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4
Health Effects of Arsenic

THIS chapter presents the subcommittee's review of the evidence of health effects in humans resulting from ingestion of inorganic arsenic. The source of exposure in the large majority of studies reviewed is drinking water contaminated with inorganic arsenic from natural sources. A few studies involve other sources of exposure, however, such as industrially contaminated drinking water, medicinal use of arsenic, and arsenical pesticides. The focus of the chapter is on causal inference, which in risk-assessment terminology is often referred to as hazard identification. The chapter first provides the evidence for cancer and then other effects.

Although evidence for dose-response relationships is presented as it relates to causal inference, the actual quantification of dose-response relationships has not been undertaken in this chapter. Statistical issues in dose-response quantification for risk-assessment purposes are presented in Chapter 10.

Cancer Effects

The carcinogenic role of arsenic compounds was first noted over 100 years ago in the Hutchinson (1887) observation that an unusual number of skin tumors develop in patients treated with arsenicals. In a 1980 review of arsenic, the International Agency for Research on Cancer (IARC  1980) determined that inorganic arsenic compounds are skin and lung (via inhalation) carcinogens in humans. Data suggesting an increased risk for cancer at other sites were noted to be inadequate for evaluation. Since 1980, several additional studies of cancer and exposure to arsenic in drinking water have been completed.

The epidemiological studies outlined in this chapter clearly show associa-



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Page 83 4 Health Effects of Arsenic THIS chapter presents the subcommittee's review of the evidence of health effects in humans resulting from ingestion of inorganic arsenic. The source of exposure in the large majority of studies reviewed is drinking water contaminated with inorganic arsenic from natural sources. A few studies involve other sources of exposure, however, such as industrially contaminated drinking water, medicinal use of arsenic, and arsenical pesticides. The focus of the chapter is on causal inference, which in risk-assessment terminology is often referred to as hazard identification. The chapter first provides the evidence for cancer and then other effects. Although evidence for dose-response relationships is presented as it relates to causal inference, the actual quantification of dose-response relationships has not been undertaken in this chapter. Statistical issues in dose-response quantification for risk-assessment purposes are presented in Chapter 10. Cancer Effects The carcinogenic role of arsenic compounds was first noted over 100 years ago in the Hutchinson (1887) observation that an unusual number of skin tumors develop in patients treated with arsenicals. In a 1980 review of arsenic, the International Agency for Research on Cancer (IARC  1980) determined that inorganic arsenic compounds are skin and lung (via inhalation) carcinogens in humans. Data suggesting an increased risk for cancer at other sites were noted to be inadequate for evaluation. Since 1980, several additional studies of cancer and exposure to arsenic in drinking water have been completed. The epidemiological studies outlined in this chapter clearly show associa-

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Page 84 tions of arsenic with several internal cancers at exposure concentrations of several hundred micrograms per liter of drinking water. However, they provide few data about the degree of association at exposure concentrations below a few hundred micrograms per liter. An extensive literature describes cases of skin and internal cancers following medicinal treatment with potassium arsenite (Fowler's solution) for a variety of conditions (Sommers and McManus 1953; Rosset 1958; Robson and Jelliffe 1963; Jackson and Grainge 1975; Popper et al. 1978; Prystowsky et al. 1978; Reymann et al. 1978; Nagy et al. 1980; Falk et al. 1981; Roat et al. 1982; Robertson and Low-Beer 1983), exposure to arsenical pesticides (Sommers and McManus 1953; Kjeldsberg and Ward 1972; Popper et al. 1978), or consumption of industrially contaminated drinking water or pesticide-contaminated wine (Roth 1957). The case reports and case series do not provide the needed data for quantitative risk assessment. However, the occurrence of these tumors in high numbers after long-term ingestion of arsenic in relatively young patients, or at anatomic sites where cancer is an extremely rare occurrence (e.g., liver angiosarcoma), increases the likelihood that many of the documented cancers were induced by arsenic. The observations also assist in identifying major cancer end points. The most common types of malignancy described in the reports are skin cancer, lung cancer, angiosarcoma of the liver (probably noted because of its rarity), prostate cancer, and bladder cancer. Reports of other cancers also appear: leukemia; other hematopoietic cancers; and cancers of the breast, colon, stomach, parotid gland, nasopharynx, larynx, buccal cavity, kidney, and others. Additional case reports describe internal cancers after the appearance of Bowen's disease, a type of superficial intraepidermal carcinoma that has been linked with arsenic exposure (Graham and Helwig 1959; Epstein 1960; Peterka et al. 1961; Hugo and Conway 1967). The second group of studies comprises epidemiological investigations. Most of them did not provide the informational quality necessary for interpretation of dose-response relationships. However, many of the studies included data that are valuable in establishing the level of risk of particular internal cancers associated with a range of likely arsenic exposures (see Table 4-1). The form of arsenic was not specified in the epidemiological studies cited except for Cuzick et al. (1992), who observed mortality in a cohort of patients medicinally treated with potassium arsenite. Ecological studies are considered first, followed by cohort studies. Studies are summarized in Tables 4-1 through 4-6. When evaluating the epidemiological evidence to help judge whether arsenic in drinking water is a likely cause of internal cancers or other diseases, the subcommittee used the evaluation criteria that have been discussed by Hill (1965) and others (Cox 1972; Susser 1973; Rothman 1986).

