Abstract
A comprehensive analysis of published data indicates that arsenic exposure induces cardiovascular diseases, developmental abnormalities, neurologic and neurobehavioral disorders, diabetes, hearing loss, hematologic disorders, and various types of cancer. Although exposure may occur via the dermal, and parenteral routes, the main pathways of exposure include ingestion, and inhalation. The severity of adverse health effects is related to the chemical form of arsenic, and is also time- and dose-dependent. Recent reports have pointed out that arsenic poisoning appears to be one of the major public health problems of pandemic nature. Acute and chronic exposure to arsenic has been reported in several countries of the world where a large proportion of drinking water (groundwater) is contaminated with high concentrations of arsenic. Research has also pointed significantly higher standardized mortality rates for cancers of the bladder, kidney, skin, liver, and colon in many areas of arsenic pollution. There is therefore a great need for developing a comprehensive health risk assessment (RA) concept that should be used by public health officials and environmental managers for an effective management of the health effects associated with arsenic exposure. With a special emphasis on arsenic toxicity, mutagenesis, and carcinogenesis, this paper is aimed at using the National Academy of Science's RA framework as a guide, for developing a RA paradigm for arsenic based on a comprehensive analysis of the currently available scientific information on its physical and chemical properties, production and use, fate and transport, toxicokinetics, systemic and carcinogenic health effects, regulatory and health guidelines, analytical guidelines and treatment technologies.
Similar content being viewed by others
References
Tchounwou PB, Wilson BA, Ishaque A: Important considerations in the development of public health advisories for arsenic and arsenic-containing compounds in drinking water. Rev Environ Health 14: 1–19, 1999
Goering PL, Aposhian HV, Mass MJ, Cebrian M, Beck BD, Waalkes MP: The enigma of arsenic carcinogenesis: Role of metabolism. Toxicol Sci 49: 5–14, 1999
NAS: Arsenic. National Academy of Science, Washington DC, 1977
Rousselot P, Laboume S, Marolleau JP, Larghero T, Noguera ML, Brouet JC, Fermand JP: Arsenic trioxide and melarsoprol induce apoptosis in plasma cell lines and in plasma cells from myeloma patients. Cancer Res 59: 1041–1048, 1999
Klaue B, Blum JD: Trace analyses of arsenic in drinking water by inductively coupled plasma mass spectrometry: High resolution vs. hybride generation. Anal Chem 71: 1408–1414, 1999
ATSDR: Toxicological Profile for Arsenic (Update). Agency for Toxic Substances and Disease Registry, USDHHS, PHS, Washington DC, 1999
NRC: Arsenic in Drinking Water. Washington DC, National Research Council, 1999
Abernathy CO, Liu YP, Longfellow D, Aposhian HV, Beck B, Fowler B, Goyer R, Menzer R, Rossman T, Thompson C et al.: Arsenic: Health effects, mechanisms of actions, and research issues. Environ Health Perspect 107: 593–597, 1999
ASTDR: Toxicological Profile for Arsenic TP-92/09. Agency for Toxic Substances and Disease Registry. Center for Disease Control, Atlanta, GA, 1993
Li JH, Rossman TC: Inhibition of DNA ligase activity by arsenite: A possible mechanism of its comutagenesis. Mol Toxicol 2: 1–9, 1989
Belton JC, Benson NC, Hanna ML, Taylor RT: Growth inhibition and cytotoxic effects of three arsenic compounds on cultured Chinese hamster ovary cells. J Environ Sci Health 20A: 37–72, 1985
Goyer RA: Toxic effects of metals. In: C.D. Klaassen (ed). Cassarett and Doull's Toxicology — The Basic Science of Poisons. McGraw Hill, New York, 1996, pp 691–736
