Page 187 water in southeast Hungary. Arch. Toxicol. 66:77-78. Buchet, J.P., R. Lauwerys, and H. Roels. 1981. Comparison of the urinary excretion of arsenic metabolites after a single dose of sodium arsenite, monomethylarsonate or dimethylarsinate in man. Int. Arch. Occup. Environ. Health 48:71-79. Buchet, J.P., J. Pauwels, and R. Lauwerys. 1994. Assessment of exposure to inorganic arsenic following ingestion of marine organisms by volunteers. Environ. Res. 66:44-51. Buchet, J.P., J. Staessen, H. Roels, R. Lauwerys, and R. Fagard. 1996. Geographical and temporal differences in the urinary excretion of inorganic arsenic: A Belgian population study. Occup. Environ. Med. 53:320-327. Cant, S.M., and L.A. Legendre. 1982. Assessment of occupational exposure to arsenic, copper, and lead in a western copper smelter. Am. Ind. Hyg. Assoc. J. 43:223-226. Chiou H.Y., Y.M. Hsueh, L.L. Hsieh, L.I. Hsu, Y.H. Hsu, F.I. Hsieh, M.L. Wei, H.C. Chen, H.T. Yang, L.C. Leu, T.H. Chu, C. Chen-Wu, M.H. Yang, and C.J. Chen. 1997. Arsenic methylation capacity, body retention, and null genotypes of glutathione S-transferase M1 and T1 among current arsenicexposed residents in Taiwan. Mutat. Res. 386:197-207. Concha, G., B. Nermell, and M. Vahter. 1998a. Metabolism of inorganic arsenic in children with chronic high arsenic exposure in northern Argentina. Environ. Health Perspect. 106:355-359. Concha, G., G. Vogler, D. Lezeano, B. Nermell, and M. Vahter. 1998b. Exposure to  inorganic arsenic  metabolites during  early  human development. Toxicol. Sci.44:185-190. Cornelis, R. 1973. Neutron activation analysis of hair, failure of a mission. J. Radioanal. Chem. 15:305-316. Curry, A.S., and C.A. Pounds. 1977. Arsenic in hair. J. Forensic. Sci. Soc. 17:37-44. Das, D., A. Chatterjee, B.K. Mandal, G. Samanta, D. Chakraborti, and B. Chanda. 1995. Arsenic in ground water in six districts of West Bengal, India: The biggest arsenic calamity in the world. Part 2. Arsenic concentration in drinking water, hair, nails, urine, skin-scale and liver tissue (biopsy) of the affected people. Analyst 120:917-924. Diamond, G.L. 1988. Biological monitoring of urine for exposure to toxic metals. Pp. 515-529 in Biological Monitoring of Toxic Metals. T.W. Clarkson, L. Friberg, G.F. Nordberg, and P.R. Sager. New York: Plenum. 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. Gottlieb, K., J.R. Koehler, and J. Tessari. 1993. Non-analytic problems in

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