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Page 85 The primary criteria that were used in attempting to distinguish causal from noncausal associations included (1) strength of the association (the magnitude of the risk ratio between exposed and nonexposed populations); (2) temporality (the disease must follow the exposure); (3) biological gradient (exposure to higher concentrations of arsenic or exposure for longer periods should result in a greater effect than low-concentration exposures or exposures of short duration); and (4) epidemiological coherence (are similar observations made in diverse populations?). TABLE 4-1 Summary of Cancer End Points Available for Quantitative Risk Assessment of Cancer and Ingested Arsenic Exposures   Cancer Site Study Skin Bladder Lung Kidney Nasal Liver Prostate Other Ecological studies                 Tseng et al. 1968                 Wu etal. 1989                 Chen and Wang 1990                 Guo et al. 1997                 Hopenhayn-Rich et al.                 1996, 1998                 Smith et al. 1998                 Cohort studies                 Cuzick et al. 1992                 Tsuda et al. 1995                 Chiou et al. 1995                 Case-control studies                 Bates et al. 1995                 , cancer end points. Ecological Studies Summary results of the ecological studies are shown in Tables 4-2, 4-3, and 4-4.

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Page 86 TABLE 4-2 Bladder-Cancer Mortality, Urinary-Cancer Incidence, and Arsenic Exposure in Ecological Studies Study Location Exposure Cases, No. Study Outcome Comments Mortality studies Chen and Wang 1990 Taiwan Data from 83,656 wells, national survey   b(SE) from regression: Mortality, 1972-1983 in 314 precincts and townships; regression-coefficient (b) estimates increase in age-adjusted mortality per 100,000 per increase in arsenic at 100 mg/L of water         Male Female         National data 3.9 (0.5) 4.2 (0.5)                       Rate:     Wu et al. 1989 SW Taiwan Average arsenic: <0.30 ppm 0.30-0.59 ppm ³0.60 ppm Male Female Male Female Mortality, 1973-1986 in 42 villages in Taiwan       23 30 22.6 25.6         36 36 61.0 57.0         26 30 92.7 111.3             SMR:   Mortality, 1986-1991; national rates Hopenhayn- Rich et al. 1996,1998 Cordoba Province, Argentina Few high concentration Scattered high concentration 178 mg/L average Male Female Male Female for 1989 used as the standard for the SMR; SMR for COPD below the expected level, indicating low smoking rates; also no trend with stomach cancer SMR       113 39 0.80 (0.7-1.0) 1.21 (0.9-1.6)         93 24 1.42 (1.1-1.7) 1.58 (1.0-2.4)         131 27 2.14 (1.8-2.5) 1.82 (1.2-2.6)           SMR:     Smith et al. 1998 Region II, Northern Chile 420 mg/L average; 5-yr average ranged from below100 mg/L after 1980 to 569 µg/L in1955-1959; by city and 5- yr period, range was 40-870 µg/L Male 93 Female 64 Male 6.0(4.8-7.4) Female 6.0(4.8-7.4) Mortality, 1989-1993; national rates for 1991 used as the standard for the SMR; arsenic concentration is population-weighted average for major cities or towns in Region II, 1950-1974; information in paper adequate to calculate increase in risk per unit exposure (Table continued on next page)

