Cancer Causes & Control

, Volume 19, Issue 8, pp 829–839 | Cite as

Arsenic exposure, urinary arsenic speciation, and the incidence of urothelial carcinoma: a twelve-year follow-up study

  • Yung-Kai Huang
  • Ya-Li Huang
  • Yu-Mei HsuehEmail author
  • Mo-Hsiung Yang
  • Meei-Maan Wu
  • Shu-Yuan Chen
  • Ling-I Hsu
  • Chien-Jen Chen
Original Paper


The risk of urothelial carcinoma (UC) and urinary arsenic speciation have been evaluated in a few case–control studies; however, the association has not been verified in a prospective cohort study. The aim of this study was to examine the association between urinary arsenic speciation and the incidence of UC in a cohort study. A total of 1,078 residents of southwestern Taiwan were followed for an average of 12 years. A high-performance liquid chromatography/hydride generator and an atomic absorption spectrometry were used to measure urinary arsenite, arsenate, monomethylarsonic acid (MMAV), and dimethylarsinic acid (DMAV). The incidence of UC was estimated by examining the National Cancer Registry of Taiwan between January 1985 and December 2001. There were 37 newly diagnosed cases of UC during a follow-up period of 11,655 person-years. Significantly higher percentages of MMAV and lower percentages of DMAV existed among the patients with UC than among the healthy residents. After adjustment for age, gender, educational level, and smoking status, the percentage of urinary DMAV was shown to have an inverse association with the risk of UC, having a relative risk (RR) of the tertile strata of 1.0, 0.3, and 0.3, respectively (p < 0.05 for the trend test). The RR (95% confidence interval) of residents with a cumulative arsenic exposure (CAE) of ≥20 mg/l-year and a higher percentage of MMAV or a CAE of ≥20 mg/l-year and a lower percentage of DMAV was 3.7 (1.2–11.6) or 4.2 (1.3–13.4) compared to residents with a CAE of <20 mg/l-year and a lower percentage of MMAV or a CAE of <20 mg/l-year and a higher percentage of DMAV respectively. There was a significant association between inefficient arsenic methylation and the development of UC in the residents in the high CAE exposure strata in an area of southwestern Taiwan endemic for arseniasis.


Urinary arsenic species Long-term arsenic exposure Urothelial carcinoma risk 



Urothelial carcinoma


Percentage of DMAV


Percentage of InAs


Percentage of MMAV






Inorganic arsenic


Blackfoot disease


Cumulative arsenic exposure


Dimethylarsinic acid


Inorganic arsenic


Monomethylarsonic acid


Primary methylation indices


Standardized incidence ratios


Secondary methylation index



The study was supported by grants (NSC-89-2320-B038-013, NSC-89-2314-B038-049, NSC-90-2320-B-038-021, NSC91-3112-B-038-0019, NSC92-2321-B-038-004, NSC92-3112-B-038-001, NSC93-2321-B-038-012, NSC93-3112-B-038-001, NSC94-2314-B-038-023, and NSC95-2314-B-038-007) from the National Science Council, Executive Yuan, ROC.