Lee TC, Oshimura M, Barrett JC: Comparison of arsenic-induced cell transformation, cytotoxicity, mutation and cytogenetic effects in Syrian hamster embryo cells in culture. Carcinogenesis 6: 1421–1426, 1985
Landolph JR: Molecular and cellular mechanisms of transformation of C3H/10T1/2C18 and diploid human fibroblasts by unique carcinogenic, nonmutagenic metal compounds. A review. Biol Trace Elem Res 21: 459–467, 1989
Tchounwou PB, Wilson BA, Schneider J, Ishaque A: Cytogenetic assessment of arsenic trioxide toxicity in the Mutatox, Ames II, and CAT-Tox assays. Metal Ions Biol Med 6: 89–91, 2000
Tchounwou PB, Wilson BA, Ishaque A, Schneider J: Atrazine potentiation of arsenic trioxide-induced cytotoxicity and gene expression in human liver carcinoma cells (HepG2). Mol Cell Biochem 222: 49–59, 2001
Tchounwou PB, Wilson BA, Abdelgnani AA, Ishaque AB, Patlolla AK: Differential cytotoxicity and gene expression in human liver carcinoma (HepG2) cells exposed to arsenic trioxide and monosodium acid methanearsonate (MSMA). Int J Mol Sci 3: 1117–1132, 2002
Jacobson Kram D, Montalbano D: The reproductive effects assessment group's report on the mutagenicity of inorganic arsenic. Environ Mutagen 7: 789–804, 1985
Jha AN, Noditi M, Nilsson R, Natarajan AT: Genotoxic effects of sodium arsenite on human cells Mutat Res 284: 215–221, 1992
Hartmann A, Speit G: Comparative investigations of the genotoxic effects of metals in the single cell gel assay and the sister-chromatid test. Environ Mol Mutagen 23: 299–305, 1994
Wang Z, Rossman TG: In: L.W. Cheng (ed). The Toxicology of Metals, Vol. 1. CRC Press, Boca Raton, Fl, 1996, pp 221–243
Barrett JC, Lamb PW, Wang TC, Lee TC: Mechanisms of arsenic-induced cell transformation. Biol Trace Elem Res 21: 421–429, 1989
Vega L, Gonsebatt ME, Ostrosky-Wegman P: Aneugenic effect of sodium arsenite on human lymphocytes in vitro: An individual susceptibility effect detected. Mutat Res 334: 365–373, 1995
Nakamuro K, Sayato Y: Comparative studies of chromosomal aberration induced by trivalent and pentavalent arsenic. Mutat Res 88: 73–80, 1981
Natarajan AT, Boei JJ, Darroudi F, Van Diemen PC, Doulout F, Hande MP, Ramalho AT: Current cytogenetic methods for detecting exposure and effects of mutagens and carcinogens. Environ Health Perspect 104(suppl 3): 445–458, 1996
Gonsebatt ME, Vega L, Salazar AM, Monteror, Guzman P, Blas J, Del Razo LM, Garcai-Vargas G, Albores A, Cebrian ME, Kelsh M, Ostrosky-Wegman P: Cytogenetic effects in human exposure to arsenic. Mutat Res 386: 219–228, 1997
Ramirez P, Eastmond DA, Laclette JP, Ostrosky-Wegman P: Disruption of microtubule assembly and spindle formation for the induction of aneuploid cells by sodium arsenite and vanadium pentoxide. Mutat Res 386: 291–298, 1997
Huang SC, Lee TC: Arsenite inhibits mitotic division and perturbs spindle dynamics in HeLa S3 cells. Carcinogenesis 19: 889–896, 1998
Huang SC, Huang C-YF, Lee TC: Induction of mitosis-mediated apoptosis by sodium arsenite in HeLa S3 cells. Biochem Pharmacol 60: 771–780, 2000
Jingbo Pi, Hiroshi Y, Yoshito K, Guifan S, Takahiko Y, Hiroyuki A, Claudia HR, Nobuhiro S: Evidence for induction of oxidative stree caused by chronic exposure of Chinese residents to arsenic contained in drinking water. Environ Health Perspect 110: 331–336, 2002
Cavigelli M, Li WW, Lin A, Su B, Yushioka K, Karin M: The tumor promoter arsenite stimulates AP-1 activity by inhibiting a JNK phosphatase. EMBO J 15: 6269–6279, 1996
Kitchin K: Recent advances in arsenic carcinogenesis: Modes of action, animal model systems, and methylated arsenic metabolites. Toxicol Appl Pharmacol 172: 249–261, 2001
Simeonova PP, Luster MI: Mechanisms of arsenic carcinogenicity: Genetic or epigenetic mechanisms? J Environ Pathol Toxicol Oncol 19: 281–286, 2000