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Page 87 (Table continued from previous page) Study Location Exposure Cases,  No. Study Outcome Comments Incidence studies Guo et al. 1997a Taiwan Data from 83,656 wells, national survey: b(SE) from regression: Incidence, 1980-1987; results shown are for transitional-cell carcinoma, the most common form of bladder cancer     <0.05 ppm   Mixed results for exposure       0.05-0.08 ppm   levels; at >0.64 ppm, the       0.09-0.16 ppm   b(SE) was       0.17-0.32 ppm             0.33-0.64 ppm   Male Female       >0.64 ppm National rates 0.57 (0.07) 0.33 (0.04)   Transitional-cell carcinoma only. Abbreviations: b(SE), regression coefficient (standard error); SMR, standardized mortality ratio; COPD, chronic obstructive pulmonary disease

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Page 88 TABLE 4-3 Kidney-Cancer Mortality, Urinary-Cancer Incidence, and Arsenic Exposure in Ecological Studies Study Location Exposure Cases, No. Study Outcome Comments Mortality studies                       SMR:     Chen et al. SW Blackfoot-disease Male Female Female Male SMRs; age-specific Taiwan rates 1985 Taiwan endemic area 42 62 772 1,119 as standard Chen and Taiwan Data from 83,656     b(SE) from regression: Mortality, 1972-1983 in 314 Wang 1990   wells; national     Male Female precincts and townships;     survey National data 1.1(0.2) 1.7 (0.2) regression-coefficient (¬) estimates               increase in age-adjusted mortality               per 100,000 per increase in arsenic               at 100 pg/L of water           Rate:     Wu et al. SW Average arsenic: Male Female Male Female Mortality, 1973-1986 in 42 villages 1989 Taiwan <0.30 ppm 9 4 8.42 3.42 in Taiwan     0.30-0.59 ppm 11 13 18.90 19.42       ³0.60 ppm 6 16 25.26 57.98             SMR:     Hopenhayn- Cordoba County group: Male Female Male Female SMRs using national age-specific Rich et al. Province, Low 66 38 0.87 1.00 rates as the standard 1996,1998 Agentina Medium 66 34 1.33 1.36       High 53 27 1.57 1.81   (Table continued on next page)

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Page 89 (Table continued from previous page) Study Location Exposure Cases, No. Study Outcome Comments Incidence studies Guo et al. Taiwan Data from 83,656         Incidence, 1980-1987; results 1997a   wells; national         shown are for renal-cell carcinoma     survey:     b(SE) from regression: only     <0.05 ppm     Mixed results for exposure       0.05-0.08 ppm     levels; at >0.64 ppm, the       0.09-0.16 ppm     b(SE) was       0.17-0.32 ppm               0.33-0.64 ppm     Male Female       >0.64 ppm National rates 0.03 (0.02) 0.142 (0.013)   aTransitional-cell carcinoma only. Abbreviations: b(SE), regression coefficient (standard error); SMR, standardized mortality ratio.

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Page 90 TABLE 4-4 Lung-Cancer Mortality and Arsenic Exposure in Ecological Studies Study Location Exposure Cases, No. Study Outcome   Comments Chen and Taiwan 1974-1976 data from   b(SE) from regression:   Mortality, 1972-1983 in 314 Wang 1990   83,656 wells, national   Male Female   precincts and townships;     survey: average for   5.3(0.9) 5.3(0.7)   regression-coefficient (P)     National data         estimates increase in age-     each of 314 precincts         adjusted mortality per     or townships         100,000 per increase in               arsenic at 100 µg/L of water           Rate:     Wu et al. SW Average arsenic: Male Female Male Female Mortality, 1973-1986 in 42 1989 Taiwan <0.30 ppm 53 43 49.16 36.71 villages in Taiwan     0.30-0.59 ppm 62 40 100.67 60.82       ¬0.60 ppm 32 38 104.08 122.16             SMR:   Mortality, 1989-1993; Smith et al. Region II, 420 µg/L average; 5-yr Male Female Male Female national rates for 1991 used 1998 Northern average ranged from 544 154 3.8(3.5-4.1) 3.1(2.7-3.7) as the standard for the SMR;   Chile below 100 µg/L after         arsenic concentration is     1980 to 569 µg/L in 1955-         population-weighted average     1959; by city and 5-yr         for major cities and towns in     period, range was 40-870         Region II, 1950-1974;     µg/L         information in paper               adequate to calculate               increase in risk per unit               exposure (Table continued on next page)