  1. 1.
    IARC (1980) Some metals and metallic compounds. International Agency for Research on Cancer, Lyon, Franch, p 325Google Scholar
  2. 2.
    Chen CJ, Chuang YC, Lin TM, Wu HY (1985) Malignant neoplasms among residents of a blackfoot disease-endemic area in Taiwan: high-arsenic artesian well water and cancers. Cancer Res 45:5895–5899PubMedGoogle Scholar
  3. 3.
    Chen CJ, Chen CW, Wu MM, Kuo TL (1992) Cancer potential in liver, lung, bladder and kidney due to ingested inorganic arsenic in drinking water. Br J Cancer 66:888–892PubMedGoogle Scholar
  4. 4.
    Chiou HY, Hsueh YM, Liaw KF et al (1995) Incidence of internal cancers and ingested inorganic arsenic: a seven-year follow-up study in Taiwan. Cancer Res 55:1296–1300PubMedGoogle Scholar
  5. 5.
    National Research Council (2001) Arsenic in drinking water: 2001 update. National Academy Press, Washington, DCGoogle Scholar
  6. 6.
    Tapio S, Grosche B (2006) Arsenic in the aetiology of cancer. Mutat Res -Rev Mutat Res 612:215–246Google Scholar
  7. 7.
    Smith AH, Goycolea M, Haque R, Biggs ML (1998) Marked increase in bladder and lung cancer mortality in a region of Northern Chile due to arsenic in drinking water. Am J Epidemiol 147:660–669PubMedGoogle Scholar
  8. 8.
    Marshall G, Ferreccio C, Yuan Y et al (2007) Fifty-year study of lung and bladder cancer mortality in Chile related to arsenic in drinking water. J Natl Cancer Inst 99:920–928PubMedCrossRefGoogle Scholar
  9. 9.
    HopenhaynRich C, Biggs ML, Fuchs A et al (1996) Bladder cancer mortality associated with arsenic in drinking water in Argentina. Epidemiology 7:117–124CrossRefGoogle Scholar
  10. 10.
    Vahter M (1981) Biotransformation of trivalent and pentavalent inorganic arsenic in mice and rats. Environ Res 25:286–293PubMedCrossRefGoogle Scholar
  11. 11.
    Vahter M (2002) Mechanisms of arsenic biotransformation. Toxicology 181–182:211–217PubMedCrossRefGoogle Scholar
  12. 12.
    Buchet JP, Lauwerys R, Roels H (1981) Comparison of the urinary excretion of arsenic metabolites after a single oral dose of sodium arsenite, monomethylarsonate, or dimethylarsinate in man. Int Arch Occup Environ Health 48:71–79PubMedCrossRefGoogle Scholar
  13. 13.
    Buchet JP, Lauwerys R, Roels H (1981) Urinary excretion of inorganic arsenic and its metabolites after repeated ingestion of sodium metaarsenite by volunteers. Int Arch Occup Environ Health 48:111–118PubMedCrossRefGoogle Scholar
  14. 14.
    Vahter M (1999) Methylation of inorganic arsenic in different mammalian species and population groups. Sci Progr 82:69–88Google Scholar
  15. 15.
    Styblo M, Del Razo LM, Vega L et al (2000) Comparative toxicity of trivalent and pentavalent inorganic and methylated arsenicals in rat and human cells. Arch Toxicol 74:289–299PubMedCrossRefGoogle Scholar
  16. 16.
    Petrick JS, Jagadish B, Mash EA, Aposhian HV (2001) Monomethylarsonous acid (MMA(III)) and arsenite: LD(50) in hamsters and in vitro inhibition of pyruvate dehydrogenase. Chem Res Toxicol 14:651–656PubMedCrossRefGoogle Scholar
  17. 17.
    Nesnow S, Roop BC, Lambert G et al (2002) DNA damage induced by methylated trivalent arsenicals is mediated by reactive oxygen species. Chem Res Toxicol 15:1627–1634PubMedCrossRefGoogle Scholar
  18. 18.
    Chen YC, Su HJ, Guo YL et al (2003) Arsenic methylation and bladder cancer risk in Taiwan. Cancer Causes Control 14:303–310PubMedCrossRefGoogle Scholar
  19. 19.
    Chen YC, Guo YL, Su HJ et al (2003) Arsenic methylation and skin cancer risk in southwestern Taiwan. J Occup Environ Med 45:241–248PubMedCrossRefGoogle Scholar
  20. 20.
    Hsueh YM, Chiou HY, Huang YL et al (1997) Serum beta-carotene level, arsenic methylation capability, and incidence of skin cancer. Cancer Epidemiol Biomarkers Prev 6:589–596PubMedGoogle Scholar
  21. 21.
    Yu RC, Hsu KH, Chen CJ, Froines JR (2000) Arsenic methylation capacity and skin cancer. Cancer Epidemiol Biomarkers Prev 9:1259–1262PubMedGoogle Scholar