Barchowsky A, Dudek EJ, Treadwell MD, Wetterhahn KE: Arsenic induces oxidant stress and NFxB activation in cultured aortic endothelial cells. Free Radic Biol Med 21: 783–790, 1996
Salazar AM, Ostrowsky-Wegman P, Menedez D, Miranda E, Garcia-Carranca A, Rojas E: Induction of p53 protein expression by sodium arsenate. Mutat Res 381: 259–265, 1997
Burleson FG, Simeonova PP, Germolec DR, Luster MI: Dermatotoxic chemical stimulate of c-jun and c-fos transcription and AP-1 DNA binding in human keratinocytes. Res Commun Mol Pathol Pharmacol 93: 131–148, 1996
Simeonova PP, Wang S, Toriumi W, Kommineni C, Matheson J, Unimye N, Kayama F, Harki D, Ding M, Vallyathan V et al.: Arsenic mediates cell proliferation and gene expression in the bladder epithelium: Association with AP-1 transactivation. Cancer Res 60: 3445–3453, 2000
Styblo M, Drobna Z, Jaspers I, Lin S and Thomas DJ: The role of biomethylation in toxicity and carcinogenicity of arsenic: A research Update. Environ Health Perspect 110: 767–771, 2002
Mahata J, Basu A, Ghoshal S, Sarkar JN, Roy AK, Poddar G, Nandy AK, Banerjee A, Ray K, Natarajan AT, Nilsson R, Giri AK: Chromosomal aberrations and sister chromatid exchanges in individuals exposed to arsenic through drinking water in West Bengal, India. Mutat Res 534: 133–143, 2003
Ahmad S, Kitchin KT, Cullen WR: Arsenic species that cause release of iron from ferritin and generation of activated oxygen. Arch Biochem Biophys 382: 195–202, 2000
Zhong CX, Wang L, and Mass MJ: Differentially methylated DNA sequences associated with exposure to arsenate in cultures of human cells identified by methylation-sensitive arbitrarily-primed PCR. Toxicol Lett 122: 223–234, 2001
Vega L, Styblo M, Patterson R, Cullen W, Wang C, Germolec D: Differential effects of trivalent and pentavalent arsenicals on cell proliferation and cytokine secretion in normal human epidermal keratinocytes. Toxicol Appl Pharmacol 172: 225–232, 2001
Popovicova J, Moser GJ, Goldsworthy TL, Tice RR: Carcinogenicity and co-carcinogenicity of sodium arsenite in p53+/− male mice. Toxicologist 54: 134, 2000
Hanahan D, Weinberg RA: The hallmarks of cancer. Cell 100: 57–70, 2000
Hamadeh HK, Vargas M, Lee E, Menzel DB: Arsenic disrupts cellular levels of p53 and mdm2: A potential mechanism of carcinogenesis. Biochem Biophys Res Commun 263: 446–449, 1999
Boonchai W, Walsh M, Cummings M, Chenevix-Trench G: Expression of p53 in arsenic-related and sporadic basal cell carcinoma. Arch Dermatol 136: 195–198, 2000
Lee TC, Tanaka N, Lamb PW, Gilmer TM, Barrett JC: Induction of gene amplification by arsenic. Science 241: 79–81, 1988
National Research Council. Science and Judgement in Risk Assessment. Assessment of Toxicology (National Academy of Sciences, eds). Washington DC, National Academy Press, 1994, pp 56–67
Goulding R: Arsenic, poisoning from chemicals. In: Oxford Textbook of Medicine, Vol. 1. 2nd edn. Oxford University Press, Oxford, 1988, 6, pp 13–16
Gorby MS: Arsenic in human medicine. In: J.O. Nriagu (ed). Arsenic in the Environment; Part II: Human Health and Ecosystem Effects. John Wiley & Sons, Inc., New York, 1994, pp 1–16
Wu MM, Kuo TL, Hwang YH: Dose-response relation between arsenic concentration in well water and mortality from cancers and vascular diseases. Am J Epidemiol 130: 1123–1132, 1989
Tseng WP, Chu HM, How SW, Fong JM, Lin CS, Yeh S: Prevalence of skin cancer in an endemic area of chronic arsenicism in Taiwan. J Natl Cancer Inst 40: 453–463, 1968
Chen CJ, Chen CW, Wu MM, Kuo TL: Cancer potential in liver lung, bladder and kidney due to ingested inorganic arsenic in drinking water. Br J Cancer 66: 888–892, 1992
Chappell W, Beck B, Brown K, North D, Thornton I, Chaney R, Cothern R, Cothern CR, North DW, Irgolic K, Thornton I, Tsongas T: Inorganic arsenic: A need and an opportunity to improve risk assessment. Environ Health Perspect 105: 1060–1067, 1997