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Page 91 (Table continued from previous page) Study Location Exposure Cases, No. Study Outcome Comments           SMR:   Mortality, 1986-1991; national Hopenhayn- Cordoba County group: Male Female Male Female rates for 1989 used as the Rich et al. Province, Low 826 194 0.92(0.85-0.98) 1.24(1.06-1.42) standard for the SMR; SMR for 1998 Argentina Medium 914 138 1.54(1.44-1.64) 1.34(1.12-1.58) COPD below the expected     High 708 156 1.77(1.63-1.90) 2.16(1.83-2.52) level, indicating low smoking               rates; also no trend with               stomach cancer SMR Abbreviations: b(SE), regression coefficient (standard error); SMR, standardized mortality ratio.

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Page 92 Villages in southwestern coastal Taiwan switched from surface to groundwater (artesian wells) for drinking in the 1920s, motivated by the need to improve the microbiological quality of drinking water. Unexpectedly, aquifers were contaminated with naturally occurring arsenic, and the shift resulted in widespread exposure to relatively high concentrations. Tseng et al. (1968) and Tseng (1977) conducted individual medical examinations, with an emphasis on skin lesions, of 40,421 inhabitants of 37 villages in that area of Taiwan by the end of 1965. The arsenic content of well water ranged from 0.01 to 1.82 parts per million (ppm); most wells had arsenic concentrations of 0.4-0.6 ppm. Prevalence of skin cancer, keratoses, and hyperpigmentation were calculated for villages in three exposure groups: 0.0-0.29 ppm, 0.30-0.59 ppm, and 0.60 ppm and over. Hyperpigmentation was the most common condition (183.5/1,000), followed by keratosis (71.0/1,000) and skin cancer (10.6/1,000). In both sexes in three broad age groups, the prevalence of skin lesions increased with exposure to arsenic. For example, among males 60 and over, the prevalence of skin cancer per 1,000 persons was 46.1 in the 0.00.29-ppm group, 163.4 in the 0.30-0.59-ppm group, and 255.3 in the 0.60 ppm-and-over group. Among females 60 years of age and over, skin-cancer prevalence was 9.1, 62.0, and 110.1 per 1,000 persons in the three exposure groups. Study results were used by EPA for a risk assessment of ingested arsenic (EPA 1988). The primary limitation of this study, beyond the problems common to ecological studies, is related to the lack of detail and specificity provided for exposure estimates. Those issues are discussed in Chapter 2 of this report. Arsenic-related risks of internal and skin cancers were studied by Chen et al. (1985). This study reported standardized mortality ratios (SMRs) in 84 villages in four townships in southwestern Taiwan where blackfoot disease was prevalent and where earlier studies had detected increased skin-cancer rates. Mortality over the period 1968-1986 was compared with expected mortality based on nationwide age- and sex-specific rates. Significantly increased mortality was observed among males and females for bladder, kidney, skin, lung, liver, and colon cancers as follows: bladder-cancer SMRs = 11.0 (95% confidence interval (CI) = 9.3-12.7) for males (M) and 20.1 (95% CI = 17.0-23.2) for females (F); kidney-cancer SMRs = 7.7 (95% CI = 5.4-10.1) (M) andll.2 (95% CI = 8.4-14) (F); skin-cancer SMRs = 5.3 (95% CI = 3.8-6.9) (M) and 6.5 (95% CI = 4.7-8.4) (F); lung-cancer SMRs = 3.2 (95% CI = 2.9-3.5) (M) and 4.1 (95% CI = 3.6-4.7) (F); liver-cancer SMRs = 1.7 (95% CI = 1.5-1.9) (M) and 2.3 (95% CI = 1.9-2.7) (F); colon-cancer SMRs = 1.6 (95% CI = 1.2-2.0) (M) and 1.7 (95% CI = 1.32.1) (F). Other cancer sites (small intestine, esophagus, nasopharynx, rectum, stomach, and thyroid) did not show statistically meaningful associations. The