  22. 22.
    Pu YS, Yang SM, Huang YK et al (2007) Urinary arsenic profile affects the risk of urothelial carcinoma even at low arsenic exposure. Toxicol Appl Pharmacol 218:99–106PubMedCrossRefGoogle Scholar
  23. 23.
    Steinmaus C, Bates MN, Yuan Y et al (2006) Arsenic methylation and bladder cancer risk in case–control studies in Argentina and the United States. J Occup Environ Med 48:478–488PubMedCrossRefGoogle Scholar
  24. 24.
    Steinmaus C, Yuan Y, Kalman D, Atallah R, Smith AH (2005) Intra individual variability in Arsenic methylation in a U.S. population. Cancer Epidemiol Biomarkers Prev 14:919–924PubMedCrossRefGoogle Scholar
  25. 25.
    Hindmarsh JT (2002) Caveats in hair analysis in chronic arsenic poisoning. Clin Biochem 35:1–11PubMedCrossRefGoogle Scholar
  26. 26.
    Hughes MF (2006) Biomarkers of exposure: a case study with inorganic arsenic. Environ Health Perspect 114:1790–1796PubMedGoogle Scholar
  27. 27.
    Wu HY, Chen KP, Tseng WP, Hsu CL (1961) Epidemiologic studies on blackfoot disease: I. Prevalence and incidence of the disease by age, sex, occupation and geographical distribution. Mem College Med Natl Taiwan Univ 7:33–50Google Scholar
  28. 28.
    Chen CJ, Hsueh YM, Lai MS et al (1995) Increased prevalence of hypertension and long-term arsenic exposure. Hypertension 25:53–60PubMedGoogle Scholar
  29. 29.
    Chen CJ, You SL, Lin LH, Hsu WL, Yang YW (2002) Cancer epidemiology and control in Taiwan: a brief review. Jpn J Clin Oncol 32:S66–S81PubMedCrossRefGoogle Scholar
  30. 30.
    US Department of Health, Human Services (2001) International classification of diseases, ninth revision, clinical modification. US Public Health Service, Washington, DCGoogle Scholar
  31. 31.
    SEER Program NCI (2001) Conversion of morphology of ICD-O-2 to ICD-O-3. In: Percy C, Fritz A, Ries L (eds) National Cancer Institute, Bethedsa, pp 1–160Google Scholar
  32. 32.
    Hsueh YM, Huang YL, Huang CC et al (1998) Urinary levels of inorganic and organic arsenic metabolites among residents in an arseniasis-hyperendemic area in Taiwan. J Toxicol Environ Health A 54:431–444PubMedCrossRefGoogle Scholar
  33. 33.
    Kuo TL (1964) Arsenic content of artesian well water in endemic area of chronic arsenic poisoning. Rep Inst Pathol Natl Taiwan Univ 20:7–13Google Scholar
  34. 34.
    Lo MC, Hsen YC, Lin BK (1977) Arsenic content of underground water in Taiwan: second report. Taiwan Provincial Institute of Environmental Sanitation, TaichungGoogle Scholar
  35. 35.
    Breslow NE, Day NE (1987) Statistical methods in cancer research. vol 2. The analysis of cohort studies. International Agency for Research on Cancer, Lyon, p 120Google Scholar
  36. 36.
    Steinmaus C, Yuan Y, Kalman D, Atallah R, Smith AH (2005) Intraindividual variability in arsenic methylation in a U.S. population. Cancer Epidemiol Biomarkers Prev 14:919–924PubMedCrossRefGoogle Scholar
  37. 37.
    Hopenhayn-Rich C, Biggs ML, Smith AH, Kalman DA, Moore LE (1996) Methylation study of a population environmentally exposed to arsenic in drinking water. Environ Health Perspect 104:620–628PubMedCrossRefGoogle Scholar
  38. 38.
    Hsueh YM, Hsu MK, Chiou HY, Yang MH, Huang CC, Chen CJ (2002) Urinary arsenic speciation in subjects with or without restriction from seafood dietary intake. Toxicol Lett 133:83–91PubMedCrossRefGoogle Scholar
  39. 39.
    Concha G, Nermell B, Vahter MV (1998) Metabolism of inorganic arsenic in children with chronic high arsenic exposure in northern Argentina. Environ Health Perspect 106:355–359PubMedCrossRefGoogle Scholar
  40. 40.
    Vahter M, Concha G, Nermell B, Nilsson R, Dulout F, Natarajan AT (1995) A unique metabolism of inorganic arsenic in native Andean women. Eur J Pharmacol 293:455–462PubMedCrossRefGoogle Scholar
  41. 41.