Aschengran A, Zierler S, Cohen A: Quality of community drinking water and the occurrence of spontaneous abortion. Arch Environ Health 44: 283–290, 1989
NRCC: Effects of arsenic in the environment. National Research Council of Canada. Natl Res Counc Can Publ, 1978, pp 1–349
U.S. EPA. Ambient Water Quality Criteria for Arsenic. EPA 400/5-80-021. Environmental Protection Agency. Washington DC, 1980
Fierz U: Catamnestic investigations of the side effects of therapy of skin diseases with inorganic arsenic. Dermatologia 131: 41–58, 1965
Chiou HY, Chiou ST, Hsu YH, Chou YL, Tseng CH, Wei ML, Chen CJ: Incidence of transitional cell carcinoma and arsenic in drinking water: A follow-up study of 8,102 residents in an arseniasis-endemic area in northeastern Taiwan. Am J Epidemiol 153: 411–418, 2001
Chen CJ, Lin LJ: Human carcinogenicity and atherogenicity induced by chronic exposure to inorganic arsenic. In: J.O. Nriagu (ed). Arsenic in the Environment; Part II: Human Health and Ecosystem Effects. John Wiley & Sons, Inc., New York, 1994, pp 109–131
Risk Assessment forum. Special Report on Ingested Arsenic: Skin Cancer; Nutritional Essentiality. EPA/625/3-87/013, U.S. Environmental Protection Agency, Washington, DC, 1988
Marcus WL, Rispin AS: Threshold carcinogenicity using arsenic as an example. In: C.R. Cothern, M.A. Mehlman (eds). Advances in Modern Environmental Toxicology: Risk Assessment and Risk Management of Industrial and Environmental Chemicals. Princeton Publishing Company, Princeton, NJ, 1988, pp 133–158
Smith AH, Hopenhayn-Rich C, Bates MN, Goeden HM, Hertz-Picciotto I, Duggan HM, Wood R, Kosnett MJ, Smith MT: Cancer risks from arsenic in drinking water. Environ Health Perspect 97: 259–267, 1992
Warner ML, Moore LE, Smith MT: Increased micronuclei in exfoliated bladder cells of persons who chronically ingest arsenic-contaminated water in Nevada. Cancer Epidemiol Biomarkers Prev 3: 583–590, 1994
Rudel R, Slayton TM, Beck BD: Implications of arsenic genotoxicity for dose-response of carcinogenic effects. Regul Toxicol Pharmacol 23: 87–105, 1996
Mass MJ, Wang L: Alterations of methylation of the tumor suppressor gene p53: Insights into potential mechanisms of arsenic carcinogenesis. In: C.O. Abernathy, R.L. Calderon, W.R. Chappell (eds). Arsenic Exposure and Health Effects. Chapman & Hall, New York, 1997, pp 338–348
IARC: Monographs on the Evaluation of Carcinogenic Risks of Chemicals to Humans. Supplement F. Overall Evaluation of Carcinogenicity. International Agency for Research on Cancer. World Health Organization. Lyon, France, 1987, pp 29–57
IRIS: Integrated Risk Information System. U.S. EPA. Washington, DC, 1992
National Academy of Science: Arsenic in Drinking Water. The National Academies Press, Washington DC, 1999, pp 299–301
U.S. EPA: National primary drinking water regulations. Fed Regist 50: 46931–47022, 1985
National Research Council: Arsenic in Drinking Water. 2001 Update. On line at: http://www.nap.edu/books/0309076293/html/
WHO: Guidelines for Drinking Water Quality. World Health Organization, Geneva, Switzerland, 1984
OSHA: Occupational Safety and Health Administration. Fed Reg 54: 2332–2335, 1989
Jekel MR: Removal of arsenic in drinking water treatment. In: J.O. Nriagu (ed). Arsenic in the Environment, Part I: Cycling and Characterization. John Wiley & Sons, Inc., New York, 1994, pp 119–132
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Tchounwou, P.B., Centeno, J.A. & Patlolla, A.K. Arsenic toxicity, mutagenesis, and carcinogenesis – a health risk assessment and management approach. Mol Cell Biochem 255, 47–55 (2004). https://doi.org/10.1023/B:MCBI.0000007260.32981.b9
Issue Date:
DOI: https://doi.org/10.1023/B:MCBI.0000007260.32981.b9