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Page 93 SMR for leukemia was 1.4 (95% CI = 1.0-1.8) for men and 0.9 (95% CI = 0.5-1.3) for women. Concentrations of arsenic in the drinking water were not presented in the Chen et al. (1985) report. However, an exposure-response gradient for risk of bladder, kidney, skin, lung, and liver cancers was noted in evaluating the risk in areas with shallow wells (presumably low arsenic exposure), both shallow and artesian wells (intermediate exposure), and artesian wells only (highest exposure). In villages with artesian wells, SMRs were approximately 30.0, 9.0, 10.0, 5.0, and 2.0 (CIs not reported) for bladder, kidney, skin, lung, and liver cancers, respectively. Wu et al. (1989) provided quantitative information on arsenic concentrations in the drinking water of 42 villages in southwestern Taiwan and calculated age-adjusted cancer mortality during the period 1973-1986 within three groups of villages stratified by exposure concentration (less than 0.30 mg/L, 0.30-0.59 mg/L, and 0.60 mg/L or more). Among males, mortality increased with increasing arsenic concentrations in water for cancers of all sites combined, and cancers of the bladder, kidney, skin, lung, liver, prostate, and leukemia when considered separately. Among females, increases in mortality were observed for all sites combined and cancers of the bladder, kidney, skin, lung, and liver. Nationwide mortality rates for those cancers were not provided by Wu et al. (1989). However, age-adjusted mortality for Taiwan was noted by Chen et al. (1985) for the years 1968-1982. Among males, the ratio of mortality in high-arsenic-exposure villages compared with national mortality, varied with increases of about 3-fold for liver cancer and 30-fold and over for bladder cancer. Among females, analogous mortality ratios increased more than 80-fold for bladder cancer. Chen and Wang (1990) analyzed nationwide mortality data from Taiwan using water arsenic concentrations from 83,656 wells located in 314 precincts and townships from 1974 to 1976. Using a multiple regression approach, the authors compared age-adjusted mortality for 1972-1983 with the arsenic concentrations in those locations. A significant association with arsenic concentration was found for cancers of the liver, nasal cavity, lung, skin, bladder, and kidney in both sexes and for prostate cancer in males. Using multiple linear regression models, Chen and Wang calculated a regression coefficient indicating the change in age-adjusted mortality per 100,000 person-years for every 0.1-ppm increase in arsenic in well water, after adjusting for indices of industrialization and urbanization. The regression coefficients were 6.8, 0.7, 5.3, 0.9, 3.9, and 1.1 for men and 2.0, 0.4, 5.3, 1.0, 4.2, and 1.7 for women for cancers of the liver, nasal cavity, lung, skin, bladder, and kidney, respectively. The regression coefficient for prostate cancer was 0.5. Regression models included indices of urbanization and industrialization and were weighted by the square root of person-years at risk in each place. The

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Page 139 A. Albores, and M.E. Cebrian. 1994. Lymphocyte replicating ability in individuals exposed to arsenic via drinking water. Mutat. Res. 313:293299. Graham, J.H., and E.B. Helwig. 1959. Bowen's disease and its relationship to systemic cancer. Arch. Dermatol. 80:133-159. Greenberg, C., S. Davies, T. McGowan, A. Schorer, and C. Drage. 1979. Acute respiratory failure following severe arsenic poisoning. Chest 76:596-598. Grobe, J.V. 1976. Peripheral circulatory disorders and acrocyanosis in arsenic exposed Moselle wine-growers. [ in German]. Berufsdermatosen 24(3):78-84. Guha Mazumder, D.N., J. Das Gupta, A. Santra, A. Pal, A. Ghose, S. Sarkar, N. Chattopadhaya, and D. Chakraborti.  1997. Non-cancer effects of chronic arsenicosis with special reference to liver damage. Pp. 112-123 in Arsenic: Exposure and Health Effects, C.O. Abernathy, R.L. Calderon, and W.R. Chappell, eds. London: Chapman & Hall. Guha Mazumder, D.N., R. Haque, N. Ghosh, B.K. De, A. Santra, D. Chakraborty, and A.H. Smith. 1998. Arsenic levels in drinking water and the prevalence of skin lesions in West Bengal, India. Int. J. Epidemiol. 27:871-877. Guo, H.R., H.S. Chiang, H. Hu, S.R. Lipsitz, and R.R. Monson. 1997. Arsenic  in  drinking  water and  incidence of urinary  cancers. Epidemiology 8:545-550. Hamada T., and S. Horiguchi. 1976. Occupational chronic arsenical poisoning: On the cutaneous manifestations. Jpn. J. Ind. Health 18(2): 103115. Harrington, J.M., J.P. Middaugh, D.L. Morse, and J. Housworth. 1978. A survey of a population exposed to high concentrations of arsenic in well water in Fairbanks, Alaska. Am. J. Epidemiol. 108:377-385. Hazelton Laboratories. 1990. Two-generation dietary reproductive study with arsenic acid in mice. Study No. HLA 6120-138. Hazleton Laboratories America, Vienna, Va. Hertz-Picciotto, I., and A.H. Smith. 1993. Observations on the doseresponse curve for arsenic exposure and lung cancer. Scan. J. Work Environ. Health 19:217-226. Heyman, A. J.B. Pfeiffer, R.W. Willett, and H.M. Taylor. 1956. Peripheral neuropathy caused by arsenical intoxication: A study of 41 cases with observations on the effects of BAL (2,3 dimercapto-propanol). N. Engl. J. Med. 254:401-409. Heywood, R., and R.J.Sortwell. 1979. Arsenic intoxication in the rhesus monkey. Toxicol. Lett. 3:137-144.