    Chiou HY, Hsueh YM, Hsieh LL et al (1997) Arsenic methylation capacity, body retention, and null genotypes of glutathione S-transferase M1 and T1 among current arsenic-exposed residents in Taiwan. Mutat Res -Rev Mutat Res 386:197–207Google Scholar
  42. 42.
    Marnell LL, Garcia-Vargas GG, Chowdhury UK et al (2003) Polymorphisms in the human monomethylarsonic acid (MMA V) reductase/hGSTO1 gene and changes in urinary arsenic profiles. Chem Res Toxicol 16:1507–1513PubMedCrossRefGoogle Scholar
  43. 43.
    Schmuck EM, Board PG, Whitbread AK et al (2005) Characterization of the monomethylarsonate reductase and dehydroascorbate reductase activities of Omega class glutathione transferase variants: implications for arsenic metabolism and the age-at-onset of Alzheimer’s and Parkinson’s diseases. Pharmacogenet Genomics 15:493–501PubMedCrossRefGoogle Scholar
  44. 44.
    Wood TC, Salavaggione OE, Mukherjee B et al (2006) Human arsenic methyltransferase (AS3MT) pharmacogenetics: gene resequencing and functional genomics studies. J Biol Chem 281:7364–7373PubMedCrossRefGoogle Scholar
  45. 45.
    Francesconi KA, Kuehnelt D (2004) Determination of arsenic species: a critical review of methods and applications, 2000–2003. Analyst 129:373–395PubMedCrossRefGoogle Scholar
  46. 46.
    Thomas DJ, Styblo M, Lin S (2001) The cellular metabolism and systemic toxicity of arsenic. Toxicol Appl Pharmacol 176:127–144PubMedCrossRefGoogle Scholar
  47. 47.
    Vega L, Styblo M, Patterson R, Cullen W, Wang C, Germolec D (2001) Differential effects of trivalent and pentavalent arsenicals on cell proliferation and cytokine secretion in normal human epidermal keratinocytes. Toxicol Appl Pharmacol 172:225–232PubMedCrossRefGoogle Scholar
  48. 48.
    Drobna Z, Jaspers I, Thomas DJ, Styblo M (2003) Differential activation of AP-1 in human bladder epithelial cells by inorganic and methylated arsenicals. FASEB J 17:67–69PubMedGoogle Scholar
  49. 49.
    Gong ZL, Lu XF, Cullen WR, Le XC (2001) Unstable trivalent arsenic metabolites, monomethylarsonous acid and dimethylarsinous acid. J Anal At Spectrum 16:1409–1413CrossRefGoogle Scholar
  50. 50.
    Del Razo LM, Styblo M, Cullen WR, Thomas DJ (2001) Determination of trivalent methylated arsenicals in biological matrices. Toxicol Appl Pharmacol 174:282–293PubMedCrossRefGoogle Scholar
  51. 51.
    Valenzuela OL, Borja-Aburto VH, Garcia-Vargas GG et al (2005) Urinary trivalent methylated arsenic species in a population chronically exposed to inorganic arsenic. Environ Health Perspect 113:250–254PubMedCrossRefGoogle Scholar
  52. 52.
    Le XC, Cullen WR, Reimer KJ (1994) Human urinary arsenic excretion after one-time ingestion of seaweed, crab, and shrimp. Clin Chem 40:617–624PubMedGoogle Scholar
  53. 53.
    Ma M, Le XC (1998) Effect of arsenosugar ingestion on urinary arsenic speciation. Clin Chem 44:539–550PubMedGoogle Scholar
  54. 54.
    Steinmaus C, Yuan Y, Kalman D, Atallah R, Smith AH (2005) Intraindividual variability in arsenic methylation in a U.S. population. Cancer Epidemiol Biomarkers Prev 14:919–924PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2008

Authors and Affiliations

  • Yung-Kai Huang
    • 1
  • Ya-Li Huang
    • 2
  • Yu-Mei Hsueh
    • 2
    Email author
  • Mo-Hsiung Yang
    • 3
  • Meei-Maan Wu
    • 2
  • Shu-Yuan Chen
    • 4
  • Ling-I Hsu
    • 5
  • Chien-Jen Chen
    • 5
    • 6
  1. 1.Graduate Institute of Medical Sciences, College of MedicineTaipei Medical UniversityTaipeiTaiwan
  2. 2.Department of Public Health, School of MedicineTaipei Medical UniversityTaipeiTaiwan
  3. 3.Department of Nuclear ScienceNational Tsing-Hua UniversityHsinchuTaiwan
  4. 4.Department of Public HealthTzu Chi UniversityHualienTaiwan
  5. 5.Graduate Institute of Epidemiology, College of Public HealthNational Taiwan University TaipeiTaipeiTaiwan
  6. 6.Genomics Research CenterAcademia SinicaTaipeiTaiwan

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