Evaluation of the carcinogenicity of inorganic arsenic

Samuel Monroe Cohen, Lora L Arnold, Barbara D. Beck, Ari S. Lewis, Michal Eldan

Research output: Contribution to journalReview article

83 Citations (Scopus)

Abstract

Inorganic arsenic (iAs) at high exposures is a human carcinogen, affecting mainly the urinary bladder, lung and skin. We present an assessment of the mode of action (MOA) of iAs's carcinogenicity based on the United States Environmental Protection Agency/International Programme on Chemical Safety (USEPA/IPCS) framework, focusing primarily on bladder cancer. Evidence is presented for a MOA involving formation of reactive trivalent metabolites interacting with critical cellular sulfhydryl groups, leading to cytotoxicity and regenerative cell proliferation. Metabolism, kinetics, cell transport, and reaction with specific proteins play a critical role in producing the effects at the cellular level, regardless of cell type, whether urothelium, lung epithelium or epidermis. The cytotoxicity induced by iAs results in non-cancer toxicities, and the regenerative cell proliferation enhances development of epithelial cancers. In other tissues, such as vascular endothelium, different toxicities develop, not cancer. Evidence supporting this MOA comes from in vitro investigations on animal and human cells, from animal models, and from epidemiological studies. This MOA implies a non-linear, threshold dose-response relationship for both non-cancer and cancer end points. The no effect levels in animal models (approximately 1ppm of water or diet) and in vitro (>0.1M trivalent arsenicals) are strikingly consistent. Cancer effects of iAs in humans generally are not observed below exposures of 100-150ppb in drinking water: below these exposures, human urine concentrations of trivalent metabolites are generally below 0.1M, a concentration not associated with bladder cell cytotoxicity in in vitro or animal models. Environmental exposures to iAs in most of the United States do not approach this threshold.

Original languageEnglish (US)
Pages (from-to)711-752
Number of pages42
JournalCritical Reviews in Toxicology
Volume43
Issue number9
DOIs
StatePublished - Oct 1 2013

Fingerprint

Arsenic
Animals
Cytotoxicity
Animal Models
Cell proliferation
Metabolites
Toxicity
Neoplasms
Urinary Bladder
Chemical Safety
Cell Proliferation
Arsenicals
Urothelium
United States Environmental Protection Agency
Enzyme kinetics
Lung
Environmental Exposure
Vascular Endothelium
Environmental Protection Agency
Nutrition

Keywords

  • Arsenic
  • Bladder
  • Cell proliferation
  • Cytotoxicity
  • Epidemiology
  • Lung
  • Skin

ASJC Scopus subject areas

  • Toxicology

Cite this

Evaluation of the carcinogenicity of inorganic arsenic. / Cohen, Samuel Monroe; Arnold, Lora L; Beck, Barbara D.; Lewis, Ari S.; Eldan, Michal.

In: Critical Reviews in Toxicology, Vol. 43, No. 9, 01.10.2013, p. 711-752.

Research output: Contribution to journalReview article

Cohen, Samuel Monroe ; Arnold, Lora L ; Beck, Barbara D. ; Lewis, Ari S. ; Eldan, Michal. / Evaluation of the carcinogenicity of inorganic arsenic. In: Critical Reviews in Toxicology. 2013 ; Vol. 43, No. 9. pp. 711-752.
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