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Page 140 Hill, A.B. 1965. The environment and disease: Association or causation? Proc. R. Soc. Med. 58:295-300. Hindmarsh, J.T., O.R. McLetchie, L.P. Heffernan, O.A. Hayne, H.A. Ellenberger, R.F. McCurdy, and H.J. Thiebaux. 1977. Electromyographic abnormalities in chronic environmental arsenicalism. J. Anal. Toxicol. 1:270-276. Holmberg, R.E., and V.H. Ferm. 1969. Interrelationships of selenium, cadmium, and arsenic in mammalian teratogenesis. Arch. Environ. Health 18:873-877. Hood, R.D. 1972. Effects of sodium arsenite on fetal development. Bull. Environ. Contam. Toxicol. 7:216-222. Hood, R.D., and S.L. Bishop. 1972. Teratogenic effects of sodium arsenate in mice. Arch. Environ. Health 24:62-65. Hood, R.D., and W.P. Harrison. 1982. Effects of prenatal arsenite exposure in the hamster. Bull. Environ. Contarn. Toxicol. 29:679-687. Hood, R.D., G.T. Thacker, B.L. Patterson, and G.M. Szczech. 1978. Prenatal effects of oral versus intraperitoneal sodium arsenate in mice. J. Environ. Pathol. Toxicol. 1:671-678. Hood, R.D., G.C. Vedel-Macrander, M.J. Zaworotko, F.M. Tatum, and R.G. Meeks.  1987. Distribution, metabolism and fetal uptake of pentavalent arsenic in pregnant mice following oral or intraperitoneal administration. Teratology 35:19-25. Hood, R.D., G.C. Vedel, M.J. Zaworotko, and R.G. Meeks, 1988. Uptake, distribution, and metabolism of trivalent arsenic in the pregnant mouse. J. Toxicol. Environ. Health 25:423-434. Hopenhayn-Rich, C., M.L. Biggs, A. Fuchs, R. Bergoglio, E.E. Tello, H. Nicolli, and A.H. Smith. 1996. Bladder cancer mortality associated with arsenic in drinking water in Argentina. Epidemiology 7:117-124. Hopenhayn-Rich C., M.L. Biggs, and A.H. Smith. 1998. Lung and kidney cancer mortality associated with arsenic in drinking water in Córdoba, Argentina. Int. J. Epidemiol. 27:561-569. Hotta, N.  1989. Clinical aspects of chronic arsenic poisoning due to environmental and occupational pollution in and around a small refining spot [in Japanese]. Nippon Taishitsugaku Zasshi [Jpn. J. Const. Med.] 53(1/2):49-70. Hugo, N.E., and H. Conway.  1967. Bowen's disease: Its malignant potential and relationship to systemic cancer. Plast. Reconstr. Surg. 39:190-194. Hutchinson, J. 1887. Arsenic cancer. Br. Med. J. 2:1280-1281. IARC (International Agency for Research on Cancer). 1980. Some Metals and Metallic Compounds. IARC Monographs on the Evaluation of

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